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)

Bach Ardalan, H. N. Jayaram, R. K. Johnson

Research output: Contribution to journalArticle

6 Citations (Scopus)

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

Fingerprint

acivicin
Leukemia P388
Aspartic Acid
Acids
Pyrimidine Nucleosides
nucleoside phosphotransferase
Transferases
Carbamyl Phosphate
Purine Nucleosides
Purine Nucleotides
Cytidine Triphosphate
Antimetabolites
Uridine Triphosphate
Hypoxanthine
Adenine
Ligases
Guanosine Triphosphate
Nucleotides
Adenosine Triphosphate

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

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title = "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)",
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.",
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AU - Johnson, R. K.

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