Separate Mechanisms for Procarbazine Spermatotoxicity and Anticancer Activity¹

Procarbazine causes dose-dependent decreases in sperm count after a single i.p. injection in (C57BL/6 × DBA/2)F₁ male mice. Two antioxidants, N-acetylcysteine and sodium ascorbate, administered with equimolar doses of procarbazine decreased the spermatotoxicity of procarbazine. At the highest doses of procarbazine (400 mg/kg) that caused a 56% decrease in sperm count, equimolar doses of N-acetylcysteine coadministered with procarbazine caused only a 17% decrease in sperm count, and equimolar doses of ascorbate coadministered with procarbazine caused only a 13% decrease in sperm count. Thus, protection against the spermatotoxic effects of procarbazine was demonstrated with either antioxidant. The effect of the antioxidants on the chemotherapeutic efficacy of procarbazine against murine L1210 leukemia was also assessed. Procarbazine at the highest dose (600 mg/kg) increased mean survival time of mice inoculated i.p. with 1 × 10⁵ L1210 leukemia cells by 31%. Simultaneous administration of equimolar doses of either N-acetylcysteine or ascorbate given with procarbazine caused no change in the increased mean survival time of tumor-bearing mice. These results indicate a decrease in the toxicity of procarbazine when coadministered with antioxidants, via decreased spermatotoxicity without changing anticancer efficacy. The results also indicate that different mechanisms are involved in the spermatotoxicity and anticancer activity of procarbazine.