Potentiation of quinazoline antifolate (CB3717) toxicity by dipyridamole in human lung carcinoma, A549, cells.
A potent quinazoline antifolate inhibitor of thymidylate synthase, CB3717, inhibits the growth of A549 human lung carcinoma cells: ID50 2.74 +/- 0.53 microM. The toxic effects of thymidylate synthase inhibition may be prevented by salvage of exogenous thymidine. The nucleoside transport inhibitor, dipyridamole, at the non-toxic concentration of 1 microM, inhibited [3H]thymidine uptake/incorporation by more than 95% and significantly reduced the ID50 of CB3717 to 0.98 +/- 0.28 microM. Elimination of salvageable thymidine by the use of dialysed serum also enhanced CB3717 toxicity. Since dipyridamole was equally effective in the presence or absence of dialysed serum and was more effective than dialysed serum alone, inhibition of nucleoside efflux may be an important aspect of its potentiation. Efflux of [5-3H]deoxyuridine was inhibited by 89% and [3H]thymidine efflux by 61% in the presence of 1 microM dipyridamole. Inhibition of thymidylate synthase increases the deoxyuridine nucleotide/thymidine nucleotide pool ratio. Dipyridamole could exacerbate the nucleotide pool imbalance caused by CB3717, thereby potentiating its toxicity.
Curtin
N J
NJ
Cancer Research Unit, University of Newcastle upon Tyne, Royal Victoria Infirmary, U.K.
Harris
A L
AL
D002277:Carcinoma / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects; D004247:DNA / Q000378:metabolism; D004176:Dipyridamole / Q000494:pharmacology*; D004357:Drug Synergism; D005492:Folic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D005493:Folic Acid Antagonists / Q000494:pharmacology*; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology; D011799:Quinazolines / Q000494:pharmacology*; D013936:Thymidine / Q000378:metabolism; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors*; D014407:Tumor Cells, Cultured / Q000187:drug effects
D005493:Folic Acid Antagonists; D011799:Quinazolines; D004176:Dipyridamole; C031662:CB 3717; D004247:DNA; D005492:Folic Acid; D013940:Thymidylate Synthase; D013936:Thymidine