Affiliations of authors: M. Hejna, M. Raderer, Department of Medicine I, Division of Oncology, University Hospital, Vienna, Austria; C. C. Zielinski, Department of Medicine I, Division of Oncology, University Hospital, Vienna, Chair of Medical-Experimental Oncology, Department of Medicine I, University Hospital, and Ludwig Boltzmann Institute for Clinical Experimental Oncology, Vienna.
Correspondence to: Christoph C. Zielinski, M.D., Department of Medicine I, Division of Oncology, University Hospital, Waehringer Guertel 18-20, A-1090 Vienna, Austria (e-mail: christoph.zielinski{at}akh-wien.ac.at).
![]() |
ABSTRACT |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
![]() |
INTRODUCTION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
The metastatic process involves a series of distinct steps that are required before a metastatic tumor is firmly established in a new environment. After intravasation, a metastatic cell must survive its passage through the bloodstream, come to rest in a blood vessel in the potential target organ, and finally pass through the epithelium of that vessel into the new organ where it will form a tumor. The metastatic tumor must then form a blood supply that branches from the host's circulatory system and is sufficient for continued growth. Although it seems logical that the bloodstream carries tumor cells to sites in distant organs, the mechanisms that the malignant cells use to adhere to and finally migrate into these organs involve cellular and molecular interactions that are not completely elucidated. Apart from the intrinsic properties of the tumor cell, it has been hypothesized (4-7) that vascular factors and components of the clotting pathways play crucial roles throughout the natural history of metastatic tumors. On the basis of recent experimental and clinical data, including therapeutic interventions with anticoagulant drugs, some investigators have argued that components of the clotting pathway(s) might contribute to the progression of malignancy (4-11).
In this review, we critically evaluate the current knowledge of the role played by the components of the clotting pathways in the formation of metastatic tumors and the therapeutic potential of inhibiting metastases with anticoagulants. To this end, we reviewed the English-language literature on this subject that was published between 1952 and 1998 through the use of computerized (MEDLINE®) and manual searches.
![]() |
IN VITRO EXPERIMENTS AND ANIMAL STUDIES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Large numbers of tumor cells are released into the blood during the metastatic process. Liotta et al. (12) found that the number of cells released from an implanted MTW9 mammary carcinoma increased as the vascularized tumor grew, with 1.4 x 103 cells released or shed from the tumor per 24 hours on day 5, 3.0 x 104 cells shed on day 10, and 1.5 x 105 cells shed on day 15. Butler and Gullino (13) quantitated cell shedding into the efferent blood of a rat mammary adenocarcinoma and found that 3-4 x 106 cells were shed in 24 hours per gram of tumor or 1.6-2.0 x 104 cells were shed per milliliter of blood. Glaves (14) showed that Lewis lung carcinoma cells and B16 melanoma cells were detectable in the systemic circulation 1-3 days after initiation of primary tumor growth. The median number of cells shed throughout the whole tumor development was 1 x 108 cells for Lewis lung carcinoma cells and 2.4 x 106 cells for B16 melanoma cells. In human patients with cancer, circulating tumor cells have been identified in the venous blood (15-19). Although transport of tumor cells in the bloodstream is an essential component of the metastatic process, it is important to note that the mere presence of tumor cells in the circulation does not inevitably lead to the formation of metastases.
The physiologic conditions of the blood provide a hostile environment for tumor cells. Fidler (20) intravenously injected radiolabeled murine B16 melanoma cells into mice and found that most cells were destroyed within 24 hours and that less than 0.1% of the cells injected were viable after 3 days. Similar observations have been reported with various experimental models (21-25). The rapid destruction of tumor cells has been attributed to a variety of mechanisms, including natural killer cells (26-29), macrophages (30-32), polymorphonuclear leukocytes (33), antibodies (34-36), and mechanical trauma (37). These mechanisms could operate while tumor cells were in circulation in larger blood vessels or after they had lodged in capillaries. In the peripheral blood, tumor cells may interact with each other and with other blood components. Homotypic aggregation of tumor cells can influence their implantation in capillaries and has a permissive effect on the frequency of metastases (38-41). Heterotypic interactions of tumor cells with platelets (42-45), lymphocytes (46,47), or polymorphonuclear leukocytes (48) have been observed that may facilitate the formation of metastases. In addition, the release of platelet-derived factors that increase vascular permeability or stimulate tumor cell growth and/or motility could enhance the metastatic process (49-51). Various treatments that interfere with tumor-platelet interactions have been shown to decrease the probability of the formation of metastases (52-58).
Circulating tumor cells are thromboplastic; i.e., tumor cells can cause or accelerate clot formation in the bloodstream. Various tumor cell-associated procoagulant activities have been described, such as an activity similar to tissue factor (59,60), an activity that can activate factor X (61-64), and an activity that is associated with plasma membrane vesicles and that stimulates the generation of prothrombinase (65,66). O'Meara (60) demonstrated that fibrin is always found in and around all cancerous lesions, particularly at the growing edge. According to these data, cancer cells actually use the fibrin lattice structure as a support, and fibrin appears to "attract" new blood vessels in the tumor. O'Meara (67) also demonstrated that cancer cells have increased coagulative activity as a result of "cancer coagulative factor," a compound thought to have thromboplastic activity. Subsequently, fibrolysin was found to counteract cancer coagulative factor (68,69), and plasmin was found to be the most active inhibitor of cancer coagulative factor. The plasmin-induced inhibition of cancer coagulative factor can be reversed by plasmin inhibitors. Thornes and Martin (70) also reported that plasmin has a cytopathic effect on cancer cells, an effect that was not found with streptokinase or plasminogen, the two components of plasmin.
However, more convincing evidence that fibrinogen-related proteins are localized in solid tumors came from the work (71,72) showing that, when fibrinogen and anti-fibrinogen antibody were administered systemically to animals with tumors or to humans with tumors, both proteins were later detected in the tumors. Laki and Yancey (73) demonstrated that, when placed in a fibrinogen solution, cultured malignant cells could directly convert fibrinogen to fibrin. After the inoculation of tumor cells into mice, fibrin was observed, by electron microscopy, to be adjacent to the tumor cells. Other investigators (74,75) using immunofluorescence techniques have identified fibrinogen-related proteins in several experimental and human neoplasms. The conclusions from these early reports, which were interpreted as being indicative of fibrin deposition within tumors, were met with appropriate reluctance. The identification of fibrin by routine histologic studies is problematic, and heterogeneous antisera developed against fibrinogen used for the immunolocalization studies were not able to distinguish fibrin from fibrinogen, which is also a component of the tumoral stroma. Furthermore, the demonstration that fibrin is located in the tumoral stroma is not sufficient evidence to support a direct role for fibrin in the progression of cancer, because the deposition of fibrinogen and/or fibrin is a general phenomenon in diseases other than cancer (e.g., inflammation, atherosclerosis, and renal disease) (68), the deposition could also be associated with focal zones of tumor necrosis, or the deposition could represent an artifact resulting from clot formation during the procurement of the specimen.
More recent data have resolved certain of these objections. The use of antiserum, and in particular monoclonal antibodies, of defined specificity (69,76-78) with immunohistochemistry and the use of electron microscopic analysis (79,80) to characterize fibrin patterns have established that fibrin is a constituent of the stroma of some experimental tumors and some human tumors (78-88). In addition, fibrin deposition related to tumor necrosis may be distinguished from artifacts caused by tumor manipulation by the examination of the microanatomic distribution and by the fact that coagulation activation in situ is strictly associated with specific anatomic features in tumor masses (79-89). The occurrence of fibrin in some tumor types and its absence in other tumor types, even when both tumor types were obtained in the same manner, argue against it being an artifact of the procurement procedure. In addition, the existence of cause-and-effect relationships between activated coagulation and cancer progression is supported by a growing body of literature that provides evidence that therapeutic manipulation of the coagulation pathways alters either the dissemination of experimental cancer or the progression of certain types of cancer in the patient (6,8,90-94).
The deposition of fibrin, which occurs when fibrinogen is cleaved at thrombin-specific cleavage sites, in the connective tissue surrounding viable tumor may influence the progression of the tumor in several ways. Fibrin deposits around tumor cells may serve as a barrier that keeps host inflammatory cells from invading and destroying the tumor (9,81,95). This hypothesis is based on histologic evidence that inflammatory cells, particularly lymphocytes, are confined to the tumor-host interface and do not substantially penetrate the tumor (81,95). Recent studies of macrophage migration in fibrin gels offer some explanation of these findings. Depending on the concentrations of fibrin and thrombin, fibrin matrices can either enhance or inhibit macrophage migration (96). In addition, studies by Gorelik and colleagues (97-99) suggested that fibrin can protect tumor cells from the cytotoxic activity of natural killer or lymphokine-activated killer cells. A protective effect was obtained only when coagulation occurred before formation of target-effector conjugates, probably because contact between target and effector cells was prevented rather than because of some change in the lytic phase of lymphokine-activated killer cytotoxicity (99).
Fibrin might also enhance angiogenesis in the metastatic tumor. Olander et al. (100) reported that endothelial cells became organized into vascular channels when cells were cultured in a fibrin gel. It has also been shown that tumor cells can be fixed in the capillaries by fibrin (101-103). In addition, Wood (104) demonstrated that infused tumor cells became fixed in a clump with fibrin and penetrated the vascular wall to reach the extravascular space. Locally injected fibrinolysin readily reversed the clumping of tumor cells and the penetration of the vessel wall by tumor cells (105).
Alternatively, the thrombin, which is available to the surface of tumor cells, might have a fibrin-independent effect on the progression of cancer. Studies in various model systems have shown that thrombin or thrombin-protein complexes bind to the surface of certain normal and transformed cell types (106-109). Thrombin-initiated signal transduction across the cell membrane results in protein kinase C-mediated enhancement of phosphoinositol turnover and calcium mobilization (110-112) and is associated with a reduction in the level of intracellular cyclic adenosine monophosphate (113). Thrombin can also stimulate cell contraction, cellular secretion, and the expression of tissue factor (114) and the c-myc proto-oncogene (115). These effects of thrombin could contribute to metastasis by promoting cell migration through tissues, stimulation of autocrine growth factor secretion, or preservation of local fibrin through the enhanced production of plasminogen activator type I. In addition, because thrombin can initiate synthesis of deoxyribonucleic acid and mitosis (115,116), it has been referred to as a growth factor.
Cliffton and Grossi (117) demonstrated that heparin markedly prolonged survival of rabbits that were given an injection of VX2 carcinoma cells (118). Both heparin and fibrinolysin, when given before the injection of tumor cells, diminished and prevented, respectively, the appearance of pulmonary and liver metastases (118,119). In addition, studies were performed (120-131) to evaluate the effect of heparin and fibrinolysin on the intravascular inoculation of cell suspensions of Walker 256 carcinosarcoma in the rat. All of these studies indicate that lodging of cancer cells introduced into the circulation depends on a fibrin mesh that allows implantation (120-131). Fisher and Fisher (123) have also reported and confirmed the use of anticoagulants in the prevention of metastases in rats. Furthermore, an accumulating body of evidence demonstrates that fibrinolytic agents are effective agents for the reduction of metastases (117,122-126).
The combination of fibrinolysin with other types of treatment, such as radiation, seems to provide enhanced therapeutic activity. Similar incidences of pulmonary metastases were observed in animals given an injection of irradiated tumor cells (1000 rad) and in animals given an injection of nonirradiated tumor cells. However, the formation of metastases was markedly reduced (125) when fibrinolysin was added to cell suspensions before intravenous injection.
In an attempt to simulate a clinical situation (e.g., the release of cells from a tumor during colonic resection), an artificial cecal tumor was generated with the Walker 256 carcinosarcoma (120) in animal models. The tumor was explored at a resectable stage, massaged, and finally resected. Liver metastases were found in 34% of control animals compared with 19% of fibrinolysin-treated animals. In addition, inhibitors of fibrinolysis tend to increase the number of metastases (126,127) in some models.
Inhibitors of Platelet Aggregation
The results were analyzed statistically using the unpaired Student's t test; all P values were two-sided. Schwalke et al. (132) evaluated the effect of prostacyclin on hepatic metastases of a human pancreatic cancer in a nude mouse model system. The surface of the implanted tumor was measured after a defined time as an objective indicator of the influence of prostacyclin on tumor growth. The mean surface area of the liver covered with tumor was statistically significantly reduced in all treatment groups. Specifically, in the untreated control group, the mean surface area of the liver covered with tumor was 485 mm2. Animals treated with 200 µg of prostacyclin 0.5 hour before the injection of tumor cells had tumors covering a surface area of only 21 mm2 (P = .004), and animals treated with 400 µg of prostacyclin had tumors covering a surface area of 20 mm2 (P = .004). Thus, there appeared to be no substantial difference in response to the lower dose versus the higher dose. If 200 µg of prostacyclin was administered 4.0 hours after injection of the tumor cells, the surface area of tumor was 85 mm2 (P = .017). The maximal reduction of tumor surface area (to only 11 mm2) was observed when 200 µg of prostacyclin was given 0.5 hour before and 4.0 hours after the injection of tumor cells (P = .003). These results indicate that prostacyclin has statistically significant antitumoral activity on hepatic metastases from human pancreatic adenocarcinoma in the nude mouse.
Prostacyclin, which is among the most potent inhibitors of platelet aggregation, was also used by Honn et al. (56), who reported a reduction in pulmonary metastases and a complete elimination of hepatic metastases in the B16 amelanotic melanoma model. Additional studies by the same group (57,58) found that cathepsin B levels were associated with both platelet aggregation and metastatic potential. Local proteolysis of the extracellular matrix by proteinases released from tumor cells has been implicated in tumor invasiveness and metastasis. A cathepsin B-like cysteine proteinase has been shown to be released from tumors, and cathepsin B levels are elevated in the serum of patients with several types of cancer. There is a positive association between cathepsin B activity and the metastatic potential of tumor cells, as well as a positive association between the ability of tumor cells to promote platelet aggregation and their metastatic potential. The mechanism by which tumor cell cathepsin B induces platelet aggregation is as yet unidentified (133,134). Cathepsin B-induced platelet aggregation can be effectively inhibited with prostacyclin. Of particular interest to the study of human pancreatic carcinoma was the observation that cathepsin B levels were elevated in the pancreatic secretions of a patient with pancreatic cancer (135).
Additional detailed studies revealed that prostacyclin reduced phorbol 12-myristate 13-acetate- and 12-(S)-hydroeicosatetraenoic acid-stimulated adhesion of tumor cells to subendothelial cell matrix and fibronectin and that prostacyclin reduced endothelial cell retraction (136). Prostacyclin analogues, such as iloprost and cicaprost, had the same effects in vitro(137), and iloprost reduced the number of colonies in the lungs of animals given an intravenous injection of B16 melanoma and Lewis lung carcinoma cells. After a single intravenous administration, iloprost reduced metastases and increased the survival time of an animal with a spontaneously metastasizing Lewis lung carcinoma tumor (137). Another analogue, TEI 8153, inhibited the formation of colonies in the lung of intravenously injected fibrosarcoma cells.
The first data from a continuous-treatment schedule were obtained with eptaloprost, a prodrug derived from cicaprost. In rats, treatment with eptaloprost led to a substantial reduction in the number of metastases from subcutaneously implanted R3327 MAT Lu prostate carcinoma tumors without inhibiting the growth of primary tumors (137). When the antimetastatic effects of eptaloprost and cicaprost were compared, effects of both were equivalent (138). It is interesting that cicaprost did not affect the growth of primary tumors, exerted a weak effect on Lewis lung carcinoma (50%), and reduced the median number of metastases from most other tumor types investigated (137-141).
Schirner and Schneider (140) evaluated the effect of cicaprost on the growth of mammary carcinomas (SMT2a and the 13762 NF MTLn3 line) that preferentially metastasize to the lung and lymph nodes of experimental animals. Cicaprost substantially reduced the median number of metastases from SMT2a tumors. All rats in the control group had between 10 and 45 lung metastases, whereas five of 10 animals in the group treated with cicaprost were free of metastases and the remaining five had only a small number of lymph node lesions. The most intriguing result, however, was an approximately 40% reduction in the weight of axillary lymph nodes. (Weight is a measure of the number of metastatic cells in an organ, such as the lymph nodes.) The MTLn3 line is a tumor that predominantly metastasizes to both regional and distant lymph nodes. Cicaprost, when tested in this model at a daily oral dose of 0.01, 0.03, or 0.1 mg/kg, caused a dose-dependent decrease in the median number of metastases. Although all control animals developed metastases, 43% of the rats treated with circaprost at 0.1 mg/kg were free of metastases. The weight of the lung was significantly decreased (two-sided P = .05; Student's t test) by the two higher doses of cicaprost used. Cicaprost also reduced the weight of the ipsilateral axillary lymph nodes to about 50% at all three doses used and reduced the weight of the contralateral lymph nodes to the level of lymph nodes from a non-tumor-bearing animal (141). Cicaprost was administered from day 11 after orthotopic MTLn3 tumor cell implantation until the end of the experiment (i.e., day 21). In fact, therapy was started when palpable primary tumors and infiltrated lymph nodes were already present. Cicaprost given at a daily oral dose of 0.1 mg/kg substantially suppressed the median number of metastases to about 20, compared with more than 500 metastases in control animals. Surgical removal of the primary tumor at day 12, on the other hand, did not have a statistically significant effect on this parameter (142). A similar experiment was performed in the SMT2a mammary tumor model. Animals were treated from day 10 until day 32. Cicaprost (0.1 mg/kg orally) reduced the median number of metastases to about 20% of the control value (143). These data show that prostacyclin analogues have antimetastatic activity in advanced disease. Prostacyclin and its stable analogues act by binding to a specific receptor (144). In vivo, cicaprost exerts a prominent antimetastatic effect on MTLn3 mammary carcinomas (141), which have functional prostacyclin-binding sites, but cicaprost has no effect on RUCA endometrial carcinomas, which lack functional receptors. In vitro, transendothelial migration of MTLn3 cells is inhibited by cicaprost (145).
In an extension of the experiments performed with cicaprost, Schirner and Schneider (146) evaluated the combined use of cicaprost and various chemotherapeutic agents in the MXT-OVEX mouse mammary carcinoma model system. Cicaprost at daily doses of 0.5 mg/kg and 1.0 mg/kg given orally had no effect on the growth of subcutaneously implanted tumors. Cisplatin at a dose of 1.5 mg/kg strongly inhibited tumor growth, but cisplatin at a dose of 0.75 mg/kg had only weak effects. The efficacy of both concentrations of cisplatin was not altered by addition of cicaprost (0.5 mg/kg orally) administered in two different schedules. Cyclophosphamide (400 mg/kg subcutaneously) completely inhibited the growth of an MXT-OVEX tumor, but doxorubicin (2.5 mg/kg subcutaneously) and 5-fluorouracil (10 mg/kg subcutaneously) had only minimal efficacy. The combination of cicaprost with cyclophosphamide, doxorubicin, or 5-fluorouracil did not alter the antineoplastic activity of any of the drugs. Although an additive or synergistic effect seems unlikely, Schirner and Schneider (146) concluded that the antimetastatic agent cicaprost can be used in combination with cytostatic regimens without decreasing their therapeutic efficacy.
Apart from prostacyclins, agents widely used for pain management or inhibition of platelet aggregation have been implicated as inhibitors of metastases on the basis of experimental data suggesting that metabolites of arachidonic acid may influence the metastatic process (147,148). Increased levels of thromboxane and decreased levels of prostacyclin have been observed in the plasma or in the tumors of patients with cancer of the lung, ovary, breast, or bone (149-152). Increased thromboxane and decreased prostacyclin are associated with an enhanced potential for platelet aggregation. The leucotrienes, which are other arachidonic acid metabolites, have profound effects on vascular integrity (153-155). Nardone et al. (156) demonstrated that ketoconazole inhibited pulmonary metastases in the B16 melanoma model. Ketoconazole, apart from its antimycotic potential, acts as a selective inhibitor of the thromboxane synthase and 5-lipooxygenase pathways. Furthermore, Nardone et al. (156) postulated that a combination of the inhibition of platelet aggregation and the protection of vascular epithelial integrity was responsible for these observations.
Conde et al. (157) found that prostaglandin D2 inhibited malignant glioma cells by biomodulation of cell morphology and the cytoskeleton. This effect was dose dependent and could be seen only above a prostaglandin D2 threshold of 2.5 µg/mL. Prostaglandin D2 at greater than 10 µg/mL was clearly cytotoxic and produced the highest cell killing within 12-24 hours of administration. These findings are in line with the results obtained in a mouse glioma model (158) and a human glioma model (159), although these latter groups reported a cytostatic effect but did not report cytotoxicity. More recently, prostaglandin J2, a serum-mediated catabolite, was postulated to be the metabolite responsible for the antitumoral action of prostaglandin D2 (160,161).
A statistically significant potentiation of the antineoplastic effect of cytotoxic drugs was found when flurbiprofen, an inhibitor of prostaglandin synthase, was added, as shown by an increased survival of mice bearing syngeneic metastasizing tumors (162). In similar experiments, Maca (163) found that nontoxic doses of indomethacin augmented the sensitivity of cultured tumor cells to etoposide (VP-16). Although an increased intracellular accumulation of VP-16 was observed, the mechanism through which the combination of VP-16 and indomethacin act has not been elucidated (163).
Furthermore, there are possible antimetastatic and antiangiogenetic effects of many agents that inhibit membrane-active platelet aggregation and have prostacyclin-releasing activity, including flubiprofen (164), dipyridamole (165-167), mopidamole (166), pentoxifylline (167), ticlopidine (165,167), diltiazem (165), and trapidil (165). Some of these agents have also been shown to potentiate the antineoplastic effect of interferons (168-170).
![]() |
CLINICAL TRIALS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
The hypothesis that anticoagulants have antitumor activity was further supported by the results of a study by Salsali and Cliffton (131), who showed that, for an obstruction of the superior vena cava that was caused by a cancer of the lung, a combined treatment that included anticoagulants increased survival. These authors (131) reported that, in 136 patients treated with x-ray therapy alone or with x-ray therapy plus nitrogen mustard, there was only one survivor after 5 years. Of 15 patients who were treated with fibrinolytic agents and radiotherapy, one patient survived 5 years and another patient survived 4 years. The latter patient had a primary brain tumor at autopsy but had no evidence of residual or metastatic lung cancer. In six of these patients, there was documented recanalization of the superior vena cava after treatment with fibrinolysin and radiotherapy. However, a direct influence of antithrombotic treatment on survival resulting in a diminished rate of (lethal) cardiovascular complications cannot be completely ruled out.
Another study (171) evaluated the use of anticoagulants and conventional anticancer therapy in 50 patients with a malignant obstruction of the superior vena cava. Thirty-one of the patients had carcinoma of the lung, 11 patients had lymphoma, six patients had carcinoma of the stomach, one patient had soft tissue sarcoma of the chest wall, and one patient had melanoma. Twenty-five patients were treated with irradiation and/or chemotherapy only, and 25 patients received anticoagulants in addition to irradiation and/or chemotherapy. Heparin was initially given as a continuous intravenous drip that was later changed to intermittent intravenous administration. After 10-14 days, the patients were placed on coumarin for the rest of their radiotherapy. The overall survival of the entire group was poor. Thirteen patients died after 1 month, and only 11 patients survived more than 1 year. The patients who received heparin, coumarin, and conventional therapy had a better clinical course, as shown by a shorter hospital stay, but the prognosis of the disease was not changed significantly. In the 31 patients with lung cancer, none of the patients treated conventionally survived more than 17 months. In the group treated with anticoagulants, three patients survived longer than 17 months. Thus, survival was prolonged, although for only a few months, by the anticoagulants.
Thornes (172) in studies on the use of fibrinolytic therapy to treat leukemia reported encouraging results that suggest that plasmin and the anticoagulant warfarin (sodium salt) have a direct effect on cancer cells. In a controlled trial using warfarin for maintenance therapy in patients with advanced cancer, 26 patients who received the anticoagulant were alive after 24 months compared with only 11 patients in the untreated control group (173).
In fact, only a few studies have been performed in a controlled
randomized way. Apart from the differences in the designs of the
studies reported in the literature (case reports; phase I, II, and III
studies; and largely retrospective epidemiologic reviews), most studies
were done in combination with cytotoxic drugs. Tables
1-3
give an overview of reports of phase I, II, and III studies, as well as
largely retrospective epidemiologic reviews.
|
|
|
|
|
Nonsteroidal anti-inflammatory drugs appear to warrant further study for prevention of colonic polyposis and subsequent colorectal cancer (174-179). Dipyridamole, a coronary vasodilator and inhibitor of thrombocyte aggregation, interacts with the pyrimidine salvage pathway of 5-fluorouracil. The multimodal biochemical modulation of 5-fluorouracil by folinic acid, interferon, and dipyridamole did not change response rates; in fact, it seems to increase the response but not statistically significantly (180-182). The injection of protease inhibitors into a localized colorectal carcinoma lead to the infiltration of inflammatory cells and to the regression of the tumor, as observed by subsequent tumor resection (183).
Protease inhibitors (183) and also the combination of dipyridamole, interferon, and 5-fluorouracil (181,182) merit additional consideration for definitive investigation in colon cancer.
Lung Cancer
Data from randomized trials (see Table 2) suggest that
small-cell lung cancer (SCLC) consistently responds (184-187)
to heparin and vitamin K antagonists but that non-small-cell lung
cancer (NSCLC) does not respond (184,188) to these
anticoagulants. Other randomized clinical trials suggest that NSCLC
consistently responds to mopidamole (RA-233), an analogue of
dipyridamole (189,190). On the basis of existing knowledge of
mechanisms (191-193) and favorable pilot data (194),
fibrinolytic agents in SCLC and protease inhibitors in NSCLC
(195) merit additional consideration for definitive investigation.
![]() |
CONCLUSIONS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
The experimental evidence strongly suggests that anticoagulants or agents interfering with platelet aggregation can prevent metastases. Despite uncertainties about the exact nature of the interaction between anticoagulants and cancer cells, anticoagulants may inhibit the adherence (or trapping) of cancer cells to capillary walls, so that cancer cells remain in systemic circulation and thus are exposed for a prolonged period to a hostile environment with the potential to eliminate cancer cells. The rationale for the use of anticoagulants seems to be at least partly based on the hypothesis that circulating cancer cells need a fibrin meshwork to initiate the formation of a metastatic tumor in a new location. If this fibrin meshwork can be decreased or prevented, the natural mechanisms of cellular control would probably be able to effectively overcome the metastatic process.
However, caution is still warranted in the interpretation of various experiments. Several publications describe the effects of prostacyclin and its analogues on heterotypic tumor cell interactions, especially tumor cell-platelet interactions (136,143,197) or inhibition of the adhesion of cancer cells to endothelial cells (136). Apart from the fact that these observations could not be reproduced in all models investigated, different mechanisms that can be attributed to the use of prostacyclins could also be involved. The direct antiproliferative activity of prostacyclins has been observed during investigations of chronic inflammatory processes. In addition, these compounds have been shown to inhibit adhesion of tumor cells to endothelial cells, to subendothelial cell matrix, and to fibronectin and to reduce endothelial cell retraction (136).
Apart from a direct effect of various agents on existing tumors in vitro, the most impressive results could be obtained in the prevention of the formation of metastatic tumors in animals given an injection of various tumor cells. This is especially important, since it has been suspected that an increased incidence of metastases occurs after surgical manipulation. Thus, anticoagulation during (and probably for a prolonged period after) surgery seems a logical approach and deserves further evaluation. This would not place the patients at an additional risk because anticoagulation with low-molecular-weight heparin is currently a routinely performed procedure in the perioperative period.
According to data obtained so far, the addition of anticoagulants to conventional adjuvant treatment seems to be especially attractive. Although experimental and clinical data suggest that heparin and vitamin K antagonists are effective compounds for the prevention of metastases, the most effective anticoagulant for cancer prevention may not have been discovered. However, an agent for adjuvant application should meet certain requirements, such as being convenient to give to patients and having a favorable safety record. From the treatment and prevention of thromboses with low-dose low-molecular-weight heparin, perhaps this drug would be an ideal anticoagulant for the prevention of metastases because this treatment has proven to have a highly effective anticoagulant activity and a very low risk of complications (i.e., major hemorrhage). In addition, low-molecular-weight heparin can be safely given on an outpatient basis.
At the moment, there are few studies of anticoagulants that in fact fulfill modern criteria of controlled randomized clinical studies to evaluate drug efficacy. The published studies have different designs (case reports; phase I, II, and III studies; and largely retrospective epidemiologic reviews), and most studies have tested anticoagulants in combination with cytotoxic drugs, which makes evaluation of the results more difficult. In some cases, the anticoagulant drugs appear to act by changing the pharmacokinetic profile of cytotoxic drugs rather than by acting directly on the blood clotting system (198,199).
In general, there is apparently more than one mechanism of action for the drugs tested (platelet aggregation inhibitors or anticoagulants); for example, in addition to an anticoagulation activity, warfarin has a direct cytotoxic effect on cells and dipyridamole may cause the disappearance of drug resistance (193,200). Several other tumor types, including colon carcinoma, prostate carcinoma, and NSCLC, failed to respond to treatment with the anticoagulant warfarin and apparently did not produce thrombin (193). More recently, in a prospective, randomized, and double-blind trial, Rajan et al. (201) reported the safety and efficacy of low-dose warfarin for prevention of thromboembolism in a woman who was receiving chemotherapy for advanced breast cancer. They comment, however, that warfarin had no effect on the natural history of breast cancer, in contrast to observations with SCLC. We thus add breast cancer to the list of tumor types (colon carcinoma, prostate carcinoma, and NSCLC) that can be considered unresponsive to warfarin. Correspondingly, breast cancer cells also apparently do not produce thrombin in situ. Instead, these cells produce urokinase (202) and its receptor (203), which have been implicated in growth and promotion of breast cancer (193,202). These molecules are potential therapeutic targets for the treatment of breast cancer. Similarly, because thrombin can enhance tumor growth by several mechanisms, perhaps the partial beneficial effects found for warfarin and heparin therapy of SCLC may be improved by use of more potent and specific inhibitors of blood coagulation (such as hirudin, antistatin, and low-molecular-weight heparin) and extended to the treatment of renal cell carcinoma (193), malignant melanoma (193), and ovarian carcinoma (204), cancers that also produce thrombin.
From the data obtained so far, we draw the following conclusions: 1) For SCLC, therapy with warfarin may lead to a longer period of disease-free survival and overall survival. 2) Therapy with RA-233, a dipyridamole analogue, leads to an increased overall survival in patients with localized NSCLC. 3) The efficacy of low-dose acetylsalicylic acid in colorectal cancer is still the subject of controversy. Treatment with sulindac, another nonsteroidal anti-inflammatory drug, leads to a statistically significant reduction in amount and size of colon polyps in adenomatosis coli.
Further studies are needed to confirm the existing (mostly preclinical) data and to determine whether vitamin K antagonists, heparin, low-molecular-weight heparin, or platelet aggregation inhibitors effectively prevent the formation of metastatic tumors.
![]() |
REFERENCES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
1 Trousseau A. Phlegmasia alba dolens. Clin Med Hotel Dieu de Paris. Vol 3. London (U.K.): New Sydenham Society; 1895. p. 94.
2 Billroth T. Lectures on surgical pathology and therapeutics (translated from ed. 8). London (U.K.): The New Sydenham Society; 1878.
3 Sack GH Jr, Levin J, Bell W. Trousseau's syndrome and other manifestations of chronic disseminated coagulopathy in patients with neoplasms: clinical, pathophysiologic, and therapeutic features. Medicine 1977;56:1-37.[Medline]
4 Zacharski LR, Rickles FR, Henderson WG, Martin JF, Forman WB, Van Eeckhout JP, et al. Platelets and malignancy. Rationale and experimental design for the VA Cooperative Study of RA-233 in the treatment of cancer. Am J Clin Oncol 1982;5:593-609.[Medline]
5 Zacharski LR, Memoli VA, Costantini V, Wojtukiewicz MZ, Ornstein DL. Clotting factors in tumour tissue: implications for cancer therapy. Blood Coagul Fibrinolysis 1990;1:71-8.[Medline]
6 Zacharski LR, Costantini V, Wojtukiewicz MZ, Memoli VA, Kudryk BJ. Anticoagulants as cancer therapy. Semin Oncol 1990;17:217-27.[Medline]
7 Zacharski LR, Wojtukiewicz MZ, Costantini V, Ornstein DL, Memoli VA. Pathways of coagulation/fibrinolysis activation in malignancy. Semin Thromb Hemost 1992;18:104-16.[Medline]
8 Donati MB, Poggi A, Semerano N. Coagulation and malignancy. In: Poller L, editor. Recent advances in blood coagulation. Vol 3. New York (NY): Livingston; 1981. p. 375-91.
9 Dvorak HF. Tumor: wounds that do not heal. N Engl J Med 1986;315:1650-9.[Medline]
10 Rickles FR, Edwards RL. Activation of blood coagulation in patients with cancer: Trousseau's syndrome revisited. Blood 1983;62:14-31.[Medline]
11 Zacharski LR, Henderson WG, Rickles FR, Forman WB, Cornell CJ Jr, Forcier RJ, et al. Rationale and experimental design for the VA Cooperative Study of Anticoagulation (Warfarin) in the Treatment of Cancer. Cancer 1979;44:732-41.[Medline]
12 Liotta LA, Kleinermann J, Saidel GM. Quantitative relationships of intravascular tumor cells, tumor vessels, and pulmonary metastases following tumor implantation. Cancer Res 1974;34:997-1004.[Medline]
13 Butler TP, Gullino PM. Quantitation of cell shedding into efferent blood of mammary adenocarcinoma. Cancer Res 1975;35:512-6.[Abstract]
14 Glaves D. Correlation between circulating cancer cells and incidence of metastases. Br J Cancer 1983;48:665-73.[Medline]
15 Gerson JM, Schlesinger HR, Sereni P, Moorhead PS, Hummeler K. Isolation and characterization of a neuroblastoma cell line from peripheral blood in a patient with disseminated disease. Cancer 1977;39:2508-12.[Medline]
16 Golinger RC, Gregorio RM, Fisher ER. Tumor cells in venous blood draining mammary carcinomas. Arch Surg 1977;112:707-8.[Abstract]
17 Griffiths JD, McKinna JA, Rowbotham HD, Tsolakidis P, Salsbury AJ. Carcinoma of the colon and rectum: circulating malignant cells and five-year survival. Cancer 1973;31:226-36.[Medline]
18 Koo J, Fung K, Siu KF, Lee NW, Lett Z, Ho J, et al. Recovery of malignant tumor cells from the right atrium during hepatic resection for hepatocellular carcinoma. Cancer 1983;52:1952-6.[Medline]
19 Sako K, Marchetta FC. Radioautography of in vitro labeled tumor cells in postoperative wound drainage. Cancer 1966;19:735-7.[Medline]
20 Fidler IJ. Metastasis: quantitative analysis of distribution and fate of tumor emboli labeled with 125I-5-iodo-2'-deoxyuridine. J Natl Cancer Inst 1970;45:773-82.[Medline]
21 Hewitt HB, Blake E. Quantitative studies of translymphonodal passage of tumour cells naturally disseminated from a nonimmunogenic murine squamous carcinoma. Br J Cancer 1975;31:25-35.[Medline]
22 Kodama M, Kodama T. Enhancing effect of hydrocortisone on hematogenous metastasis of Ehrlich ascites tumor in mice. Cancer Res 1975;35:1015-21.[Abstract]
23 Liotta LA, DeLisi C. Method for quantitating tumor cell removal and tumor cell-invasive capacity in experimental metastases. Cancer Res 1977;37:4003-8.[Abstract]
24 Proctor JW. Rat sarcoma model supports both "soil "seed" and "mechanical" theories of metastatic spread. Br J Cancer 1976;34:651-4.[Medline]
25 Weston BJ, Carter RL, Easty GC, Connell DI, Davies AJ. The growth and metastasis of an allografted lymphoma in normal, deprived and reconstituted mice. Int J Cancer 1974;14:176-85.[Medline]
26 Hanna N. Expression of metastatic potential of tumor cells in young nude mice is correlated with low levels of natural killer cell-mediated cytotoxicity. Int J Cancer 1980;26:675-80.[Medline]
27 Hanna N. Inhibition of experimental tumor metastasis by selective activation of natural killer cells. Cancer Res 1982;42:1337-42.[Abstract]
28 Hanna N, Fidler IJ. Role of natural killer cells in the destruction of circulating tumor emboli. J Natl Cancer Inst 1980;65:801-9.[Medline]
29 Herberman RB, Holden HT. Natural cell-mediated immunity. Adv Cancer Res 1978;27:305-77.[Medline]
30 Fidler IJ. Eradication of metastases by tumoricidal macrophages: therapeutic implications. In: Liotta LA, Hart IR, editors. Tumor invasion and metastasis. Boston (MA): Martinus-Nijhoff; 1982. p. 15-27.
31 James K, McBride B, Stuart A. The macrophage and cancer. Edinburgh (U.K.): Econoprint; 1977.
32 Key ME. Macrophages in cancer metastases and their relevance to metastatic growth. Cancer Metastasis Rev 1983;2:75-88.[Medline]
33 Glaves D. Role of polymorphonuclear leukocytes in the pulmonary clearance of arrested cancer cells. Invasion Metastasis 1983;3:160-73.[Medline]
34 Galton JE, Xue B, Hochwald GM, Thorbecke GJ. Derivation of transplantable, 7,12-dimethylbenz[a]anthracene-induced chicken fibrosarcoma lines: differences in metastasizing properties and organ specificity. J Natl Cancer Inst 1982;69:535-41.[Medline]
35 Vaage J. In vivo and in vitro lysis of mouse cancer cells by anti-metastatic effectors in normal plasma. Cancer Immunol Immunther 1978;4:257-61.
36 Wolosin LB, Greenberg AH. Murine natural anti-tumor antibodies. I. Rapid in vivo binding of natural antibody by tumor cells in syngeneic mice.Int J Cancer 1979;23:519-29.[Medline]
37 Sato H, Suzuki M. Deformability and viability of tumor cells by transcapillary passage, with reference to organ affinity in metastasis in cancer. In: Weiss L, editor. Fundamental aspects of metastasis. Amsterdam (The Netherlands): North-Holland; 1976. p. 311-7.
38 Fidler IJ. The relationship of embolic homogeneity, number, size and viability to the incidence of experimental metastasis. Eur J Cancer 1973;9:223-7.[Medline]
39 Liotta LA, Saidel MG, Kleinerman J. The significance of hematogenous tumor cell clumps and the metastatic process. Cancer Res 1976;36:889-94.[Abstract]
40 Lotan R, Raz A. Low colony formation in vivo and in culture as exhibited by metastatic melanoma cells selected for reduced homotypic aggregation. Cancer Res 1983;43:2088-93.[Abstract]
41 Zeidman I, Buss JM. Transpulmonary passage of tumor cell emboli. Cancer Res 1952;12:731-3.[Medline]
42 Gasic GJ, Gasic TB, Stewart CC. Antimetastatic effects associated with platelet reduction. Proc Natl Acad Sci U S A 1968;61:46-52.[Medline]
43 Gasic GJ. Role of plasma, platelets, and endothelial cells in tumor metastasis. Cancer Metastasis Rev 1984;3:99-114.[Medline]
44 Pearlstein E, Salk PL, Yogeeswaran G, Karpatkin S. Correlation between spontaneous metastatic potential, platelet-aggregating activity of cell surface extracts, and cell surface sialyation in 10 metastatic-variant derivatives of a rat renal sarcoma cell line. Proc Natl Acad Sci U S A 1980;77:4336-9.[Abstract]
45 Warren BA. Environment of the blood-borne tumor embolus adherent to vessel wall. J Med 1973;4:150-77.[Medline]
46 Fidler IJ. Biological behavior of malignant melanoma cells correlated to their survival in vivo. Cancer Res 1975;35:218-24.[Abstract]
47 Fidler IJ, Bucana C. Mechanism of tumor cell resistance to lysis by syngeneic lymphocytes. Cancer Res 1977;37:3945-56.[Abstract]
48 Starkey JR, Liggitt HD, Jones W, Hosick HL. Influence of migratory blood cells on the attachment of tumor cells to vascular endothelium. Int J Cancer 1984;34:535-43.[Medline]
49 Hara Y, Steiner M, Baldini MG. Platelets as a source of growth-promoting factor(s) for tumor cells. Cancer Res 1980;40:1212-6.[Abstract]
50 Kepner N, Lipton A. A mitogenic factor for transformed fibroblasts from human platelets. Cancer Res 1981;41:430-2.[Abstract]
51 Nachman RL. The platelet as an inflammatory cell. In: deGaetano G, Gerattini S, editors. Platelets: a multidisciplinary approach. New York (NY): Raven Press; 1978. p. 199-203.
52 Gasic GJ, Gasic TB, Murphy S. Anti-metastatic effect of aspirin. Lancet 1972;2:932-3.
53 Gasic GJ, Gasic TB, Galanti N, Johnson T, Murphy S. Platelet-tumor cell interactions in mice. The role of platelets in the spread of malignant disease.Int J Cancer 1973;11:704-18.[Medline]
54 Gasic GJ, Koch PA, Hsu B, Gasic TB, Niewiarowski S. Thrombogenic activity of mouse and human tumors: effects on platelets, coagulation, and fibrinolysis, and possible significance for metastasis. Z Krebsforsch Klin Onkol Cancer Res Clin Oncol 1976;86:263-77.[Medline]
55 Gasic GJ, Gasic TB, Jimenez SA. Effects of trypsin on the platelet-aggregating activity of mouse tumor cells. Thromb Res 1977;10:33-45.[Medline]
56 Honn KV, Cicone B, Skoff A. Prostacyclin: a potent antimetastatic agent. Science 1981;212:1270-2.[Medline]
57 Honn KV, Meyer J, Neagos G, Henderson T, Westley C, Ratanatharathorn V. Control of the tumor growth and metastasis with prostacyclin and thromboxane synthetase inhibitors: evidence for a new antitumor and antimetastatic agent. Prog Clin Biol Res 1982;89:295-331.[Medline]
58 Honn KV, Onoda JM, Pampalona K, Battaglia M, Neagos G, Taylor JD, et al. Inhibition by dihydropyridine class calcium channel blockers of tumor cell-platelet-endothelial cell interactions in vitro and metastasis in vivo. Biochem Pharmacol 1985;34:235-41.[Medline]
59 Colucci M, Giavazzi R, Alessandri G, Semerano N, Mantovani A, Donati MB. Procoagulant activity of sarcoma sublines with different metastatic potential. Blood 1981;57:733-5.[Abstract]
60 O'Meara RA. Coagulative properties of cancer. Irish J Med Sci 1958;6:474-9.
61 Curatolo L, Colucci M, Cambini AL, Poggi A, Morasca L, Donati MB, et al. Evidence that cells from experimental tumors can activate coagulation factor X. Br J Cancer 1979;40:228-33.[Medline]
62 Gordon SG, Franks JJ, Lewis B. Procoagulant A: a factor X activating procoagulant from malignant tissue. Thromb Res 1975;6:127-37.[Medline]
63 Gordon SG, Cross BA. A factor X-activating cysteine protease from malignant tissue. J Clin Invest 1981;67:1667-71.
64 Pineo GF, Regoeczi E, Hatton MW, Brain MC. The activation of coagulation by extracts of mucus: a possible pathway of intravascular coagulation accompanying adenocarcinomas. J Lab Clin Med 1973;82:255-66.[Medline]
65 Dvorak HF, Senger DR, Dvorak AM. Fibrin as a component of the tumor stroma: origins and biological significance. Cancer Metastasis Rev 1983;2:41-73.[Medline]
66 Dvorak HF, Quay SC, Orenstein NS, Dvorak AM, Hahn P, Bitzer AM, et al. Tumor shedding and coagulation. Science 1981;212:923-4.[Medline]
67 O'Meara RA. Fibrinolytic treatment of cancer. Lancet 1964;2:963.
68 Bini A, Mea-Tejada R, Fenoglio JJ Jr, Kudryk B, Kaplan KL. Immunohistochemical characterization of fibrin(ogen)-related antigens in human tissues using monoclonal antibodies. Lab Invest 1989;60:814-21.[Medline]
69 Kudryk B, Rohoza A, Ahadi M, Chin J, Wiebe ME. A monoclonal antibody with ability to distinguish between NH2-terminal fragments derived from fibrinogen and fibrin. Mol Immunol 1983;20:1191-200.[Medline]
70 Thornes RD, Martin WJ. The cytopathic effect of fibrinolytic agents and human placental fractions on HeLa cells. Irish J Med Sci 1961;431:487-94.[Medline]
71 Day ED, Planinsek JA, Pressman D. Localization in vivo of radioiodinated anti-rat fibrin antibodies and radioiodinated rat fibrinogen in the Murphy rat lymphosarcoma and in other transplantable rat tumor. J Natl Cancer Inst 1959;22:413-26.[Medline]
72 Spar IL, Bale WF, Marrack D, Dewey WC, McCardle RJ, Harper PV. 131-I-labeled antibodies to human fibrinogen. Diagnostic studies and therapeutic trials.Cancer 1967;20:865-70.[Medline]
73 Laki K, Yancey ST. Fibrinogen and the tumor problem. In: Laki K, editor. Fibrinogen. New York (NY): Marcel Dekker; 1968. p. 359-67.
74 Hiramoto R, Yagi Y, Pressman D. Immunohistochemical studies of antibodies in anti-Murphy lymphosarcoma sera. Cancer Res 1959;19:874-9.[Medline]
75 Hiramoto R, Bernecky J, Jurandowski J. Fibrin in human tumors. Cancer Res 1960;20:592-3.[Medline]
76 Kudryk B, Rohoza A, Ahadi M, Chin J, Wiebe ME. Specificity of a monoclonal antibody for the NH2-terminal region of fibrin. Mol Immunol 1984;21:89-94.[Medline]
77 Kudryk BJ, Grossman ZD, McAfee JG. Monoclonal antibodies as probes for fibrin(ogen) proteolysis. In: Chatal JF, editor. Monoclonal antibodies in immunoscintigraphy. Boca Raton (FL): CRC Press; 1988. p. 365-98.
78 Hui KY, Haber E, Matsueda GR. Monoclonal antibodies to a synthetic fibrin-like peptide bind to human fibrin but not fibrinogen. Science 1983;222:1129-32.[Medline]
79 Harris NL, Dvorak AM, Smith J, Dvorak HF. Fibrin deposits in Hodgkin's disease. Am Pathol 1982;108:119-29.[Abstract]
80 Zacharski LR, Schned AR Sorenson GD. Occurrence of fibrin and tissue factor antigen in human small cell carcinoma of the lung. Cancer Res 1983;43:3963-8.[Abstract]
81 Dvorak HF, Dvorak AM, Manseau EJ, Wiberg L, Churchill WH. Fibrin gel investment associated with line 1 and line 10 solid tumor growth, angiogenesis, and fibroplasia in guinea pigs. Role of cellular immunity, myofibroblasts, microvascular damage, and infarction in line 1 tumor regression. J Natl Cancer Inst 1979;62:1459-72.[Medline]
82 Zacharski LR, Memoli VA, Rousseau SM. Coagulation-cancer interaction in situ in renal cell carcinoma. Blood 1986;68:394-9.[Abstract]
83 Rickles FR, Hancock WW, Edwards RL, Zacharski LR. Antimetastatic agents. I. Role of cellular procoagulants in the pathogenesis of fibrin deposition in cancer and the use of anticoagulants and/or antiplatelet drugs in cancer treatment. Semin Thromb Hemost 1988;14:88-94.
84 Costantini V, Zacharski LR, Memoli VA, Kisiel W, Kudryk BJ, Rousseau SM. Fibrinogen deposition and macrophage-associated fibrin formation in malignant and nonmalignant lymphoid tissue. J Lab Clin Med 1992;119:124-31.[Medline]
85 Wojtukiewicz MZ, Zacharski LR, Memoli VA, Kisiel W, Kudryk BJ, Rousseau SM, et al. Abnormal regulation of coagulation/fibrinolysis in small cell carcinoma of the lung. Cancer 1990;65:481-5.[Medline]
86 Wojtukiewicz MZ, Zacharski LR, Memoli VA, Kisiel W, Kudryk BJ, Rousseau SM, et al. Malignant melanoma. Interaction with coagulation and fibrinolysis in situ.Am J Clin Pathol 1990;93:516-21.[Medline]
87 Wojtukiewicz MZ, Zacharski LR, Memoli VA, Kisiel W, Kudryk BJ, Moritz TE, et al. Fibrin formation on vessel walls in hyperplastic and malignant prostate tissue. Cancer 1991;67:1377-83.[Medline]
88 Wojtukiewicz MZ, Zacharski LR, Memoli VA, Kisiel W, Kudryk BJ, Rousseau SM, et al. Fibrinogen-fibrin transformation in situ in renal cell carcinoma. Anticancer Res 1990;10:579-82.[Medline]
89 Brown LF, Asch B, Harvey VS, Buchinski B, Dvorak HF. Fibrinogen influx and accumulation of cross-linked fibrin in mouse carcinomas. Cancer Res 1988;48:1920-5.[Abstract]
90 Zacharski LR, Donati MB. Registry of clinical trials of antithrombotic drugs in cancer. Thromb Haemostas 1989;61:526-8.[Medline]
91 Zacharski LR, Henderson WG, Rickles FR, Forman WB, Cornell CJ Jr, Forcier RL, et al. Effect of warfarin on survival in small cell carcinoma of the lung. JAMA 1981;245:831-5.[Abstract]
92 Zacharski LR, Henderson WG, Rickles FR, Forman WB, Cornell CJ Jr, Forcier RL, et al. Effect of warfarin anticoagulation on survival in carcinoma of the lung, colon, head and neck, and prostate. Final report of the VA Cooperative Study #75. Cancer 1984;53:2046-52.[Medline]
93 Chahinian AP, Propert KJ, Ware JH, Zimmer B, Perry MC, Hirsh V, et al. A randomized trial of anticoagulation with warfarin and of alternating chemotherapy in extensive small-cell lung cancer by the Cancer and Leukemia Group B. J Clin Oncol 1989;7:993-1002.[Abstract]
94 Lebeau B, Chastang CL, Brechot JM. Subcutaneous heparin treatment increases complete response rate and overall survival in small cell lung cancer. Lung Cancer 1991;7(Suppl):129.
95 Dvorak HF, Senger DR, Dvorak AM. Fibrin as a component of the tumor stroma: origins and biological significance. Cancer Metastasis Rev 1983;2:41-73.[Medline]
96 Ciano PS, Colvin RB, Dvorak AM, McDonagh J, Dvorak HF. Macrophage migration in fibrin gel matrices. Lab Invest 1986;54:62-70.[Medline]
97 Gorelik E, Bere WW, Herberman RB. Role of NK cells in the antimetastatic effect of anticoagulant drugs. Int J Cancer 1984;3:87-94.
98 Gorelik E. Augmentation of the antimetastatic effect of anticoagulant drugs by immunostimulation in mice. Cancer Res 1987;47:809-15.[Abstract]
99 Gunji Y, Gorelik E. Role of fibrin coagulation in protection of murine tumor cells from destruction by cytotoxic cells. Cancer Res 1988;48:5216-21.[Abstract]
100 Olander JV, Bremer ME, Marasa JC, Feder J. Fibrin-enhanced endothelial cell organization. J Cell Physiol 1985;125:1-9.[Medline]
101 Thornes RD. Fibrinogen and the interstitial behaviour of cancer; in endogenous factors influencing host tumor balance. Chicago (IL): University of Chicago Press; 1967. p 255-66.
102 Clarke N. Intracellular location of tissue thromboplastins and possible relation to fibrin deposits in human neoplasms. Nature 1965;205:608-10.[Medline]
103 Saphir O. Fate of carcinoma emboli in lung. Am J Pathol 1947;23:245-53.
104 Wood S Jr. Pathogenesis of metastatic formation observed in the rabbit ear chamber. Arch Pathol 1958;66:550-6.
105 Wood S Jr. Experimental studies of the intravascular dissemination of ascites V2 carcinoma cells in the rabbit with special reference to fibrinogen and fibrinolytic agents. Bull Schweiz Akad Med Wiss 1964;20:92-121.[Medline]
106 Zetter BR, Chen LB, Buchanan JM. Binding and internalization of thrombin by normal and transformed chick cells. Proc Natl Acad Sci U S A 1988;74:596-600.
107 Fair DS, Plow EF. Specific association of thrombin-antithrombin complexes with a human hepatoma cell line. Thromb Res 1986;41:67-78.[Medline]
108 Maruyuma I, Majerus PW. The turnover of thrombin-thrombomodulin complex in cultured human umbilical vein endothelial cells and A549 lung cancer cells. J Biol Chem 1985;260:432-8.
109 Tullis JL, Honegger H, Fleischaker O, Hewitt L, Kenney D, Chao FC. Thrombin inhibition by malignant and normal cells: a cell-bound antithrombin effect. Cancer 1981;48:1177-82.[Medline]
110 Carney DH, Stiernberg J, Fenton JW 2d. Initiation of proliferative events by human alpha-thrombin requires both receptor binding and enzymatic activity. J Cell Biochem 1984;26:181-95.[Medline]
111 Paris S, Pouyssegur J. Growth factors activate the Na+/H+ antiporter in quiescent fibroblasts by increasing its affinity for intracellular H+. J Biol Chem 1984;259:989-94.
112 Raben DM, Cunningham DD. Effects of EGF and thrombin on inositol-containing phospholipids of cultured fibroblasts: stimulation of phosphatidylinositol synthesis by thrombin but not EGF. J Cell Physiol 1985;125:582-90.[Medline]
113
Murayama T, Ui M. Receptor-mediated inhibition of adenylate
cyclase and stimulation of arachidonic acid release in 3T3 fibroblasts. Selective susceptibility to
islet-activating protein, pertussis toxin.J Biol Chem 1985;260:7226-33.
114 Galdal KS, Lyberg T, Evensen SA, Nilsen SE, Prydz H. Thrombin induces thromboplastin synthesis in cultured vascular endothelial cells. Thromb Haemost 1985;54:373-6.[Medline]
115 Van Obberghen-Schilling E, Chambard JC, Paris S, L'Allemain G, Pouyssegur J. Alpha-thrombin-induced early mitogenic signalling events and G0 to S-phase transition of fibroblasts require continual external stimulation. EMBO J 1985;4:2927-32.[Abstract]
116 Bar-Shavit R, Kahn AJ, Mann KG, Wilner GD. Identification of a thrombin sequence with growth factor activity on macrophages. Proc Natl Acad Sci U S A 1986;83:976-80.[Abstract]
117 Cliffton EE, Grossi CE. The effect of human plasmin on the toxic properties and growth of the VX2 carcinoma and the Brown Pearce carcinoma of rabbits. Cancer 1956;9:1147-52.[Medline]
118 Cliffton EE. Fibrinolytic therapy for thrombo-embolic disease: principles and practice. J La State Med Soc 1966;118:309-19.[Medline]
119 Cliffton EE. Effect of fibrinolysin on spread of cancer. Fed Proc 1966;25:89-93.[Medline]
120 Agostino D, Grossi CE, Cliffton EE. Effect of heparin on circulating Walker 256 carcinosarcoma cells. J Natl Cancer Inst 1961;27:17.[Medline]
121 Grossi CE, Agostino D, Cliffton EE. The effect of human fibrinolysin on pulmonary metastases of Walker 256 carcinosarcoma. Cancer Res 1960;20:605-8.[Medline]
122 Grossi CE, Agostino D, Melamed M. The effect of human fibrinolysin on the survival of the circulating Walker 256 carcinosarcoma cell. Cancer 1961;14:957-62.[Medline]
123 Fisher B, Fisher ER. Anticoagulants and tumor cell lodgement.Cancer Res 1967;27:421-5.[Medline]
124 Agostino D, Grossi CE, Cliffton EE. Effect of human fibrinolysin on hepatic metastases in stimulated colon carcinoma in rats. Ann Surg 1961;153:365-8.[Medline]
125 Cliffton EE, Agostino D. Irradiation and anticoagulation therapy to prevent pulmonary metastases of the V2 carcinoma in rabbits. Radiology 1963;80:236-43.
126 Rudenstan CM. Effect of fibrinolytic antifibrinolytic and flow promoting agents in metastases formation and tumor growth; in endogenous factors influencing host tumor balance. Chicago (IL): University of Chicago Press; 1967. p. 277-98.
127 Cliffton EE, Agostino D. Effect of inhibitors of fibrinolytic enzymes on development of pulmonary metastases. J Natl Cancer Inst 1964;33:753-63.[Medline]
128 Michaels L. Cancer incidence and mortality in patients having anticoagulant therapy. Lancet 1964;2:832-5.
129 Larsen VB, Morgensen B, Amus CJ. Fibrinolytic enzymes in the treatment of patients with cancer. Danish Med Bull 1964;11:137-40.[Medline]
130 Dahl S. Treatment of cancer patients with infusions of plasmin. Oncology 1966;20:35-8.[Medline]
131 Salsali MS, Cliffton EE. Superior vena cava obstruction with carcinoma of the lung. Surg Gynecol Obstet 1965;121:783-8.[Medline]
132 Schwalke MA, Tzanakakis GN, Vezeridis MP. Effects of prostacyclin on hepatic metastases from human pancreatic cancer in the nude mouse. J Surg Res 1990;49:164-7.[Medline]
133 Sloane BF, Dunn JR, Honn KV. Lysosomal cathepsin B: correlation with metastatic potential. Science 1981;212:1151-3.[Medline]
134 Honn KV, Cavanaugh P, Evens C, Taylor JD, Sloane BF. Tumor cell platelet aggregation: induced by cathepsin B-like proteinase and inhibited by prostacyclin. Science 1982;217:540-2.[Medline]
135 Rinderknecht H, Renner IG. Increased cathepsin B activity in pancreatic juice from a patient with pancreatic cancer [letter]. N Engl J Med 1980;303:462-3.[Medline]
136 Honn KV, Tang DG, Chen YQ. Platelets and cancer metastasis: more than epiphenomenon. Semin Thromb Hemost 1992;18:392-415.[Medline]
137 Schneider MR, Schirner M. Antimetastatic prostacyclin analogues. Drugs Future 1993;18:29-48.
138 Schirner M, Schneider MR. Antimetastatic potential of stable prostacyclin analogue cicaprost. In: Rubanyi GM, Vane J, editors. Prostacyclin: new perspectives for basic research and novel therapeutic indications. Amsterdam (The Netherlands): Excerpta Medica; 1992. p. 247-75.
139 Schirner M, Schneider MR. Cicaprost inhibits metastases of animal tumors. Prostaglandins 1991;42:451-61.[Medline]
140 Schirner M, Schneider MR. The prostacyclin analogue cicaprost inhibits metastasis of tumour of R 3327 MAT Lu prostate carcinoma and SMT 2A mammary carcinoma. J Cancer Res Clin Oncol 1992;118:497-501.[Medline]
141 Schirner M, Lichtner RB, Schneider MR. The stable prostacyclin analogue cicaprost inhibits metastasis to lungs and lymph nodes in the 13762NF MTLn3 rat mammary carcinoma. Clin Exp Metastasis 1994;12:24-30.[Medline]
142 Schirner M, Lichtner RB, Graf H, Schneider MR. Efficacy of cicaprost on metastasis in advanced tumor disease [abstract 517]. In: Proceedings of the 3rd International Conference on Eicosanoids and Other Bioactive Lipids in Cancer, Inflammation and Radiation Injury, vol 3; 1993 October 13-16. Washington (DC).
143 Schneider MR, Tang DG, Schirner M, Honn KV. Prostacyclin and its analogues: antimetastatic effects and mechanisms of action. Cancer Metastasis Rev 1994;13:349-64.[Medline]
144 Thierauch KH, Dinter H, Stock G. Prostaglandins and their receptors: II. Receptor structure and signal transduction.J Hyperten 1994;12:1-5.[Medline]
145 Graf H. Endothelial control of cell migration and proliferation. Eur Heart J 1993;14(Suppl 1):183-6.[Medline]
146 Schirner M, Schneider M. Cicaprost does not affect tumor inhibitory potential of cytostatic drugs. Anticancer Res 1993;13:743-6.[Medline]
147 Bennett A, Houghton J, Leaper DJ, Stamford IF. Cancer growth, response to treatment and survival time in mice: beneficial effect of the prostaglandin synthesis inhibitor flurbiprofen. Prostaglandins 1979;17:179-91.[Medline]
148 Honn KV, Menter D, Cavanaugh PG, Neagos G, Moilanen D, Taylor JD, et al. A review of prostaglandins and the treatment of tumor metastasis. Acta Clin Belg 1983;38:53-67.[Medline]
149 Stamford IF, Bennett A, Carrol MA, Sanger GJ, Hensby CN. Human lung cancer and prostaglandins. In: Prostaglandins and Cancer: First International Conference. New York (NY): Alan R. Liss; 1982. p. 691-5.
150 Karmali RA, Welt S, Thaler HT, Lefevre F. Prostaglandins in breast cancer: relationship to disease stage. Br J Cancer 1983;48:689-96.[Medline]
151 Mehta P, Ostrowski N, Brigmon L. Decreased stabilization of prostacyclin activity in patients with bone tumors. Cancer Res 1984;44:3132-4.[Abstract]
152 Heinonen PK, Metsa-Ketela T. Prostaglandin and thromboxane production in ovarian cancer tissue. Gynecol Obstet Invest 1984;18:225-9.[Medline]
153 Moncada S, Vane JR. The discovery of prostacyclin: a fresh insight into arachidonic acid metabolism. In: Biochemical aspects of prostaglandins and thromboxane. New York (NY): Academic Press; 1977. p. 155-77.
154 Vargaftig BB, Chignard M, Benveniste J. Present concepts on the mechanisms of platelet aggregation. Biochem Pharmacol 1981;30:263-71.[Medline]
155 Samuelsson B. Leukotrienes: mediators of immediate hypersensitivity reactions and inflammation. Science 1983;220:568-75.[Medline]
156 Nardone PA, Slotman GJ, Vezeridis MP. Ketokonazole: a thromboxane synthetase and 5-lipoxygenase inhibitor with antimetastatic activity in B16-F10 melanoma. J Surg Res 1988;44:425-9.[Medline]
157 Conde B, Tejedor M, Sinues E, Alcala A. Modulation of cell growth and differentiation induced by prostaglandin D2 in the glioma cell line C6. Anticancer Res 1991;11:289-95.[Medline]
158 Keyaki A, Handa H, Yamashita J, Tokuriki Y, Otsuka S, Yamasaki T, et al. Growth inhibitory effect of prostaglandin D2 on mouse glioma cells. J Neurosurg 1984;61:912-7.[Medline]
159 Westphal M, Neuss M, Herrmann HD. Prostaglandins: antiproliferative effect of PCD 2 on cultured human glioma cells. Acta Neurochir 1986;83:56-61.[Medline]
160 Fukushima M, Kato T, Ota K, Arai Y, Narumija S, Hayaishi O, et al. 9-Deoxy-delta 9-prostaglandin D2, a prostaglandin D2 derivative with potent antineoplastic and weak smooth muscle-contracting activities. Biochem Biophys Res Commun 1982;109:626-33.[Medline]
161 Bhuyan BK, Badiner GJ, Adams EG, Chase R. Cytotoxicity of combinations of prostaglandin D2 (PGD2) and antitumor drugs for B16 melanoma cells in culture. Invest New Drugs 1986;4:315-23.[Medline]
162 Bennett A, Berstock DA, Carroll MA. Increased survival of cancer-bearing mice treated with inhibitors of prostaglandin synthesis alone or with chemotherapy. Br J Cancer 1990;45:762-8.
163 Maca RD. Enhancement of etoposide and methotrexate sensitivity by indomethacin in vitro. Anticancer Drug Des 1991;6:453-66.[Medline]
164 Mamytbekova A, Rezabek K, Kacerovska H, Grimova J, Svobodova J. Antimetastatic effect of flubiprofen and other platelet aggregation inhibitors. Neoplasma 1986;33:417-21.[Medline]
165 Bando H, Yamashita T, Tsubura E. Effects of antiplatelet agents on pulmonary metastases. Gunn 1984;75:284-91.
166 Tzanakakis GN, Agerwal KC, Vezeridis MP. Prevention of human pancreatic cancer cell-induced hepatic metastasis in nude mice by dipyridamole and its analog RA-233. Cancer 1993;71:2466-71.[Medline]
167 Chen WH, Yin HL, Chang YY, Lan MY, Hsu HY, Liu JS. Antiplatelet drugs induce apoptosis in cultured cancer cells. Kao Hsiung I Hsueh Ko Hsueh Tsa Chih 1997;13:589-97.
168 Suzuki N, Oiwa Y, Sugano I, Inaba N, Sekiya S, Fukazawa I, et al. Dipyridamole enhances an anti-proliferative effect of interferon in various types of human tumor cells. Int J Cancer 1992;51:627-33.[Medline]
169 Kojima T, Suzuki N, Sugano I, Hayata I. Enhancement of an anti-tumor effect of interferon by dipyridamole in established human malignant melanoma cell lines. Int J Cancer 1990;46:853-7.[Medline]
170 Galabov AS, Mastikova M. Dipyridamole is an interferon inducer. Acta Virol 1982;26:137-47.[Medline]
171 Ghosh BC, Cliffton EE. Malignant tumors with superior vena cava obstruction. N Y State J Med 1973;73:283-9.[Medline]
172 Thornes RD. Fibrinolytic therapy of leukemia. J R Coll Surg Ireland 1971;6:123-8.
173 Thornes RD. Warfarin as maintenance therapy for cancer. J Irish Coll Physiol Surg 1972;2:213-6.
174 Kune G, Kune S, Watson L. Colorectal cancer risk, chronic illness, operations, and medications: case control results from the Melbourne Colorectal Cancer Study. Cancer Res 1988;48:4399-404.[Abstract]
175 Waddell WR, Ganser GF, Cerise EJ, Loughry RW. Sulindac for polyposis of the colon. Am J Surg 1989;157:175-9.[Medline]
176 Thun MJ, Namboodiri MM, Heath CW Jr. Aspirin use and reduced risk of fatal colon cancer. N Engl J Med 1991;325:1595-6.
177 Rosenberg L, Palmer JR, Zauber AG, Warshauer ME, Stolley PD, Shapiro S. A hypothesis: nonsteroidal anti-inflammatory drugs reduce the incidence of large-bowel cancer. J Natl Cancer Inst 1991;83:355-8.[Abstract]
178 Rigau J, Pique JM, Rubio E, Planas R, Tarrech JM, Bordas JM. Effects of long-term sulindac therapy on colonic polyposis. Ann Intern Med 1991;115:952-4.[Medline]
179 Labayle D, Fischer D, Vielh P, Drouhin F, Pariente A, Bories C, et al. Sulindac causes regression of rectal polyps in familial adenomatous polyposis. Gastroenterology 1991;101:635-9.[Medline]
180 Migeod F, Gerlach D, Kress M, Hoffmann W, Farroukh R, Seeber S. Sequential treatment of progressive metastatic colorectal cancer with 5-fluorouracil/folinic acid, dipyridamole and mitomycin C. Onkologie 1988;11 Suppl 2:14-20.[Medline]
181 Hansen R, Schuetz M, Vukelich M, Mueller P, Steger M, Zimmer F, et al. A phase II study of 5-fluorouracil (5-FU) infusion, interferon alpha, and dipyridamole in advanced colorectal cancer. Proc ASCO 1991;10:154.
182 Zaniboni A, Marpicati P, Simoncini E, Montini E, Meriggi F, Arcangeli G, et al. Fluorouracil, high-dose folinic acid, low dose alpha-2b interferon and dipyridamole in the treatment of advanced colorectal cancer. A pilot study.J Chemother 1991;3:180-2.[Medline]
183 Monden T, Morimoto H, Shimano T, Yagyu T, Murotani M, Nagaoka H, et al. Use of fibrinogen to enhance the antitumor effect of OK-432. A new approach to immunotherapy for colorectal carcinoma. Cancer 1992;69:636-42.[Medline]
184 Zacharski LR, Henderson WG, Rickles FR, Forman WB, Cornell CJ Jr, Forcier RJ, et al. Effect of warfarin anticoagulation on survival in carcinoma of the lung, colon, head and neck, and prostate. Final report of VA Cooperative Study 75. Cancer 1984;53:2046-52.[Medline]
185 Chahinian AP, Propert KJ, Ware JH, Zimmer B, Perry MC, Hirsh V, et al. A randomized trial of anticoagulation with warfarin and of alternating chemotherapy in extensive small-cell lung cancer by the Cancer and Leukemia Group B. J Clin Oncol 1989;7:993-1002.[Abstract]
186 Lebeau B, Chastang CL, Brechot JM. Subcutaneous heparin treatment increases complete response rate and overall survival in small cell lung cancer. Lung Cancer 1991;7 (Suppl):129-34.
187 Calvo FA, Hidalgo OF, Gonzalez F, Rebollo J, Martin-Algarra S, Ortiz de Urbina D, et al. Urokinase combination chemotherapy in small cell lung cancer. A phase II study.Cancer 1992;70:2624-30.[Medline]
188 Vallejo CT, Rabinovich MG, Perez JE, Sanchez G, Sorrelli F, Rodriguez C, et al. High-dose cisplatin with dipyridamole in advanced non-small cell lung cancer. A Grupo Oncologico Cooperativo del Sur study.Am J Clin Oncol Cancer Clin Trial 1995;18:185-8.
189
Zacharski L, Moritz TE, Baczek LA, Rickles FR, Edwards RL,
Forman WB, et al. Effect of mopidamole on survival in carcinoma of the lung and colon: final
report of VA Cooperative Study No. 188. J Natl Cancer Inst 1988;80:90-7.
190 Schneider B, Geser C, Feurer W. Effect on anticoagulation treatment with RA-233 (mopidamole) on survival in bronchial cancer. Thromb Haemostas 1987;58:508-12.
191 Rickles FR, Hancock WW, Edwards RL, Zacharski LR. Antimetastatic agents. I. Role of cellular procoagulants in the pathogenesis of fibrin deposition in cancer and the use of anticoagulants and/or antiplatelet drugs in cancer treatment. Semin Thromb Hemostas 1988;14:88-94.
192 Zacharski L, Memoli VA, Costantini V, Wojtukiewicz MZ, Ornstein DL. Clotting factors in tumour tissue: implications for cancer therapy. Blood Coagul Fibrinolysis 1990;1:71-8.[Medline]
193 Zacharski LR, Wojtukiewicz MZ, Costantini V, Ornstein DL, Memoli VA. Pathways of coagulation/fibrinolysis activation in malignancy. Semin Thromb Hemost 1992;18:104-16.[Medline]
194 Aisner J, Goutsou M, Maurer LH, Cooper R, Chahinian P, Carey R, et al. Intensive combination chemotherapy, concurrent chest irradiation, and warfarin for the treatment of limited-disease small cell lung cancer: a Cancer and Leukemia Group B pilot study. J Clin Oncol 1992;10:1230-6.[Abstract]
195 Serdengecti S, Buyuskunal E, Molinas N, Demirelli FH, Berkarda N, Eyuboglu H, et al. Overall survival results of non-small cell lung cancer patients: chemotherapy alone versus chemotherapy with combined immunomodulation. Chemotherapia 1988;7:122-6.
196 Warren BA. Origin and fate of blood-borne tumor emboli. Cancer Biol Rev 1981;2:95-169.
197 Schneider MR, Schirner M, Lichtner RB, Graf H. Antimetastatic action of the prostacyclin analogue cicaprost in experimental mammary tumors. Breast Cancer Res Treat 1996;38:133-41.[Medline]
198 Willson JK, Fischer PH, Remick SC, Tutsch KD, Grem JL, Nieting LM, et al. Methotrexate and dipyridamole combination chemotherapy based upon inhibition of nucleoside salvage in humans. Cancer Res 1989;49:1866-70.[Abstract]
199 Buzaid AC, Alberts DS, Einspha J, Penn TE, Hickox DE, Asbury RF, et al. Effect of dipyridamole on fluorodeoxyuridine cytotoxicity in vitro and in cancer patients. Cancer Chemother Pharmacol 1989;25:124-30.[Medline]
200 Desai PB, Duan J, Sridhar R, Damle BD. Reversal of doxorubicin resistance in multidrug resistant melanoma cells in vitro and in vivo by dipyridamole. Methods Find Exp Clin Pharmacol 1997;19:231-9.[Medline]
201 Rajan R, Gafni A, Levine M, Hirsh J, Gent M. Very low-dose warfarin prophylaxis to prevent thromboembolism in woman with metastatic breast cancer receiving chemotherapy: an economic evaluation. J Clin Oncol 1995;13:42-6.[Abstract]
202 Costantini V, Zacharski LR, Memoli VA, Kudryk BJ, Rousseau SM, Stump DC. Occurrence of components of fibrinolysis pathways in situ in neoplastic and nonneoplastic human breast tissue. Cancer Res 1991;51:354-8.[Abstract]
203 Zacharski LR, Barnathan ES, Memoli VA, Werling RW. Comparison of four antibodies for immunohistochemical detection of urokinase receptor (U-PAR) in tissue. Thromb Heamostas 1993;69:1234-9.
204 Zacharski LR, Memoli VA, Ornstein DL, Rousseau SM, Kisiel W, Kudryk BJ. Tumor cell procoagulant and urokinase expression in carcinoma of the ovary. J Natl Cancer Inst 1993;85:1225-30.[Abstract]
205 Torngren S, Rieger A. The influence of heparin and curable resection on the survival of colorectal cancer. Acta Chir Scand 1983;149:427-9.[Medline]
206 Lipton A, Scialla S, Harvey H, Dixon R, Gordon R, Hamilton R, et al. Adjuvant antiplatelet therapy with aspirin in colo-rectal cancer. J Med 1982;13:419-29.[Medline]
207 Lipton A, Harvey H, Dixon R. Adjuvant antiplatelets trials in small-cell lung and colorectal cancer [abstract 41]. In: Proceedings of the 4th European Conference on Clinical Oncology, vol 4; 1987.
208 Wereldsma JC, Bruggink ED, Meijer WS, Roukema JA, van Putten WL. Adjuvant portal liver infusion in colorectal cancer with 5-fluorouracil/heparin versus urokinase versus control. Results of a prospective randomized clinical trial (colorectal adenocarcinoma trial I).Cancer 1990;65:425-32.[Medline]
209 Kohne-Wompner CH, Wilke H, Weiss H, Hiddemann W, Schuller J, Lohrmann HP, et al. 5-FU, folinic acid (FA) ± dipyridamole (D) in advanced and progressive colorectal cancer (CC)a randomised multicenter phase II trial. Proc ASCO 1990;10:123.
210 Tsavaris N, Zinelis A, Karvounis N, Beldecos D, Mylonacis N, Zamanis N, et al. Multimodal biochemical modulation of 5-fluorouracil activity in advanced colorectal cancer with allopurinol, folinic acid and dipyridamol. J Chemother 1990;2:123-6.[Medline]
211 Daly L. The first international urokinase/warfarin trial in colorectal cancer. Clin Exp Metastasis 1991;9:3-11.[Medline]
212 Isacoff WH, Jocobs AD, Tylor O. Continuous infusion (CI) fluorouracil (5-FU) combined with calcium leucovorin (LV), mitomycin C (MMC), and dipyridamole (D) in advanced colorectal carcinoma. Proc ASCO 1991;10:154.
213 Fountzilas G, Zisiadis A, Kosmidis P, Basdanis G, Makrantonakis P, Paspatis A, et al. High-dose leucovorin, fluorouracil and oral dipyridamole in the treatment of advanced colorectal cancer. Anticancer Res 1991;10:865-8.
214 Mitsugi K, Yasutake T, Etoh T, Ishimaru T, Ueda A, Nakano S, et al. Successful treatment of recurrent multiple lung metastasis from colon cancer with combination chemotherapy using methotrexate, 5-fluorouracil, and high-dose leucovorin: a case report. Gan To Kagaku Ryoho 1993;20:2387-90.[Medline]
215 Sharfman WH, Urban WJ, Smith JW, Salsbury F, Harper R, Wiebe C, et al. Phase I/II trial of 5-fluorouracil, leucovorin, zidovudine and dipyridamole for patients with metastatic colorectal cancer, renal cell carcinoma and malignant melanoma. Int J Oncol 1995;6:579-83.
216 Chahinian AP, Ware JH, Zimmer B, Perry M, North WG, Maurer LH, et al. Update on anticoagulation with warfarin and an alternating chemotherapy in extensive small cell lung cancer. Proc ASCO 1985;4:191.
217 Lebeau B, Chastang C, "Petites Cellules" Group. First interim analysis of a randomised clinical trial of aspirin like a platelet aggregation inhibitor in small cell lung cancer (320 patient). Bull Eur Physiopat Resp 1986; 22(Suppl 8):1595.
218 Lipton A, Harvey H, Walker BR, Gordon R, Ueda W. Chemotherapy plus RA-233 in the treatment of oat-cell lung cancer. Am J Clin Oncol Cancer Clin Trials 1989;12:259-63.
219 Lebeau B, Chastang C, Brechot JM, Capron F, Dautzenberg B, Delaisements C, et al. Subcutaneous heparin treatment increases survival in small cell lung cancer. "Petites Cellules" Group.Cancer 1994;74:38-45.[Medline]
220 Maurer LH, Herndon JE 2nd, Hollis DR, Aisner J, Carey RW, Skarin AT, et al. Randomized trial of chemotherapy and radiation therapy with or without warfarin for limited-stage small-cell lung cancer: a Cancer and Leukemia Group B study. J Clin Oncol 1997;15:3378-87.[Abstract]
221 Murphy B, Rynard S, Pennington K, Grosh W, Loehrer PJ. A phase II trial of vinblastine plus dipyridamole in advanced renal cell carcinoma. A Hoosier Oncology Group study. Proc ASCO 1991;10:176.
222 Creagan ET, Twito DI, Johansson SL, Schaid DJ, Johnson PS, Flaum MA, et al. A randomized prospective assessment of recombinant leukocytes: a human interferon with or without aspirin in advanced renal adenocarcinoma. J Clin Oncol 1991;12:2104-9.
223 Thornes RD, Daly L, Lynch G, Breslin B, Browne H, Browne HY, et al. Treatment with coumarin to prevent or delay recurrence of malignant melanoma. J Cancer Res Clin Oncol 1994;120 Suppl:S32-4.[Medline]
224 Sakaguchi Y, Maehara Y, Emi Y, Kusumoto T, Kohnoe S, Sugimachi K. Dipyridamole combination chemotherapy can be used safely in treating gastric cancer patients. Anticancer Drugs 1991;2:139-43.[Medline]
225 Kobayaski T, Sasaki T, Ibuka T, Imai K, Monma K, Sakaki N, et al. Sequential MTX and 5-FU therapy of gastric cancer with systemic bone metastasis and disseminated intravascular coagulation. Gan To Kagaku Ryoho 1992;11:69-74.
226 Astedt B. Adjuvant treatment of ovarian carcinoma with tranexamic acid. J Clin Pathol Suppl 1980;14:74-6.
227 Kikuchi Y, Kizawa I, Oomori K, Momose E, Ishida M, Sunaga H, et al. Adjuvant effects of tranexamic acid to chemotherapy in ovarian cancer patients with large amounts of ascites. Acta Obstet Gynecol Scand 1986;65:453-6.[Medline]
228 Nieminen U, Kauppila A, Gronroos M, Kuoppala T, Vayrynen M. Placebo-controlled study on the efficacy of the pyrimido-pyrimidine derivative RA 233 in ovarian cancer. Gynecol Oncol 1990;8:226-31.
229 Daniel F, Rao DG, Tyrrell CJ. A pilot study of stanozolol for advanced breast carcinoma. Cancer 1991;67:2966-8.[Medline]
230 Powles TJ, Dady PJ, Williams J, Easty GC, Coombes RC. Use of inhibitors of prostaglandin synthesis in patients with breast cancer. Adv Prostaglandin Thromboxane Res 1980;6:511-6.[Medline]
231 Weppelmann B, Monkemeier D. The influence of prostaglandin antagonists on radiation therapy of carcinoma of the cervix. Gynecol Oncol 1984;17:196-9.[Medline]
232 Waddell WR, Kirsch WM. Testolactone, sulindac, warfarin, and vitamin K1 for unresectable desmoid tumors. Am J Surg 1991;10:416-21.
233 Willson JK, Fischer PH, Tutsch K, Alberti D, Simon K, Hamilton RD, et al. Phase I clinical trial of a combination of dipyridamole and acivicin based upon inhibition of nucleoside salvage. Cancer Res 1988;48:5585-90.[Abstract]
234 Higano CS, Livingston RB. Oral dipyridamole and methotrexate in human solid tumors: a toxicity trial. Cancer Chemother Pharmacol 1989;23:259-62.[Medline]
235 Budd GT, Jayaraj A, Grabowski D, Adelstin D, Bauer L, Boyett J, et al. Phase I trial of dipyridamole with 5-fluorouracil and folinic acid. Cancer Res 1990;50:7206-11.[Abstract]
236 Israel L, Breau J, Morere J. Anticancer effects of oral and intratumoral prostaglandin inhibitors. In: Honn K, Marnett S, Nigam S, Walden TJ, editors. Eicosanoids and other bioactive lipids in cancer and radiation injury. Boston (MA): Klewer; 1991. p. 487-8.
Manuscript received April 1, 1998; revised June 12, 1998; accepted November 4, 1998.
This article has been cited by other articles in HighWire Press-hosted journals:
![]() |
||||
|
Oxford University Press Privacy Policy and Legal Statement |