Treatment of human glioma and medulloblastoma tumor lines in athymic mice with diaziquone and diaziquone-based drug combinations.

ABSTRACT

We used diaziquone (NSC 182986) alone and in combination with other antineoplastic drugs to treat six human glioma and one human medulloblastoma tumor lines growing s.c. in athymic mice. Pharmacokinetic studies of diaziquone in the plasma of athymic mice indicated rapid clearance with a half-life of approximately 11.5 min. Diaziquone produced significant growth delays in at least one experiment using each of seven different tumor lines, and it produced consistent and significant delays in five of the seven. There was no obvious difference between a single dose and a dose administered once daily for 5 days, and tumor regressions to a volume smaller than that at treatment were uncommon in any of the single-drug experiments. Using our most extensively characterized human glioma line, D-54 MG, we found striking enhancement of the therapeutic effect by using nontoxic combinations of either diaziquone and carmustine (1,3-bis(2-chloroethyl)-1-nitrosourea, NSC 409962) or diaziquone and procarbazine (NSC 77213). These combinations produced significant increases in the median growth delay, significant increases in the number of tumor regressions, and some instances in which no palpable tumors were present 100 days after treatment. In contrast, in experiments using diaziquone -based chemotherapy combinations with either cyclophosphamide, cis-platinum, or vincristine, there was only slight enhancement of the therapeutic effect. These results, using human glioma and medulloblastoma tumor lines in athymic mice, suggest a broad range of activity of diaziquone against primary nervous system tumors and enhancement of its therapeutic effect with either 1,3-bis(2-chloroethyl)-1-nitrosourea or procarbazine. If Phase II and Phase III clinical trials corroborate these findings, the value of the nude mouse system for the evaluation of new therapeutic approaches to brain neoplasms would be further confirmed.