Dipyridamole potentiates antipurine antifolate activity in the presence of hypoxanthine in tumor cells but not in normal tissues in vitro.
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.
Marshman
E
E
Cancer Research Unit, Medical School, University of Newcastle upon Tyne, United Kingdom.
Newell
D R
DR
Calvert
A H
AH
Dickinson
A M
AM
Patel
H R
HR
Campbell
F C
FC
Curtin
N J
NJ
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D004176:Dipyridamole / Q000494:pharmacology*; D004357:Drug Synergism; D005493:Folic Acid Antagonists / Q000494:pharmacology*; D006131:Growth Inhibitors / Q000494:pharmacology; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D019271:Hypoxanthine / Q000494:pharmacology*; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000166:cytology / Q000187:drug effects; D020014:K562 Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D013763:Tetrahydrofolates / Q000494:pharmacology; D014407:Tumor Cells, Cultured
C105065:6R-2',5'-thienyl-5,10-dideazatetrahydrofolic acid; D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D005493:Folic Acid Antagonists; D006131:Growth Inhibitors; D013763:Tetrahydrofolates; D019271:Hypoxanthine; D004176:Dipyridamole; C045894:lometrexol; D000255:Adenosine Triphosphate