Potentiation of Methotrexate Toxicity by Dipyridamole1

Dipyridamole, an inhibitor of facilitated transport systems for purines and pyrimidines, was shown to enhance the toxicity of methotrexate (MTX) against cells in culture and in mice. Under certain incubation conditions, the availability of preformed pu rines and pyrimidines in undialyzed serum appeared to render Chinese hamster ovary cells insensitive to MTX. Addition to the culture of nontoxic levels of dipyridamole conferred sensitivity to MTX. Inhibition of [3H]thymidine uptake by dipyridamole paral leled the enhanced MTX toxicity in a comparison of the doseeffect relationships. Inhibition of [3H]hypoxanthine uptake also occurred, although approximately 10-fold higher levels of dipyri damole were required. In vivo dipyridamole enhanced MTX tox icity in mice; however, the antitumor activity of MTX toward Ridgway osteogenic sarcoma and L1210 leukemia was not dramatically improved.