Flavone acetic acid (FAA) is a new antitumor agent that has recently entered Phase I clinical trials. In preclinical studies, we have found that FAA was broadly active against a variety of transplantable solid tumors of mice (colon #51, #07, #10, #26; pancreatic ductal adenocarcinomas #02 and #03; mammary adenocarcinoma #16/C/Adr; M5076 reticulum cell sarcoma and Glasgow's osteosarcoma). FAA was curative for colon adenocarcinoma #10 and pancreatic ductal adenocarcinoma #03. Thus, for the first time an agent has been identified with very broad, perhaps nearly universal solid tumor activity. FAA was also found to be orally active and stable in solution at 37 degrees C for 48 h. FAA was selectively cytotoxic in vitro for solid tumors over leukemias L1210 and P388 (in a soft-agar colony formation assay), thus correlating cellular selectivity in vitro with in vivo antitumor activity. The finding that FAA was active in vitro, established that the agent did not need metabolism (activation) outside the tumor cell. The main drawback of FAA was an unusual 'threshold' behavior in which only a narrow range of doses were active and splitting the dose markedly decreased activity.

The ability of amphotericin B (AmB) to potentiate the cytotoxicity of several different anticancer agents against two murine tumor models was examined. A spleen colony assay was used to quantitate the cytotoxicity of BCNU, CCNU, and L-PAM, either alone or in combination with AmB against the MOPC-315 plasmacytoma. A high level of potentiation of the effects of CCNU and L-PAM by AmB occurred, but AmB did not increase the cytotoxicity of BCNU. Tumor growth curves and calculation of cell survival demonstrated significant potentiation of the cytotoxicity of CCNU by AmB against SC Lewis lung carcinoma.

Dose-response curves in AKR or CD2F1 mice were obtained for AKR leukemia, L1210 leukemia, and hematopoietic stem cells following in vivo administration of one of the following anticancer agents alone or in combination with amphotericin B (AmB): doxorubicin, lomustine, or melphalan. AmB potentiated drug cytotoxicity of all agents against both leukemias. Potentiation of all three agents was greatest with the AKR leukemia demonstrating dose-modifying factor (DMF) values of 1.8, 3.0, and 2.7, respectively, for lomustine, melphalan, and doxorubicin. L1210 leukemia was somewhat less sensitive to drug potentiation by AmB with respective DMF values of 1.8, 1.8, and 1.3. AmB did not potentiate the action of any agent against hematopoietic stem cells. The increased life-span assays generally confirmed the clonogenic assays supporting the validity of the latter results. The specificity of AmB potentiation of anticancer agent cytotoxicity for tumor cells indicates that AmB may be a useful addition to antitumor drug combinations.

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