PMID: 6171343Dec 1, 1981Paper

Selective activation of 5'-deoxy-5-fluorouridine by tumor cells as a basis for an improved therapeutic index

Cancer Research
R D Armstrong, R B Diasio

Abstract

The intracellular metabolism of a new fluoropyrimidine, 5'-deoxy-5-fluorouridine (5'-dFUrd), was compared with the metabolism of 5-fluorouracil (FUra), 5-fluorouridine (FUrd), and 5-fluoro-2'-deoxyuridine (FdUrd) in freshly isolated bone marrow cells and Ehrlich ascites tumor cells. Following exposure to tumor cells, all four fluoropyrimidines were metabolized to identical products (i.e., FUra, 5-fluorouridine 5'-monophosphate, 5-fluorouridine 5'-diphosphate, 5-fluorouridine 5'-triphosphate, and 5-fluoro-2'-deoxyuridine 5'-monophosphate), all produced an incorporation of FUra into RNA (FUd greater than FUra greater than FdUrd greater than 5'-dFUrd), and all completely inhibited thymidylate synthetase activity by 1 hr. However, in bone marrow cells, very different patterns were observed. 5'-dFUrd accumulated in the cells, but there were no measurable metabolism, no incorporation of FUra into RNA, and no inhibition of thymidylate synthetase activity. In contrast, both FUra and FUrd were metabolized and produced an incorporation of FUra into RNA (2.7 pmol FUra per micrograms RNA and 4.8 pmol FUra per micrograms RNA at 2 hr, respectively) in bone marrow. Only a minor inhibition of thymidylate synthetase activity was detected. FdUrd...Continue Reading

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