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Effects of N-(Phosphonacetyl)-L-aspartate on Murine Tumors and Normal Tissues in Vivo and in Vitro and the Relationship of Sensitivity to Rate of Proliferation and Level of Aspartate Transcarbamylase¹

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

The growth of three murine solid tumors (Lewis lung carcinoma, B16 melanoma, and glioma 26) implanted s.c. was inhibited markedly by treatment with N-(phosphonacetyl)-L-aspartate (PALA). On the other hand, PALA had no activity against four murine leukemias. Similar relative sensitivity of these tumors toward PALA was obtained in tissue culture by measuring inhibition of cell growth. Growth of the more sensitive cells in vitro was inhibited by half at a concentration of PALA 20 times lower than that required to inhibit growth of the less sensitive cells. The more sensitive cells have about half the aspartate transcarbamylase specific activity of the less sensitive cells. There was also a correlation between doubling time in vitro and aspartate transcarbamylase levels.

With C13/SV28 hamster tumor cells in vitro, combinations of PALA with pyrazofurin or D-galactosamine, other inhibitors of pyrimidine nucleotide metabolism, were not synergistic in inhibiting growth or in reducing uridine triphosphate levels. Similarly, treatment with PALA plus either of these agents was no better than treatment with PALA alone in mice bearing B16 melanoma implanted i.p.

In contrast to cyclophosphamide PALA did not impair the ability of C57BL/6 mice to reject a tumor allograft (L1210 leukemia derived from DBA/2 mice), indicating that PALA does not inhibit substantially the cell-mediated immune response. Even at toxic dose levels, PALA spared the hematopoietic system and epithelium of the small intestine of mice, rapidly proliferating tissues that are sensitive to the toxic effects of most antineoplastic agents. Histological evaluation revealed that the toxic effects in mice treated daily with PALA were evident in the liver.

¹ Supported in part by Grant 17827 awarded by the National Cancer Institute, Department of Health, Education and Welfare.

² Present address: Arthur D. Little, Inc., Acorn Park, Cambridge, Mass. 02140.

³ To whom requests for reprints should be addressed.

Received 8/26/77. Accepted 11/11/77.