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Combined Effects of Streptozotocin and Mitozolomide against Four Human Cell Lines of the Mer⁺ Phenotype

Laboratory of Molecular Pharmacology, Division of Cancer Treatment, National Cancer Institute, NIH, Bethesda, Maryland 20205 [N. W. G., J. A. H.], and Laboratory of Cell Biology and Pharmacology, Section of Hematology and Oncology, Loyola University, Stritch School of Medicine, Maywood, Illinois 60153 [D. B., L. C. E.]

The majority of human tumor cell lines are proficient in the repair of guanine O⁶-alkylations (designated Mer⁺) and are thus capable of preventing the cytotoxic effects of chloroethylating agents. It has been proposed that in these cells guanine O⁶-chloroethylations are rapidly removed by the enzyme O⁶-alkylguanine DNA alkyltransferase before the formation of DNA interstrand cross-links can occur. In this study pretreatment of four Mer⁺ human cells (A2182 lung carcinoma, A375 melanoma, HT-29 colon carcinoma, and IMR-90 normal lung fibroblasts) with the DNA methylating agent streptozotocin apparently saturates the monoadduct repair system and allows mitozolomide to form interstrand cross-links in these cells. The inhibition of the alkyltransferase results in the continued presence of guanine O⁶-chloroethylations which then undergo a series of reactions that lead to DNA interstrand cross-link formation. As observed by colony forming assays, streptozotocin pretreatment causes a dramatic increase in the sensitivity of these four Mer⁺ cell lines to the cytotoxic effects of mitozolomide. These results indicate that a combination of streptozotocin pretreatment followed by mitozolomide may be useful in the treatment of human cancer.

¹ Present address: Department of Pharmacology, Fox Chase Cancer Center, Central and Shelmire Avenues, Philadelphia, PA 19111. To whom requests for reprints should be addressed.

Received 2/19/86. Revised 6/19/86. Accepted 6/27/86.

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