Hydroxyurea and etoposide: in vitro synergy and phase I clinical trial

L1210 murine leukemia cells were treated with hydroxyurea (10-200 microM) for 24 hours and/or etoposide (0.17-3.4 microM) for 2 hours. Combination treatments used a fixed molar hydroxyurea:etoposide ratio of 58.9:1, and drug-drug interactions were quantitated according to the median effect principle. Hydroxyurea and etoposide were antagonistic at low doses at which the survival fraction was greater than 0.5 and synergistic at higher doses at which the survival fraction was less than 0.25. In a phase I clinical trial, 19 patients were treated with the two drugs at one of three dose levels. The dose-limiting toxic effect was myelosuppression. Doses of 100 mg of etoposide/m2 per day by continuous infusion and 500 mg of hydroxyurea orally every 4 hours, both for 3 days, are recommended for phase II trials.