Drug Safety Evaluation, Bristol-Myers Squibb Pharmaceutical Research Institute, Syracuse, New York
Received June 27, 2000; accepted October 30, 2000
![]() |
ABSTRACT |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Key Words: retinoic acid receptor antagonist; testicular toxicity; rats; rabbits; toxicity; retinoids; Vitamin A; oral; in vivo; safety assessment.
![]() |
INTRODUCTION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Synthetic vitamin A analogs are used successfully in the treatment of skin diseases such as acne, psoriasis, and other keratinizing dermatoses (Orfanos et al., 1987, 1997
). They are also being investigated for potential activity as anticancer agents and in cancer chemoprevention (Armstrong et al., 1992
; Matsushimi et al., 1992
; Meister et al., 1998
). Therapeutic use of these compounds is limited by a number of side effects, including mucocutaneous toxicity (cheilitis, xerosis, epistaxis, pruritus, desquamation, erythema, and scaling), headache, hypertriglyceridemia, teratogenicity, and bone toxicity (Armstrong et al., 1992
; Kamm, 1982
; Kovacs and Shear, 1993
). Retinoid toxicities are mediated through activation of the RARs (Standeven et al., 1996a
,b
,c
; Thatcher et al., 1997
), and may be blocked or retarded by the actions of RAR antagonists (Kochhar et al., 1998
; Standeven et al., 1996a
,b
,c
). A number of retinoid antagonists have been synthesized (Apfel et al., 1992
; Eyrolles et al., 1994
) with varying degrees of receptor subtype specificity. Retinoid-receptor antagonists have proven to be useful mechanistic tools for delineating the contribution of retinoid receptor subtypes in mediating the biological activity of retinoids (Yang et al., 1999
). These antagonists have been shown to block various retinoid-induced toxicities including hyperlipidemia, teratogenicity, and bone toxicity, and have shown preclinical utility as a treatment for retinoid intoxication (Apfel et al., 1992
; Eckhardt and Schmitt, 1994
; Standeven et al., 1996 Standeven et al., 1997).
BMS-189453 is a synthetic RAR antagonist having good (8298%) oral bioavailability in rats and monkeys. BMS-189453 binds but does not activate the , ß, and
retinoid receptors (Gehin et al., 1999
). BMS-189453 is chemically classified as an "arotinoid" (Loeliger et al., 1980
). The chemical structure of BMS-189453 is shown in Figure 1
.
|
![]() |
MATERIALS AND METHODS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Animals.
Sprague-Dawley rats (males 8 or 11 weeks of age, 206290 g; females 8 weeks of age, 154187 g) were received from Harlan Sprague Dawley, Frederick, MD and individually housed in stainless-steel cages with Purina® Certified Rodent Chow (#5002) and water available ad libitum. In the animal room, a 12-h light/dark cycle (lights on at 0600 h), a temperature range of 73 ± 5° F, and a relative humidity range of 45 ± 15% were maintained. After a 2-week acclimation period, rats were randomly assigned to groups, via a computer-generated random list, and identified by tail tattoos.
Male New Zealand White rabbits (approximately 1 year of age, 24 kg) were received from Hazleton Research Products, Denver, PA and individually housed in stainless-steel cages and fed Certified Rabbit Diet (#5325, PMI Feeds, Inc., St. Louis, MO). In the animal room, a 12-h light/dark cycle (lights on at 0600), a temperature range of 67 ± 6°F, and a relative humidity range of 45 ± 15% were maintained. After a 1-month acclimation period, rabbits were randomly assigned to groups, via a computer-generated random list, and identified by ear tags. All animal use was approved by the Institutional Animal Care and Use Committee and was in accordance with the USDA guidelines for humane animal care.
Experimental designs.
For each experiment described below, BMS-189453 was administered by gavage once daily at a dose volume of 10 ml/kg. All animals were observed at least once daily for changes in condition and behavior, body weights were measured twice weekly, food consumption was measured once weekly (rats) or daily (rabbits), and physical examinations were conducted pretreatment and prior to scheduled necropsies. At the scheduled necropsies, all animals were euthanized by pentobarbital anesthesia followed by exsanguination. At necropsy, all major organs and tissues were examined for gross visible lesions, selected organs were weighed, and all major tissues were fixed and preserved in 10% formalin (Experiments 1 and 4 below) except the testes and right epididymis, which were preserved in Bouin's fixative (in all experiments). Subsequently, tissues were embedded in paraffin, sectioned at 24 µm, and stained with periodic acid Schiff (PAS) and/or hematoxylin and eosin. For Experiments 1 and 4, all tissues from the high-dose and control groups and target organs from all groups were examined microscopically, whereas for Experiments 2 and 3, the testes and epididymides from all groups were examined. For experiments where epididymal sperm counts were performed (i.e., Experiments 1 and 2 below), one epididymis (left) was separated from the testis, trimmed, weighed, and immediately frozen. The epididymal sperm counts were then determined as described by Blazak et al., 1985.
Experiment 1: One-month oral toxicity study in rats.
BMS-189453 was administered orally via gavage to male and female rats (10/sex) at 16, 60, or 240 mg/kg for 30 days. Controls received 10 ml/kg/day of aqueous 1.5% Avicel®. Blood and urine samples were collected following an overnight fast during week 4, for routine clinical pathology evaluation.2 All rats were sacrificed on day 30 and subjected to a gross necropsy. Selected organ weights and all major tissues were collected, preserved, processed, and examined microscopically as described above. Epididymal sperm counts were conduced as described above.
Doses for this study were chosen based on results from a preliminary 2-week pharmacology study in rats, in which edema of paws and swelling and redness of the ears occurred at 75 mg/kg/day. These effects were reduced when the dose was lowered to 50 mg/kg/day. Based on these results, doses of 15, 60, and 240 mg/kg were chosen for study. The high dose was expected to cause significant toxicity, the intermediate dose was expected to cause minimal toxicity, and the low dose was expected to cause little or no toxicity. In addition, the low dose of 60 mg/kg was 6-fold higher than the predicted human therapeutic dose of 10 mg/kg.
Experiment 2: One-week oral toxicity study in rats.
BMS-189453 was administered orally via gavage to male rats (10/group) at daily doses of 12.5, 25, 50, or 100 mg/kg for 7 days. Controls received 10 ml/kg of aqueous 1.5% Avicel® for 7 days. The first 5 rats/group were sacrificed on day 8, and the remaining rats on day 36, and all were subjected to gross necropsy. The testis and epididymides from all animals were weighed, preserved, processed, and examined microscopically. In addition, epididymal sperm counts were conducted as described above.
Daily doses ranging from 12.5 to 100 mg/kg were selected, based on the testicular toxicity observed in the previous 1-month oral toxicity study. A 1-week duration of dosing was chosen to determine the effect of a shorter dosing duration on the testicular toxicity observed in the previous study. In addition, a 1-month post-dose period was incorporated into the study design to assess the reversibility or progression of testicular changes.
Experiment 3: One-, three-, and seven-day oral toxicity study in rats.
BMS-189453 was administered orally via gavage to male rats (10/group) at daily doses of 2, 10, or 50 mg/kg for 1, 3, or 7 days (9 separate groups). Controls received 10 ml/kg/day of aqueous 1.5% Avicel® for 7 days. The first 5 rats/group were sacrificed on day 35, and the remaining rats were sacrificed on day 124, and all were subjected to gross necropsy. The testis and epididymides from all animals were weighed, preserved, processed, and examined microscopically.
Doses were chosen based on the results of the previous 1-week oral toxicity study. Variable 1-, 3-, or 7-day dosing schedules and lower doses of 2, 10, or 50 mg/kg were chosen to determine the effect of shorter dosing duration and lower BMS-189453 doses on the testicular toxicity observed in the previous study. In addition, necropsies were scheduled at 1 and 4 months post-dose to assess the reversibility or progression of the testicular changes.
One-week oral toxicity study in rabbits.
BMS-189453 was administered orally via gavage to male rabbits (5/group) at daily doses of 2, 10, or 50 mg/kg for 7 days. Controls received 10 ml/kg of aqueous 1.5% Avicel® for 7 days. The rabbit was chosen to assess interspecies differences in testicular toxicity following oral administration of BMS-189453. Doses of 2, 10, or 50 mg/kg were identical to those used in the previous rat study to allow comparison of equivalent doses between the species. Necropsies were conducted on the first 2 rabbits/group at the end of the 1-week dosing period (day 8) and on the remaining rabbits at 1 month post-dose (day 36) to assess progression or reversibility of testicular changes. Selected organs were weighed, all major tissues were collected, preserved, processed and examined microscopically as describe previously.
Data analysis.
Body weight, absolute and relative (to body weight) organ weights, and clinical laboratory data in treated groups were compared to those of the control group by Dunnett's test (Dunnett, 1962). Statistical analysis of the anatomic pathology data was performed by Fisher's Exact test (Dixon and Massey, 1983). We considered p values < 0.05 to be statistically significant. The term significant, when used in describing results, refers to statistically significant differences unless stated otherwise.
![]() |
RESULTS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Mean body weight and food consumption values were comparable to controls at 15 mg/kg (Fig. 2). In males at 60 mg/kg, mean body weight and food consumption values were significantly lower (12 to 15% and 11 to 29%, respectively) than controls, beginning on day 22, and remained decreased for the study duration. However, at 240 mg/kg, mean body weight and food consumption values were significantly lower (9 to 22% and 15 to 26%, respectively) than controls for the study duration. Decreases in mean body weight and food consumption values also occurred in females at 240 mg/kg, but were not statistically significant (data not shown).
|
|
|
At the day-8 necropsy, there were no significant differences in mean testicular weights or epididymal sperm counts between treatment groups (Fig. 4). Minimal decreases (12 to 22%) in mean epididymal sperm counts were evident at 25-mg/kg and higher groups, but did not reach statistical significance. However, following the 1-month drug-free observation period (day-36 necropsy), mean testicular weights and epididymal sperm counts were significantly lower (64 to 66% and 67 to 84%, respectively) than controls at all doses. Relative testicular weights were similarly affected (data not shown).
|
|
|
|
On the single-dose schedule, significant decreases (57 and 41%, respectively) in mean testicular weights occurred at the day-35 and -124 necropsies at 50 mg/kg only (Fig. 7). On the 3-day dosing schedule, significant decreases (43 and 57%) in mean testicular weights occurred at 10 and 50 mg/kg at the day-35 necropsy, and at 50 mg/kg (63% lower) at the day-124 necropsy. On the 7-day dosing schedule, significant decreases (57 to 64%) in mean testicular weight occurred at all doses at the day-35 and day-124 necropsies. Relative testicular weights were similarly affected (data not shown).
|
|
|
There were no significant differences in mean testicular weights between groups or histopathologic testicular changes at the day-8 necropsy. At the day-35 necropsy, there were no significant differences in mean testicular weights, although one rabbit at 50 mg/kg had a comparatively lower (35%) testis weight than the control animals (data not shown). At the day-35 necropsy, histopathologic testicular changes included minimal to mild necrosis and degeneration of germinal cells and atrophy of the seminiferous tubules in 2 of 3 rabbits at 50 mg/kg. Affected tubules were generally aspermatogenic. A single layer of Sertoli cells lined the most severely affected tubules. Less affected tubules contained, in addition to Sertoli cells, one or two layers of germinal cells, a variable amount of necrotic cellular debris, and occasional spermatid giant (syncytial) cells (Fig. 9). The lesion was multifocal rather than diffuse. Severity was based upon the number of tubules affected and ranged from 5 to 12% of tubules in the 2 affected rabbits. Epididymides were unaffected.
|
![]() |
DISCUSSION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Similarities between BMS-189453, vitamin A, and retinoid-agonist toxicities were evident; however, specific differences were noted. Although SMR2 and SMR6 induced leukocytosis, they were also associated with leukopoiesis in the spleen and bone marrow, which may have been due to either a direct effect and/or secondary response to subacute inflammatory skin reactions (Lindamood et al., 1987). All trans- and 13-cis-retinoic acid produced increases in alkaline phosphatase that were associated with bone toxicity, whereas administration of retinylidene dimedone (a retinoid agonist) had no effect on alkaline phosphatase, even in the presence of mild bone toxicity (Hixson and Denine, 1978
; Kurtz et al., 1984
). Although increases in leukocyte counts and serum alkaline phosphatase activity occurred with BMS-189453, no microscopic evidence of increased leukopoiesis or bone toxicity was evident. In general, BMS-189453 appeared to affect male rats to a greater extent than females. Sex-related differences in pharmacokinetic or metabolic profiles of BMS-189453 are plausible explanations for this difference; however, these endpoints were not measured in the present experiments. Retinoic acid agonists are also associated with a multiplicity of effects not seen with BMS-189453. For example, retinoid agonists are associated with decreased erythrocyte counts and hyperlipidemia (Hixson et al., 1979
; Kurtz et al, 1984
; Sani and Meeks, 1983
; Standeven et al. 1996a
). SMR2 and SMR6 were associated with lesions in the bone, thymus, lymph nodes, spleen, pituitary gland, and stomach. Oral administration of 13-cis- and all-trans-retinoic acids produced inflammation, necrosis, degeneration, and biliary hyperplasia in the livers of rats (Lindamood et al., 1987
; 1990; Sani and Meeks, 1983
). These effects did not occur with BMS-189453. Although BMS-189453-related elevations in serum ALT levels were noted in rats, no microscopic liver changes were noted.
In rats, the testis was exquisitely sensitive to the effects of BMS-189453. Testicular degeneration/atrophy with epididymal hypospermia occurred at low doses that produced no other signs of toxicity (2 mg/kg for 7 days and 10 mg/kg for 3 days). The testicular effects were progressive with time, relative to dosing, and were long lasting. The early lesion, degeneration of germinal cells, was evident following a 7-day exposure. The initial injury to germinal cells progresses, over time, to testicular atrophy. In rats, the progressive loss of all viable germ cells and the irreversibility of effect are consistent with the hypothesis that the critical insult is to stem cells. In rabbits, BMS-189453 also produced testicular toxicity after 7 daily doses of 50 mg/kg, and although the lesions were somewhat similar, they were less severe than those observed in rats. These findings seem to indicate that this testicular toxicity results from a direct effect of BMS-189453 on the testis and not secondary to a general toxicity.
Vitamin A (retinol/retinoic acid) is essential in maintaining testosterone levels and testicular function and viability (Griswold et al., 1989; Mitranond et al., 1979
; Sobhon et al., 1979
). The testis and epididymides are known to be rich in RARs, especially within Sertoli cells (Kato et al., 1985
). Vitamin A deficiency (VAD) results in decreased testicular RAR levels that precipitously increase in Sertoli cells following retinol replenishment. In addition, VAD is associated with testicular apoptosis or selective loss of germ cells in the testes of rats (Akmal et al., 1998
) and is known to affect the visual system in adult rats (Coward et al., 1969
). No observable clinical or microscopic changes in the eyes were noted with BMS189453. However, subtle, drug-related functional changes in the visual system cannot be ruled out.
Similar to BMS-189453-related testicular changes, VAD in male rats causes progressive degeneration or loss of germ cells that is characterized by seminiferous tubules containing mainly Sertoli cells, unlike BMS-189543, however, spermatogonia and a small number of spermatocytes are still present (Huang and Hembree, 1979). In addition, testicular effects of VAD in rats are rapidly reversible with supplementation of retinol or its aldehyde derivative retinyl acetate (Huang and Marshall, 1983
). Interestingly, BMS-189453, even after a single dose, appeared to induce a state of "functional VAD in the testes," presumably by antagonizing the effects of retinoic acid at its receptor. This state of functional VAD was expressed as testicular atrophy within 1 month of treatment, and was still present 4 months after treatment was terminated when animals were maintained on a vitamin A-sufficient diet. The BMS-189453-induced functional VAD in the testes does not spare spermatogonia, as is reported with dietary-induced VAD. As expected, BMS-189453-induced testicular toxicity was not specific to the rat since similar, yet less severe, changes were noted in rabbits treated at comparable doses of BMS-189453.
Oral administration of retinoid agonists to rats, mice, and dogs produces testicular changes analogous to those seen with BMS-189453; however, repeated administrations are necessary for the expression of toxicity (Kamm, 1982; Kurtz et al., 1984
; Lindamood et al., 1987
). As is the case with VAD, retinoid-induced testicular toxicity is reversible following cessation of treatment (Kamm, 1982
; Teelmann, 1981
). Testicular toxicity and marked decreases in circulating and testicular retinol levels were associated with repeated administration of Ro 232895 (a retinoid agonist) to rats (Bosakowski et al., 1991
). These findings suggest that, in rats, alterations in retinol homeostasis (e.g., functional VAD) may play a significant role in the degenerative testicular changes induced by retinoid agonists.
In conclusion, oral administration of the triple RAR antagonist BMS-189453 to rats produced a spectrum of toxicologically significant effects that, at high doses, share common properties with those observed after excessive vitamin A intake. At lower doses, BMS-189453 selectively produced progressive testicular toxicity and hypospermia, a result that shares some similar characteristics with vitamin A deficiency (VAD). Unlike VAD, however, BMS-189453-related testicular toxicity resulted in almost complete loss of spermatogonia and was not readily reversible following cessation of treatment. Lastly, the BMS-189453-induced testicular toxicity was not specific to rats, as similar lesions occurred in rabbits under identical experimental conditions of dose and duration.
|
![]() |
ACKNOWLEDGMENTS |
---|
![]() |
NOTES |
---|
1 Clinical pathology tests included hematologyerythrocyte count, hemoglobin, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, platelet count, reticulocyte count, and total and differential (absolute) leukocyte counts, prothrombin time, activated partial thromboplastin time, and fibrinogen. Serum chemistry included alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, glucose, urea nitrogen, creatinine, total protein, albumin, globulins, A/G ratio, cholesterol, triglycerides, total bilirubin, calcium, phosphorus, sodium, potassium, and chloride. Urinalysis tests included: volume, color, appearance, specific gravity, pH, microscopic examination of urinary sediment; and qualitative determination of protein, glucose, ketone, bilirubin, blood, and urobilinogen.
![]() |
REFERENCES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Apfel, C., Bauer, F., Crettax, M., Forni, L., Kamber, M., Kaufmann, F., LeMotte, P., Pirson, W., and Klaus, M. (1992). A retinoic acid receptor antagonist selectively counteracts retinoic acid effects. Proc. Natl. Acad. Sci. 89, 71297133.[Abstract]
Armstrong, R. B., Kim, H. J., Grippo, J.F., and Levin, A. A. (1992). Retinoids for the future: Investigational approaches for the identification of new compounds. J. Am. Acad. Dermatol. 27, S3842.[ISI][Medline]
Blazak, W. F., Ernst, T. L., and Stewart, B. D. (1985). Potential indicators of reproductive toxicity: Testicular sperm production and epididymal sperm number, transit time, and motility in Fisher 344 rats. Fundam. Appl. Toxicol. 5, 10971103.[ISI][Medline]
Bollag, W. (1985). New retinoids with potential use in human. In Retinoids: New Trends in Research and Therapy (J. H. Saurat, Ed.), pp. 274288. Karger, Bassel.
Bosakowski, T., Levin, A. A., and Durham, S. K. (1991). Time course of testicular degeneration in rats induced by a synthetic retinoid (RO 232895) and evidence for induction of hypovitaminosis A in the testes. Toxicology 66, 105118.[ISI][Medline]
Coward, W. A., Howell, J. M., Thompson, J. N., and Pitt, G. A. (1969). The retinol requirements of rats for spermatogenesis and vision. Br. J. Nutr. 23, 619626.[ISI][Medline]
Eckhardt, K., and Schmitt, G. (1994). A retinoic-acid receptor antagonist counteracts retinoid teratogenicity in vitro and reduced incidence and/or severity of malformations in vivo. Toxicol. Lett. 70, 299308.[ISI][Medline]
Eyrolles, L., Kegechika, H., Kawachi, E., Fukasawa, H., Iijimi,T., Matsushimi, Y., Hashimoto, Y., and Shudo, K. (1994). Retinobenzoic acids: VI. Retinoid antagonists with a heterocyclic ring. J. Med. Chem. 37, 15081517.[ISI][Medline]
Gehin, M., Vivat, V., Wurtz, J. M., Losson, R., Chambon, P., Moras, D., and Gronemeyer, H. (1999). Structural basis for engineering of retinoic acid receptor isotype-selective agonists and antagonists. Chem. Biol. 6, 519529.[ISI][Medline]
Griswold, M. D., Bishop, P. D., Kim, K. H., Ping, R., Siiteri, J. E., and Morales, C. (1989). Function of Vitamin A in normal and synchronized seminiferous tubules. Ann. NY Acad. Sci. 564, 154172.[Abstract]
Hixson, E. J., Burdeshaw, J. A., Denine, E. P., and Harrison, S. D., Jr. (1979). Comparative subchronic toxicity of all-trans- and 13-cis-retinoic acid in Sprague-Dawley rats. Toxicol. Appl. Pharmacol. 47, 359365.[ISI][Medline]
Hixson, E. J., and Denine, E. P. (1978). Comparative subacute toxicity of all trans-, and 13-cis-retinoic acid in Swiss mice. Toxicol. Appl. Pharmacol. 44, 2940.[ISI][Medline]
Huang, H. F., and Hembree, W.C. (1979). Spermatogenic response to vitamin A in vitamin A-deficient rats. Biol. Reprod. 21, 891904.[ISI][Medline]
Huang, H. F., and Marshall, G. R. (1983). Failure of spermatid release under various vitamin A statesan indication of delayed spermiation. Biol. Reprod. 28, 11631172.[Abstract]
Kamm, J. J. (1982). Toxicology, carcinogenicity, and teratogenicity of some orally administered retinoids. J. Am. Acad. Dermatol. 6, 652659.[ISI][Medline]
Kato, M., Sung, W. K., Kato, K., and Goodman, D. S. (1985). Immunohistochemical studies on the localization of cellular retinol-binding protein in rat testis and epididymis. Biol. Reprod. 32, 173189.[Abstract]
Kistler, A., Galli, B., and Howard, W. B. (1990). Comparative teratogenicity of three retinoids: The arotinoids Ro 137410, Ro 136298, and Ro 151570. Arch. Toxicol. 64, 4348.[ISI][Medline]
Kochhar, D. M., Jiang, H., Penner, J. D., Johnson, A. T., and Chandraratna, R. A. (1998). The use of a retinoid receptor antagonist in a new model to study vitamin A-dependent developmental events. Int. J. Dev. Biol. 42, 601608.[ISI][Medline]
Kovacs, J. A., and Shear, N. H. (1993). Adverse non-reproductive effects of retinoids in humans. In Retinoids in Clinical Practice: The Risk-Benefit Ratio. (G. Koren, Ed.), pp. 241260, Dekker, New York.
Kurtz, P. J., Emmerling, D. C., and Donofrio, D. J. (1984). Subchronic toxicity of all-trans-retinoic acid and retinylidene dimedone in Sprague-Dawley rats. Toxicology 30, 115124.[ISI][Medline]
Lindamood, C., III, Cope, F. O., Dillehay, D. L., Everson, M. P., Giles, H. D., Lamon, E. W., McCarthy, D. J., Sartin, J. L., and Hill, D. L. (1990). Pharmacological and toxicological properties of arotinoids SMR-2 and SMR-6 in mice. Fundam. Appl. Toxicol. 14, 1529.[ISI][Medline]
Lindamood, C., III, Giles, H. D., and Hill, D. L. (1987). Preliminary toxicity profile of arotinoids SMR-2 and SMR-6 in male B6D2F1 mice. Fundam. Appl. Toxicol. 8, 517530.[ISI][Medline]
Loeliger, P., Bollag, W., and Mayer, H. (1980). Arotinoids, a new class of highly active retinoids. Eur. J. Med. Chem-Chem. Ther. 15, 915.
Lotan, R. (1980). Effects of vitamin A and its analogs (retinoids) on normal and neoplastic cells. Biochem. Biophys. Acta 605, 3391.[ISI][Medline]
Mangelsdorf, D. J., Umesono, K., and Evans R. M. (1994). The retinoid receptors. In Retinoids: Biology, Chemistry, and Medicine (M.B. Sporn, A.B. Roberts, and D. S. Goodman, Eds.), pp. 319349. Raven Press, New York.
Matsushimi, Y., Kawachi, E., Tanaka, H., Kagechika, H., Hashimoto, Y., and Shudo, K. (1992). Differentiation-inducing activity of retinoic acid isomers and their oxidized analogs on human promyelocytic leukemia HL-60 cells. Biochem. Biophys. Res. Comm. 189, 11361142.[ISI][Medline]
Meister, B., Fink, F.-M., Hittmair, A., Marth, C., and Widschwendter, M. (1998). Antiproliferative activity and apoptosis induced by retinoic acid receptor- selectively binding retinoids in neuroblastoma. Anticancer Res. 18, 17771786.[ISI][Medline]
Mitranond, V., Sobhon, P., Tosukhowong, P., and Chindaduangrat, W. (1979). Cytological changes in testes of vitamin-A-deficient rats: I. Quantitation of germinal cells in the seminiferous tubules. Acta. Anat. 103, 159168.[ISI][Medline]
Moore, T. (1967). Effect of Vitamin A deficiency in animals: Pharmacology and toxicity of Vitamin A. In The Vitamins. (W.H. Sebrell and R. S. Harris, Eds.), Vol. 1, pp. 245266. Academic Press, New York.
Olsen, D. R., Hickok, N. J., and Uitto, J. (1990). Suppression of ornithine decarboxylase gene expression by retinoids in cultured human keratinocytes. J. Invest. Der. 94, 3336.
Orfanos, C. E., Ehlert, R., and Gollnick, H. (1987). The retinoids. A review of their clinical pharmacology and therapeutic use. Drugs 34, 459503.[ISI][Medline]
Orfanos, C. E., Zouboulis, C. C., Almond-Roesler, B., and Geilen, C. C. (1997). Current use and future potential role of retinoids in dermatology. Drugs 53, 358388.[ISI][Medline]
Sani, B. P., and Meeks, R. G. (1983). Subacute toxicity of all-trans- and 13-cis-isomers of n-ethyl retinamide, n-2-hydroxyethyl retinamide, and n-4-hydroxyphenyl retinamide. Toxicol. Appl. Pharmacol. 70, 228235.[ISI][Medline]
Sobhon, P., Mitranond, V., Tosukhowong, P., and Chindaduangrat, W. (1979). Cytological changes in the testes of vitamin-A-deficient rats: II. Ultrastructural study of the seminiferous tubules. Acta Anat. 103, 169183.[ISI][Medline]
Standeven, A. M., Beard, R. L., Johnson, A. T., Boehm, M. F., Escobar, M., Heyman, R. A., and Chandraratna, R. A. (1996a). Retinoid-induced hypertriglyceridemia in rats is mediated by retinoic acid receptors. Fundam. Appl. Toxicol. 33, 264271.[ISI][Medline]
Standeven, A. M., Davies, P. J., Chandraratna, R. A., Mader, D. R., Johnson, A. T., and Thomazy, V. A. (1996b). Retinoid-induced epiphyseal plate closure in guinea pigs. Fund. Appl. Toxicol. 34, 9198.[ISI][Medline]
Standeven, A. M., Johnson, A. T., Escobar, M., and Chandraratna, R. A. (1996c). Specific antagonist of retinoid toxicity in mice. Toxicol. Appl. Pharmacol. 138, 169175.[ISI][Medline]
Teelmann, K. (1981). Experimental toxicology of the aromatic retinoid Ro 109359 (Etretinate). In Retinoids: Advances in Basic Research and Therapy. (D. E. Orfanos, Ed.), pp. 4147.
Thatcher, S. M., Standeven, A. M., Athanikar, J., Kopper, S., Castilleja, O., Escobar, M., Beard, R. L., and Chandraratna, R. A. (1997). Receptor specificity of retinoid-induced epidermal hyperplasia: Effect of RXR-selective agonists and correlation with topical irritation. J. Pharmacol. Exp. Ther. 282, 528534.
Vincenti, M. P., Coon, C. I., Lee, O., and Brickerhoff, C. E. (1994). Regulation of collagenase gene expression by IL-1ß requires transcriptional and post-transcriptional mechanisms. Nucleic Acids Res. 22, 48184827[Abstract]
Wang, S., and Guda, L. J. (1988). Protein synthesis inhibitors prevent the induction of laminin B1, collagen IV (1), and other differentiation-specific mRNA's by retinoic acid in F9 teratocarcinoma cells. J. Cell. Phys. 136, 305311.[ISI][Medline]
Yang, L., Munoz-Medellin, D., Kim, H. T., Ostrowski, J., Reczek, P., and Brown, P. H. (1999). Retinoic acid receptor antagonist BMS453 inhibits the growth of normal and malignant breast cells without activating RAR-dependent gene expression. Breast Cancer Res. Treat. 56, 277291.[ISI][Medline]