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Antitumor Properties of (2R,5R)-6-Heptyne-2,5-diamine, a New Potent Enzyme-activated Irreversible Inhibitor of Ornithine Decarboxylase, in Rodents

Merrell-Dow Research Institute, Strasbourg Centre 16, rue d'Ankara, 67084 Strasbourg-Cedex, France

(2R,5R)-6-Heptyne-2,5-diamine hydrochloride (MDL 72175) is a new, potent, and selective inhibitor of mammalian ornithine decarboxylase. MDL 72175 given p.o. in drinking fluid reduced by 80% the growth of EMT6 sarcoma in mice and of HTC hepatoma in rats. It prolonged the survival of mice bearing L1210 or P388 leukemias and inhibited the development of Lewis lung carcinoma in mice at doses 10- to 20-fold lower than those of -difluoromethylomithine, the most widely used irreversible inhibitor of ornithine decarboxylase. MDL 72175 depleted putrescine and spermidine levels in the tumors to the same extent as did -difluoromethylomithine. In the EMT6 sarcoma, MDL 72175 achieved at low doses a greater maximal antitumor effect than did -difluoromethylomithine.

In combination therapy, MDL 72175 plus Adriamycin gave at least additive antitumor effects on solid tumors and experimental leukemias in animals. The combination MDL 72175 plus methylglyoxal bis(guanylhydrazone) also gave additive antitumor effects on P388 leukemia, associated with an increased uptake of methylglyoxal bis(guanylhydrazone); in contrast, antagonistic effects were observed with this combination on EMT6 tumors in mice.

Since MDL 72175 did not present toxicity at effective antitumor doses, this new omithine decarboxylase inhibitor can be considered as a promising antitumor drug.

¹ To whom requests for reprints should be addressed.

Received 5/ 9/84. Accepted 7/30/84.