Mechanisms of sensitivity and resistance of murine tumors to 5-fluorouracil

Bach Ardalan, D. A. Cooney, H. N. Jayaram, C. K. Carrico, R. I. Glazer, J. Macdonald, P. S. Schein

Research output: Contribution to journalArticle

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Abstract

The biochemical basis for the resistance of murine leukemia P388 to 5-fluorouracil (FUra) was systematically investigated by examining the transport and metabolism of FUra, or its anabolites, as well as the inhibition of enzymes and processes known to be affected by the drug. Of these parameters, only three were found to be altered significantly in the resistant line: (a) the enzyme required for the phosphorylation of uridine 5'-monophosphate to uridine 5'-diphosphate was present at a significantly lower specific activity in the resistant line than in its sensitive counterpart; (b) the rates of generation and persistance of 5-fluoro-2'-deoxyuridine 5'-monophosphate were significantly lower and shorter in the variant; and (c) there was a 1.6- and 3-fold decrease in the incorporation of FUra into polyadenylic acid-containing RNA and polyadenylic acid-lacking RNA, respectively, in resistant versus sensitive cells. Taken together, these findings suggest a dual mechanism for resistance to FUra in these leukemic cells, namely, a depressed capacity to generate di- and triphosphates of the riboside and deoxyriboside of the drug leading to lower pools of the proximate antimetabolite, fluorouridine 5'-triphosphate, and acceleration excretion of 5-fluoro-2'-deoxyuridine 5'-monophosphate, so that thymidylate synthetase is perturbed in a less than lethal way.

Original languageEnglish
Pages (from-to)1431-1437
Number of pages7
JournalCancer Research
Volume40
Issue number5
StatePublished - Jul 4 1980
Externally publishedYes

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Fluorouracil
Fluorodeoxyuridylate
Poly A
Neoplasms
Leukemia P388
RNA
Uridine Monophosphate
Antimetabolites
Thymidylate Synthase
Uridine Diphosphate
Diphosphates
Enzymes
Pharmaceutical Preparations
Phosphorylation
triphosphoric acid

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Ardalan, B., Cooney, D. A., Jayaram, H. N., Carrico, C. K., Glazer, R. I., Macdonald, J., & Schein, P. S. (1980). Mechanisms of sensitivity and resistance of murine tumors to 5-fluorouracil. Cancer Research, 40(5), 1431-1437.

Mechanisms of sensitivity and resistance of murine tumors to 5-fluorouracil. / Ardalan, Bach; Cooney, D. A.; Jayaram, H. N.; Carrico, C. K.; Glazer, R. I.; Macdonald, J.; Schein, P. S.

In: Cancer Research, Vol. 40, No. 5, 04.07.1980, p. 1431-1437.

Research output: Contribution to journalArticle

Ardalan, B, Cooney, DA, Jayaram, HN, Carrico, CK, Glazer, RI, Macdonald, J & Schein, PS 1980, 'Mechanisms of sensitivity and resistance of murine tumors to 5-fluorouracil', Cancer Research, vol. 40, no. 5, pp. 1431-1437.
Ardalan B, Cooney DA, Jayaram HN, Carrico CK, Glazer RI, Macdonald J et al. Mechanisms of sensitivity and resistance of murine tumors to 5-fluorouracil. Cancer Research. 1980 Jul 4;40(5):1431-1437.
Ardalan, Bach ; Cooney, D. A. ; Jayaram, H. N. ; Carrico, C. K. ; Glazer, R. I. ; Macdonald, J. ; Schein, P. S. / Mechanisms of sensitivity and resistance of murine tumors to 5-fluorouracil. In: Cancer Research. 1980 ; Vol. 40, No. 5. pp. 1431-1437.
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