Methotrexate and Dipyridamole Combination Chemotherapy Based Upon Inhibition of Nucleoside Salvage in Humans

We have carried out a clinical trial in 23 patients to determine whether dipyridamole modulates the clinical effect of methotrexate. This trial was based upon in vitro studies which indicate that dipyridamole potentiates the cytotoxic action of methotrexate through inhibition of thymidine salvage. Methotrexate was given as a bolus injection 24 h after initiation of a high dose dipyridamole infusion. The trial was designed so that methotrexate was escalated in individuals until toxicity occurred and then the methotrexate dose resulting in toxicity was repeated without dipyridamole. During the course of this study the methotrexate dose was escalated from 10 to 130 mg/m2. While individual patient tolerance varied, moderate to severe myelosuppression and/or mucositis occurred frequently in patients receiving the combination with methotrexate doses ≥60 mg/m2. Ten of 10 patients who experienced moderate or severe toxicity with the combination had significantly less toxicity when treated with methotrexate alone. Dipyridamole did not increase toxicity by an alteration in methotrexate elimination. The potentiation of methotrexate by dipyridamole in these patients suggests that physiological thymidine levels are sufficient to perturb the clinical effects of methotrexate and that thymidine salvage may represent a mechanism for clinical resistance to methotrexate. These results also suggest that a high dose dipyridamole regimen can be used as a pharmacological approach to test the role of nucleoside membrane flux on the clinical action of other standard chemotherapeutic drugs. Phase II studies testing the clinical efficacy of this combination should use a methotrexate dose of 60 mg/m2 with a provision for methotrexate dose escalation based upon individual patient tolerance.