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Antitumor Activity of N-(Phosphonacetyl)-L-aspartic Acid, a Transition-State Inhibitor of Aspartate Transcarbamylase

Laboratory of Experimental Chemotherapy, National Cancer Institute, NIH, Bethesda, Maryland 20014 [R. K. J., T. I., A. G.], and Department of Biochemistry, Stanford University School of Medicine, Stanford, California 94305 [G. R. S.]

N-(Phosphonacetyl)-L-aspartate (PALA) is an analog of the transition state for the aspartate transcarbamylase reaction and has been reported previously to be a potent and specific inhibitor of de novo pyrimidine nucleotide biosynthesis. It is now shown that PALA has considerable antitumor activity against certain transplantable tumors in mice. PALA, unlike other antimetabolites, was less effective against ascitic leukemias than against two solid tumors, B16 melanoma and Lewis lung carcinoma. Another solid tumor, Ridgway osteogenic sarcoma, which is sensitive to many established chemotherapeutic agents, did not respond to PALA. Daily or intermittent treatment with PALA did not significantly increase the life-span of mice bearing i.p. leukemia L1210. The survival time of mice bearing i.p. P388 leukemia was prolonged by PALA treatment by up to 64%. In a number of experiments mice bearing i.p. B16 melanoma survived 77 to 86% longer than did controls when treated with PALA (490 mg/kg) on Days 1, 5, and 9. Lewis lung carcinoma, a tumor refractory to most established antineoplastic agents, was highly sensitive to PALA. Treatment on Days 1, 5, and 9 following s.c. implantation of Lewis lung carcinoma was curative to 50% of the mice. If treatment was delayed until s.c. Lewis lung tumors had reached about 500 mg, PALA neither cured the mice nor produced significant tumor regression. However, extensive delay of tumor growth and prolongation of survival were still observed.

¹ To whom requests for reprints should be addressed, at Bldg. 37, Room 5E-14, NIH, Bethesda, Md. 20014.

² Present address: Kanebo, Ltd., Miyakojima-ku, Osaka, Japan.

Received 3/ 8/76. Accepted 4/28/76.

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