CORRESPONDENCE

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

Oreste Gallo

Correspondence to: Oreste Gallo, M.D., Institute of Otolaryngology, Head and Neck Surgery, Viale Morgagni 85, 50134 Florence, Italy (e-mail: o.gallo{at}dfc.unifi.it).

Milas and co-workers (1) reported in a recent issue of the Journal a potential adjuvant effect of selective cyclooxygenase-2 (COX-2) inhibition on tumor response to radiotherapy in an animal model. These authors postulated that the COX-2 inhibitor 4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-l-yl)] benzenesulfonamide (SC-'236) is able to enhance response of the mouse sarcoma NFSA to local {gamma}-radiation mainly because of an antiangiogenic activity. These findings extend the recently published results by Gorski et al. (2), who first reported the possible increase of tumor response to ionizing radiation by blocking the potent tumor-released angiogenic factor, vascular endothelial growth factor (VEGF). These authors demonstrated that ionizing radiation is able to induce VEGF production in several human tumor cell lines and that the treatment of tumor-bearing mice with a neutralizing antibody to VEGF-165 before irradiation is associated with a greater than additive antitumor effect showed by the single treatment per se.

We have recently reported a possible regulation of VEGF-165 messenger RNA (mRNA) and protein expression in two human epidermoid carcinoma cell lines (A-431 and SCC-9) by a COX-2 pathway as well as a statistically significant association between COX-2 pathway up-regulation (increase in COX-2 mRNA and protein expression, and prostaglandin E2 biosynthesis) and angiogenesis in human head and neck cancers. Moreover, we demonstrated that COX-2 inhibition, by nonselective and more selective drugs, i.e., indomethacin and nimesulide, respectively, are able to reduce the synthesis of VEGF165 in A-431 and SCC-9 cell lines in vitro(3). An analogous role of COX-2 metabolites in controlling tumor angiogenesis in colon cancer cell lines has been also reported (4). Based on these findings, it is likely that the antiangiogenic effect of SC-'236, potentially responsible for the enhancement of tumor response to ionizing radiation (1), was mainly due to a reduced VEGF production by tumor cells. More recently, Jones et al. (5) also suggested an inhibition of angiogenesis by anti-COX-2 drugs through direct effects on endothelial cells.

Taken together, these results further support the hypothesis that different antiangiogenic therapies are able to increase the antitumor effects of ionizing radiation (6); however, the exact mechanism(s) responsible for this effect remains to be elucidated. Gorski et al. (2) have postulated a model in which irradiation is able to induce a stress response in irradiated cells characterized by VEGF production. The stress-related VEGF release might protect tumor blood vessels from radiation-mediated cytotoxicity and, thus, contribute to tumor resistance. The pretreatment with selective COX-2 inhibitors or with a neutralizing antibody to VEGF might counteract the biologic effects of radiation-induced VEGF release with lack of protection of tumor blood vessels resulting in a decreased tumor vascularization and increased tumor radiosensitivity.

Furthermore, the recently reported proapoptotic effect of COX-2 inhibition in human tumor xenografts suggests alternative mechanism(s) (7) by which COX-2 inhibitors might improve the efficacy of tumor response to radiotherapy in vivo, currently under investigation in our laboratory. It is possible to postulate that COX-2 inhibitors increased sensitivity to radiation because of a direct proapoptotic effect on tumor cells or, alternatively, because of an indirect proapoptotic effect on tumor cells stressed by an alteration of tumor blood supply.

REFERENCES

1 Milas L, Kishi K, Hunter N, Mason K, Masferrer JL, Tolifon 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, 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]

3 Gallo O, Magnelli L, Sardi I, Franchi A, Boddi V, Chiarugi V, et al. Regulation of cyclooxygenase-2 pathway in human carcinoma cells by nitric oxide. Possible effects on VEGF-induced tumor angiogenesis. J Cancer Res Clin Oncol1999 ;125(Suppl 2):S121.

4 Tsujii M, Kawano S, Tsuji S, Sawaoka H, Hori M, Du Bois RN. Cyclooxygenase regulates angiogenesis induced by colon cancer cells. Cell 1998;93:705-16.[Medline]

5 Jones MK, Wang H, Peskar BM, Levin E, Itani RM, Sarfeh IJ, et al. Inhibition of angiogenesis by nonsteroidal anti-inflammatory drugs: insight into mechanisms and implications for cancer growth and ulcer healing. Nat Med 1999;5:1418-23.[Medline]

6 Mauceri HJ, Hanna NN, Beckett MA, Gorski DH, Staba MJ, Stellato KA, et al. Combined effects of angiostatin and ionizing radiation in antitumour therapy. Nature 1998;394:287-91.[Medline]

7 Sawaoka H, Kawano S, Tsuji S, Tsuji M, Gunawan ES, Takei Y, et al. Cyclooxygenase-2 inhibitors suppress the growth of gastric cancer xenografts via induction of apoptosis in nude mice. Am J Physiol 1998;274(6 Pt 1):G1061-7.[Abstract/Free Full Text]



             
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