Response of transplantable tumors of mice to anthracenedione derivatives alone and in combination with clinically useful agents.

Other investigators have demonstrated that dihydroxyanthracenedione (DiOHA) and anthracenedione acetate (AA) are active against a broad spectrum of transplantable mouse tumors. DiOHA and AA are in clinical trial in the US; AA is in clinical trial in Europe. Because of the broad spectrum of activity of these DNA binders against murine tumors and due to their promising clinical utility, we have evaluated these agents in combination with a variety of clinically useful antitumor drugs. Studies were carried out against three colon adenocarcinomas (38, 06/A, and 11/A), three mammary adenocarcinomas (13/C, 16/C, and 14), and two lymphocytic leukemias (P388 and L1210). The therapeutic synergism of one of these combinations, DiOHA and cisplatin, has been previously reported. Four additional combinations which were found to have confirmed therapeutic synergism are reported here: DiOHA and palmO-ara-C, DiOHA or AA and 5-FU, DiOHA or AA and vincristine, and DiOHA and decarbazine. The combination toxicity indices (CTI; a measure of the degree of overlap in dose-limiting toxic effects) were obtained for all the following combinations: DiOHA and palmO-ara-C = 1.25-1.6; DiOHA or AA and 5-FU = 1.2-1.3; DiOHA or AA and vincristine = 1.6; and DiOHA and dacarbazine = 1.3-1.5. A CTI of 1.0 indicates complete overlap in dose-limiting toxic effects, eg, only 50% of the maximum tolerated dose of each agent can be used in combination. On the other hand, a CTI of 2.0 indicates no overlap in toxicity, and 100% of the maximum tolerated dose of each agent can be used in combination.