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Selective Inhibition of Pyrimidine Synthesis and Depletion of Nucleotide Pools by N-(Phosphonacetyl)-L-aspartate¹

Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06510

The urinary excretion of orotidine and orotate in mice treated with pyrazofurin has been used to monitor total body alterations in pyrimidine metabolism. In the 24 hr after a single dose of pyrazofurin (10 mg/kg), mice excreted 14 µmol orotic acid and 7 µmol orotidine. This measure of de novo synthesis can be reduced 78% by repeated s.c. injections of uridine. The continued excretion of orotate (3 µmol/day) despite maximally tolerated doses of N-(phosphonacetyl)-L-aspartate (PALA) (500 mg/kg) administered simultaneously with pyrazofurin indicates residual pyrimidine synthesis de novo in some tissues. Inhibition of the excretion of orotate and orotidine induced by pyrazofurin is detectable for 4 days after a single dose of PALA. High orotidine concentrations occur in mouse spleen and Lewis lung tumor 3 hr after pyrazofurin administration. PALA is much more effective in preventing this accumulation in Lewis lung tumor than in spleen.

PALA produced striking depletions of uridine triphosphate and cytidine triphosphate in cultured L1210 and Lewis lung cells, but adenosine triphosphate and guanosine triphosphate pools increased. PALA reduced pyrimidine pools at much lower concentrations in cultured Lewis lung cells than in L1210 cells. In mice, PALA (500 mg/kg) reduced only slightly (<20%) the total uracil and cytosine nucleotides in spleen, lung, or liver as measured by high-pressure liquid chromatography. In Lewis lung tumor, however, PALA caused marked reductions in total uracil and cytosine nucleotides even at much lower doses of PALA (12.5 mg/kg). The antitumor activity of PALA at doses which allow host pyrimidine synthesis to continue may account for its success in treating Lewis lung carcinoma.

¹ Supported by USPHS Grant CA16359 and American Cancer Society Grant CH675.

² To whom requests for reprints should be addressed.

Received 2/ 6/79. Accepted 4/26/79.

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