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Sulfone Metabolite of Sulindac Inhibits Mammary Carcinogenesis¹

AMC Cancer Research Center, Lakewood, Colorado 80214 [H. J. T., C. J., J. L.]; Cell Pathways, Aurora, Colorado 80012 [G. A. P., N. S. P., R. P.]; Department of Surgical Oncology, University of Illinois, Chicago, Illinois 60612 [R. G. M.]; and Department of Veterans Affairs Medical Center, Denver, Colorado 80220 [D. J. A.]

Sulindac sulfoxide, a commonly prescribed anti-inflammatory drug, has cancer chemopreventive activity. During its metabolism, the inactive prodrug sulindac sulfoxide undergoes either reduction to the active anti-inflammatory metabolite sulindac sulfide or irreversible oxidation to sulindac sulfone, which lacks prostaglandin synthetase inhibitory activity. Interestingly, sulindac sulfone has been reported to have cancer chemopreventive activity. The objective of the experiments reported here was to investigate the chemopreventive activity of sulindac sulfone against mammary carcinogenesis and to study its mechanism. Rats were injected with either 12.5 or 37.5 mg of 1-methyl-1-nitrosourea (MNU)/kg body weight at 50 days of age. Sulindac sulfone was incorporated into a purified diet at a concentration of either 0.03 or 0.06% (w/w) and fed to rats beginning 7 days after the injection of MNU. Sulindac sulfoxide at a level of 0.06% (w/w) was fed as a reference for comparison. Thirty rats were assigned to each dietary group treated with the high dose of MNU, and 44 rats were assigned to each dietary group treated with the low dose of MNU. The sulfone reduced cancer incidence and the number of cancers per rat irrespective of the dose of MNU injected, and its chemopreventive activity was comparable to that of sulindac sulfoxide. Cancer latency was also prolonged significantly by sulindac sulfone; the effect was particularly notable at the low dose of carcinogen, at which the prolongation of latency was >8 weeks. The sulfone inhibited the occurrence of mammary carcinomas that were classified as having either a wild-type or a mutant codon 12 in the Ha-ras gene; however, the inhibitory effect was greater against carcinomas with a mutant Ha-ras genotype. Using a mammary gland organ culture transformation assay, it was observed that sulindac sulfone also inhibited the formation of 7,12-dimethylbenz(a)anthracene-induced hyperplastic alveolar nodules and that the inhibitory activity of the sulfone was comparable to that of the sulfoxide. These data indicate that the observed effect of the sulfone on mammary carcinogenesis in vivo is likely to be due to a tissue-specific effect rather than to other systemic effects. The findings that both the prodrug and the sulfone inhibited carcinogenesis in vivo and nodule formation in organ culture and that the sulfone lacks inhibitory activity on prostaglandin synthesis suggest a mechanism(s) of chemoprevention that is independent of the prostaglandin pathway. A candidate mechanism for the apparent clonal selection pressure exerted by the sulfone against mammary carcinogenesis is apoptosis. To test this hypothesis, MCF-7 cells were exposed to a range of concentrations of sulindac sulfone and sulfoxide. Both compounds inhibited cell growth and induced apoptosis in the absence of necrosis. Collectively, these data support a specific chemopreventive effect of sulindac sulfone against mammary carcinogenesis and indicate that this compound may have a selective effect against carcinogenesis involving alterations in the signal transduction cascade of which Ha-ras is a component. Evidence is consistent with the involvement of apoptosis in the cancer-inhibitory activity observed.

¹ This work was supported by Cell Pathways and Department of Veterans Affairs Merit Review Grant 131.

² To whom requests for reprints should be addressed, at Division of Laboratory Research, AMC Cancer Research Center, 1600 Pierce St., Lakewood, CO 80214. Phone: (303) 239-3464; Fax: (303) 239-3443.

Received 8/19/96. Accepted 11/15/96.

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