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Effect of 6-Azauridine on Plasma Cell Tumors of Mice: Correlation of Antitumor Effect with Inhibition of Orotic Acid Metabolism¹

Departments of Medicine and Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06516

This investigation was undertaken to correlate the antineoplastic effects of 6-azauridine (AzUR) with the activity of orotic acid metabolism and its inhibition in vitro by AzUR in a series of plasma cell tumors of mice. Although AzUR suppressed tumor growth only moderately and to widely different degrees in different tumors, its antitumor effects in vivo appeared to follow its inhibition of orotic acid metabolism in vitro. It was noted that after initial suppression of orotic acid metabolism, enzyme activity returned to pretreatment levels despite continuation of AzUR. The simultaneous administration of AzUR with urethan, which was a much more potent agent than AzUR in murine plasma cell tumors, did not augment their individual effects.

These investigations suggest that the in vitro inhibition of orotic acid metabolism by AzUR may permit the selection of tumors susceptible to AzUR therapy. The development of enzymatic adaptation to continuous AzUR therapy suggests that intermittent, combined, or alternate therapy may enhance the antineoplastic effect of AzUR.

The use of a spectrum of transplantable plasma cell tumors of mice provides an experimental model for attempts to correlate specific biochemical characteristics with the antineoplastic effects of chemotherapeutic agents.

¹ This material was presented in part at the National Meeting of the American Federation for Clinical Research, Atlantic City, New Jersey, May 3, 1964, and was supported in part by Grants C2727 and CA05944 of the USPHS, T335 of the American Cancer Society, and the Stratfield Fund.

Received 7/26/66. Accepted 11/15/66.