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Dipyridamole potentiates antipurine antifolate activity in the presence of hypoxanthine in tumor cells but not in normal tissues in vitro

Lookup NU author(s): Professor Herbie Newell, Professor Alan Calvert, Professor Anne Dickinson, Professor Frederick Campbell, Professor Nicola Curtin

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Abstract

The cytotoxicity of the antifolate inhibitors of de novo purine biosynthesis, lometrexol (LTX) and LY309887, can be abolished by hypoxanthine (HPX) salvage. The nucleoside transport inhibitor, dipyridamole (DP) can prevent HPX rescue from LTX growth inhibition in a cell line-specific manner. The studies described here have shown that, excluding colon and hematological malignancies, DP prevents HPX rescue from LTX growth inhibition in approximately one-third of cell lines with otherwise limited tissue specificity. The clinical dose-limiting toxicities of antipurine antifolates are to the bone marrow and gastrointestinal tract. In vitro models of these normal tissues were established, and the effect of DP on HPX rescue from LY309887 treatment was studied. Growth inhibition assays are not feasible in these primary cultures; therefore, an alternative assay, cellular ATP depletion, was validated in four tumor cell lines as a marker of de novo and salvage purine synthesis. In LY309887-treated cells, DP prevented HPX- mediated maintenance of ATP levels only in cell lines in which DP inhibited HPX rescue from antifolate cytotoxicity. Hence, ATP depletion is a reliable indicator of sensitivity of HPX transport to DP when direct cell growth measurement is impractical. In primary cultures of human hematopoetic progenitor cells and mouse small intestine, coincubation with HPX prevented LY309887-mediated ATP depletion, which was not blocked by DP. These data suggest that DP would not prevent HPX rescue from antipurine antifolate growth inhibition in sensitive normal tissues, whereas activity against certain solid human tumors would be maintained.


Publication metadata

Author(s): Marshman, E., Newell, D.R., Calvert, A.H., Dickinson, A., Patel, H., Campbell, F., Curtin, N.J.

Publication type: Article

Publication status: Published

Journal: Clinical Cancer Research

Year: 1998

Volume: 4

Issue: 11

Pages: 2895-2902

Print publication date: 01/11/1998

ISSN (print): 1078-0432

ISSN (electronic): 1557-3265

PubMed id: 9829758


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