Activity of temozolomide against human tumor colony-forming units.
8-Carbamoyl-3-methylimidazo(5,1-d)-1,2,3,5-tetrazin-4(3H)-one (temozolomide) is a new imidazole tetrazinone compound with promising preclinical and clinical activity in nitrosourea-sensitive and -resistant models and manageable toxicity in Phase I and II clinical trials. In this study, we investigated the antiproliferative activity of temozolomide against a large variety of human tumors taken directly from patients in an in vitro soft agar tumor cloning system. Temozolomide was studied using a continuous exposure at final concentrations from 0.1 to 10.0 microM against a total of 222 tumor specimens, of which 101 (45%) were evaluable. A decrease in tumor colony formation was considered significant if survival of colonies treated with temozolomide was </=50% of that in controls. In vitro responses were seen in 9 of 101 [9%; 95% confidence interval (CI), 3-14], 16 of 100 (16%; 95% CI, 8. 5-23), and 35 of 101 (35%; 95% CI, 26-45) tumor specimens at concentrations of 0.1, 1.0, and 10.0 microM, respectively (P < 0. 001). The level of O6-guanine-alkyl-transferase was evaluable in 19 specimens before treatment but did not correlate with a response to temozolomide. At a concentration of 10 microM, a good cytotoxic activity was seen in breast (42%; 95% CI, 15-72), ovarian (36%; 95% CI, 11-69), and non-small cell lung cancers (27%; 95% CI, 6-61). Interestingly, activity was also seen in renal cell carcinomas (50%; 95% CI, 19-81), colon cancers (42%; 95% CI, 15-72), melanomas (33%; 95% CI, 13-59), and some other tumors, including sarcomas and both prostatic and pancreatic carcinomas that are usually considered very resistant to several conventional chemotherapy agents. Moreover, we observed that a subset of tumors that were not sensitive to dacarbazine, carmustine, cisplatin, doxorubicin, 5-fluorouracil, etoposide, and vinblastine were sensitive to temozolomide. These data indicate both that temozolomide is an active drug in vitro against a large variety of human tumors, including some tumors usually resistant to conventional chemotherapy, and that further clinical evaluation is warranted.
Raymond
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Translational Research Laboratory, Institute for Drug Development, Cancer Therapy and Research Center, San Antonio, Texas 78245-3217, USA. dan_von_hoff@msmtp.iddw.saci.org
Izbicka
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Soda
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Gerson
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Dugan
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Von Hoff
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D000310:Adrenal Gland Neoplasms / Q000473:pathology; D000970:Antineoplastic Agents / Q000494:pharmacology; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage / Q000494:pharmacology*; D001932:Brain Neoplasms / Q000473:pathology; D001943:Breast Neoplasms / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D004067:Digestive System Neoplasms / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D005260:Female; D019337:Hematologic Neoplasms / Q000473:pathology; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology; D009363:Neoplasm Proteins / Q000032:analysis; D014411:Neoplastic Stem Cells / Q000187:drug effects*; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000032:analysis; D000077204:Temozolomide; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014410:Tumor Stem Cell Assay; D014565:Urogenital Neoplasms / Q000473:pathology
D000970:Antineoplastic Agents; D018906:Antineoplastic Agents, Alkylating; D009363:Neoplasm Proteins; D003606:Dacarbazine; D019853:O(6)-Methylguanine-DNA Methyltransferase; D000077204:Temozolomide