RESPONSE OF TRANSPLANTABLE TUMORS OF MICE TO ANTHRACENEDIONE DERIVATIVES ALONE AND IN COMBINATION WITH CLINICALLY USEFUL AGENTS

  • 1 January 1982
    • journal article
    • research article
    • Vol. 66  (5) , 1187-1200
Abstract
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 USA; 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, these agents were evaluated in combination with a variety of clinically useful antitumor drugs. Studies were carried out against 3 colon adenocarcinomas (38, 06/A, and 11/A), 3 mammary adenocarcinomas (13/C, 16/C, and 14), and 2 lymphocytic leukemias (P388 and L1210). The therapeutic synergism of one of these combinations, DiOHA and cisplatin, was previously reported. Four additional combinations which were found to have confirmed therapeutic synergism are reported here: DiOHA and palmO-ara-C [N-(4-palmitoyl-1-.beta.-D-arabinosyl)cytosine], DiOHA or AA and 5-FU [5-fluorouracil], DiOHA or AA and vincristine, and DiOHA and dacarbazine. 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. 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.