Inhibition of Ascites Tumour Growth by the Trypanocide, Ethidium Bromide, in Combination with Azaserine

Abstract

ETHIDIUM bromide (3,8-diamino-5-ethyl-6-phenyl-phenanthridinium bromide) has been used to treat trypanosome infections of cattle in Africa for some time^1,2. (This chemical was kindly supplied by Dr. M. R. Gurd, Boots Pure Drug Co., Ltd., Nottingham. Its alternative name is 2,7-diamino-9-phenyl-10-ethyl-phenanthridinium bromide.) Recently we have examined the biochemical effects of this compound on Ehrlich ascites tumour cells, and have found that it inhibits completely the incorporation of preformed purines (adenine, guanine and hypoxanthine) into nucleic acids³. The possible application of this biochemical effect to cancer chemotherapy was immediately considered. It was believed, however, that ethidium bromide, if used alone, would at best be only moderately carcinostatic because it does not appreciably impair the de novo pathway of purine biosynthesis³. Because the antibiotic azaserine is well known to inhibit completely the de novo synthesis of purines, it was therefore believed that if these two compounds could be used in combination without undue host toxicity, the conditions for a complete concurrent blockade⁴ of the purine nucleotide supply for nucleic acid synthesis could be effected. Because both drugs maintain their inhibitory effects for less than 24 hr.^3,5, for more nearly maximal effect it was felt that both should be administered more often than in the daily treatment schedule usually used in tests of carcinostatic efficacy.