ACTIVITY OF TEMOZOLOMIDE AGAINST HUMAN TUMOR COLONY-FORMING-UNITS

-3-methylimidazo(5,1-6)-1,2,3,5-tetrazin-4(3H)-one (temozolomide) is a new imidazole tetrazinone compound with promising preclinical and cli nical activity in nitrosourea-sensitive and -resistant models and mana geable toxicity in Phase I and II clinical trials. In this study, we i nvestigated the antiproliferative activity of temozolomide against a l arge variety of human tumors taken directly from patients in an in vit ro soft agar tumor cloning system. Temozolomide was studied using a co ntinuous exposure at final concentrations from 0.1 to 10.0 mu M agains t a total of 222 tumor specimens, of which 101 (45%) were evaluable. A decrease in tumor colony formation was considered significant if surv ival of colonies treated with temozolomide was less than or equal to 5 0% of that in controls. III 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 mu M, respectively (P < 0.001). The level of O-6 -guanine-alkyl-transferase was evaluable in 19 specimens before treatm ent but did not correlate with a response to temozolomide. At a concen tration of 10 mu M, 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 (32%; 95% C I, 15-72), melanomas (33%; 95% CI, 13-59), and some other tumors, incl uding sarcomas and both prostatic and pancreatic carcinomas that are u sually considered very resistant to several conventional chemotherapy agents. Moreover, we observed that a subset of tumors that were not se nsitive to dacarbazine, carmustine, cisplatin, doxorubicin, 5-fluorour acil, etoposide, and vinblastine were sensitive to temozolomide. These data indicate both that temozolomide is an active drug in vitro again st a large variety of human tumors, including some tumors usually resi stant to conventional chemotherapy, and that further clinical evaluati on is warranted.