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

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Abstract

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 a 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.

Original languageEnglish (US)
Pages (from-to)1598-1601
Number of pages4
JournalCancer Research
Volume43
Issue number4
StatePublished - Apr 1 1983
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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