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Combination Chemotherapy of Cancer: Potentiation of Carcinostatic Action of 8-Azaguanine by a Riboflavin Analog^*

L. S. Dietrich and Daniel M. Shapiro

( Departments of Biochemistry and Surgery, College of Physicians and Surgeons, Columbia University, New York, N.Y.)

The ability of flavotin to enhance the carcino static action of 8-azaguanine on the 755 tumor grown in C57 female mice was found to be dependent on a temporal relationship. Positive results were obtained only if the 8-azaguanine was injected 1 hour after the administration of flavotin. Simultaneous treatment or the administration of 8-azaguanine prior to flavotin was ineffective.

The in vitro addition of flavotin had no effect on the activity of guanase or xanthine oxidase in mouse liver.

Xanthine oxidase activity was detected in the 755 tumor. The in vivo administration of flavotin was observed to antagonize the tumor xanthine oxidase activity. Under the same conditions, flavotin had no measurable effect on liver xanthine oxidase.

It was demonstrated that guanase is susceptible to product inhibition.

It was postulated that flavotin potentiates the carcinostatic action of 8-azaguanine by inhibiting tumor xanthine oxidase, thereby indirectly inhibiting guanase through product inhibition. Guanase inhibition would prevent the deamination of the carcinostatic compound, 8-azaguanine, into the noncarcinostatic compound, 8-azaxanthine, thus increasing the efficacy of 8-azaguanine as a carcinostatic agent.

^* This work was supported by the Ruth Cutting Auchincloss Memorial Gift and the Mary Madison McGuire Fund.

Dazian Foundation Fellow.

Received 4/23/53.