Combined effects of streptozotocin and mitozolomide against four human cell lines of the Mer+ phenotype.
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 Met+ 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.
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology* / Q000627:therapeutic use; D002460:Cell Line; D004260:DNA Repair / Q000187:drug effects; D006801:Humans; D008780:Methyltransferases / Q000032:analysis*; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology*; D009588:Nitrogen Mustard Compounds / Q000008:administration & dosage*; D019853:O(6)-Methylguanine-DNA Methyltransferase; D010641:Phenotype; D013311:Streptozocin / Q000008:administration & dosage*; D014410:Tumor Stem Cell Assay
D009588:Nitrogen Mustard Compounds; D013311:Streptozocin; C040369:mitozolomide; D008780:Methyltransferases; D019853:O(6)-Methylguanine-DNA Methyltransferase