CORRESPONDENCE

RESPONSE: Re: Enhancement of Tumor Response to {gamma}-Radiation by an Inhibitor of Cyclooxygenase-2 Enzyme

Luka Milas, Kathryn A. Mason, Philip J. Tofilon

Affiliation of authors: Department of Experimental Radiation Oncology, The University of Texas M. D. Anderson Cancer Center, Houston.

Correspondence: Luka Milas, M.D., Ph.D., Department of Experimental Radiation Oncology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Box 066, Houston, TX 77030-4095 (e-mail: lmilas{at}mdanderson.org).

We are pleased to see that Dr. Gallo provided additional experimental data that indirectly support the hypothesis we advanced recently (1), that inhibition of tumor angiogenesis might be involved in the dramatic enhancement of tumor radioresponse when tumor-bearing mice were treated with SC-'236, a selective inhibitor of cyclooxygenase-2 (COX-2). Our hypothesis was based on the observation that SC-'236 inhibited formation of new vessels induced by tumor cells (1) and on recent findings by other investigators (2,3) that antiangiogenic compounds, such as angiostatin and TNP-470, can produce an additive or greater than additive effect on the growth of rodent tumors or human tumor xenografts when combined with tumor irradiation. We attributed the effect of SC-'236 to its inhibition of the synthesis of prostaglandins (PGs), which possess proangiogenic activities. The findings by Gallo, presented above, show that COX-2 can stimulate tumor angiogenesis by substances other than PGs, i.e., by increasing the production of vascular endothelial growth factor (VEGF) by tumor cells. He also reports that inhibition of COX-2 resulted in the inhibition of VEGF synthesis in tumor cells. It was reported earlier that inhibition of COX-2 by the selective inhibitor celecoxib can suppress corneal angiogenesis induced by fibroblast growth factor (FGF) (4). Thus, these findings imply that the biologic role of COX-2, at least in the regulation of angiogenesis, is broader than simple mediation through PG synthesis.

Although attributing the antitumor effects of COX-2 inhibitors to the inhibition of tumor angiogenesis alone is easy to understand, its link to the enhancement of tumor radioresponse by these agents is much less clear. Solid tumors have defective microcirculation and, as a result, contain many hypoxic cells, which are considerably more radioresistant than well-oxygenated cells. In theory, inhibition of angiogenesis would result in increased tumor hypoxia and, hence, in tumor radioresistance. Yet, recent studies report enhancement of tumor radioresponse when radiation was combined with antiangiogenic agents (2,3,5). A number of possibilities may account for this. For example, severe inhibition of angiogenesis and vessel damage could lead to vascular collapse in tumors and result in massive necrosis of tumor cells, as is the case for combretastatin (6) and C225 antiepidermal growth factor receptor antibody (7). Also, some angiogenic factors, such as VEGF, FGF, and certain PGs, can act as radioprotectors and, therefore, their reduction would enhance radiation effects on both endothelial and tumor cells. These radioprotectors may influence cell radioresponse by physiologic means or may regulate intrinsic cell radiosensitivity. We recently showed (unpublished data) that SC-'236 enhanced in vitro intrinsic radiosensitivity of human glioma cells. Although this compound alone induced apoptosis, it did not enhance radioresponse by rendering tumor cells more sensitive to radiation-induced apoptosis. However, the role of apoptosis in enhancement of tumor radioresponse by COX-2-selective inhibitors requires further investigation.

In addition, other mechanisms dependent on and independent of COX-2 may be involved in the potentiation of tumor radioresponse by compounds designed to inhibit COX-2. They include immunologic mechanisms and interaction with growth factors and their signaling pathways. The biology of COX-2 and the role of this enzyme in tumor growth and tumor response to cytotoxic therapy is a rapidly evolving field in cancer research. As our understanding of the interaction between COX-2 and radiation increases, we will be better able to assess the full potential of this therapeutic strategy.

REFERENCES

1 Milas L, Kishi K, Hunter N, Mason K, Masferrer JL, Tofilon PJ. Enhancement of tumor response to {gamma}-radiation by an inhibitor of cyclooxygenase-2 enzyme. J Natl Cancer Inst 1999;91:1501-4.[Free Full Text]

2 Gorski DH, Mauceri H, Salloum RM, Gately S, Hellman S, Beckett MA, et al. Potentiation of the antitumor effect of ionizing radiation by brief concomitant exposures to angiostatin. Cancer Res 1998;58:5686-9.[Abstract]

3 Teicher BA, Holden SA, Dupuis NP, Kakeji Y, Ikebe M, Emi Y, et al. Potentiation of cytotoxic therapies by TNP-470 and minocycline in mice bearing EMT-6 mammary carcinoma. Breast Cancer Res Treat 1995;36:227-36.[Medline]

4 Masferrer JM, Leahy JM, Lei Y, Moore R, Flickinger A, Zwefel B, et al. Celecoxib: a specific cox-2 inhibitor with anti-angiogenic and anti-cancer activities [abstract]. Proc Am Assoc Cancer Research 1999;40:396.

5 Gorski DH, Beckett MA, Jaskowiak NT, Calvin DP, Mauceri HJ, Salloum RM, et al. Blockage of the vascular endothelial growth factor stress response increases the antitumor effects of ionizing radiation. Cancer Res 1999;59:3374-8.[Abstract/Free Full Text]

6 Li L, Rojiani A, Siemann DW. Targeting the tumor vasculature with combretastatin A-4 disodium phosphate: effects on radiation therapy. Int J Radiat Oncol Biol Phys 1998;42:899-903.[Medline]

7 Milas L, Mason K, Hunter N, Petersen S, Ang K, Mendelsohn J, et al. In vivo enhancement of tumor radioresponse by C225 anti-epidermal growth factor receptor antibody. Clin Cancer Res 2000. In press.



             
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