Antitumor action of pyran copolymer and tilorone against Lewis lung carcinoma and B-16 melanoma.

Abstract

Summary Pyran (copolymer of divinyl ether and maleic anhydride) and tilorone [2,7-bis(2-diethylaminoethoxy) fluoren-9-one dihydrochloride] are host resistance-inducing agents that possess antitumor activity. The possible relationship of direct cytotoxicity to antitumor activity against the Lewis lung carcinoma and B-16 melanoma tumors was examined. Tilorone and tilorone congeners exhibited significant cytotoxicity in vitro for both tumor cells and normal cells. In general the 50% cytotoxic doses ranged from 1 to 20 µg/ml, similar to 50% cytotoxic doses observed with mechlorethamine. Despite this direct cytotoxic activity, tilorone was ineffective in vivo against the Lewis lung and B-16 melanoma tumors. In contrast, pyran showed minimal cytotoxic activity in vitro. Doses of 3,000 to 11,000 µg/ml were required for 50% cytotoxicity of tumor or normal cells. Yet pyran showed potent antitumor activity against both tumors in vivo. Even when drug therapy was delayed late in the course of disease, until 8 days after Lewis lung tumor implantation, treated mice showed a 123% increased lifespan. Similar late therapy in the B-16 melanoma disease resulted in a 162% increased life-span. These experiments support once more the ineffectiveness of tissue culture systems as in vivo predicting models for clinical antitumor activity. In addition, the effectiveness of late therapeutic administration of pyran lends promise to the usefulness of nontoxic synthetic polyanion adjuvants for surgical or radiation therapy for human neoplasia.