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Collateral Sensitivity to N-(Phosphonacetyl)-L-aspartic Acid in a Line of P388 Leukemia Cells Selected for Resistance to L-(S,5S)--Amino-3-chloro-4,5-dihydro-5-isoxazoleacetic Acid (Acivicin)

Division of Medical Oncology, USC Comprehensive Cancer Center, GH 10-440, Los Angeles, California 90033 [B. A.]; Laboratory of Medicinal Chemistry and Biology, Division of Cancer Treatment, National Cancer Institute, Bethesda, Maryland 20205 [H. N. J.]; and Arthur D. Little Company, Cambridge, Massachusetts 02140 [R. K. J.]

Administration of N-(phosphonacetyl)-L-aspartic acid (PALA) is ineffective in treating mice bearing the parent P388 leukemia line; however, such treatment becomes highly effective when a cell line, P388/ACIA, derived from P388/0 was selected for resistance to another antimetabolite, acivicin. The observed phenomenon of collateral sensitivity is associated with a significantly higher inhibition of the specific activity of carbamyl phosphate synthetase II, pyrimidine nucleoside kinases, adenine phosphoribosyl transferase, and hypoxanthine phosphoribosyl transferase in the PALA-sensitive line, P388/ACIA. Twenty-four hr following administration of PALA, 200 mg/kg, the 10% lethal dose i.p. to tumor-bearing mice, the intracellular concentrations of uridine triphosphate and cytidine triphosphate were decreased in the P388/ACIA, PALA-sensitive cells, whereas no significant change in the corresponding nucleotide pool sizes was observed in P388/0, PALA-resistant line. Moreover, the purine nucleotide pool demonstrated a significant expansion of adenosine triphosphate and guanosine triphosphate only in the P388/ACIA line following a similar treatment with PALA. It is proposed that the imbalance in the generation of pyrimidine and purine nucleoside triphosphate pools may explain the observed collateral sensitivity to PALA in P388/ACIA leukemia line.

¹ To whom requests for reprints should be addressed.

Received 11/17/81. Accepted 1/ 3/83.