Repeated high doses of
trimetrexate (TMX), a potent non-classical
antifolate, have been administered as an experimental treatment for life-threatening
Pneumocystis carinii infections in man. This
therapy includes the coadministration of
leucovorin, a reduced
folate cofactor, to prevent
antifolate toxicity in the host. The purpose of this investigation was to assess possible toxicologic sequelae of this combination regimen in an animal model. TMX at daily oral doses of 25, 35, and 45 mg/kg produced dose-related myelosuppression, thymic lymphoid depletion, seminiferous tubular
atrophy, and degenerative lesions of the gastrointestinal tract. Mortality observed with TMX alone occurred earlier at higher doses and was specifically associated with severe degenerative enteropathy of the cecum. Oral
leucovorin doses of 1, 5, 20, or 50 mg/kg administered twice daily, at the time of TMX administration and 6 hr later, protected against TMX lethality and target organ toxicity in a dose-related manner.
Leucovorin was only partially protective against TMX-induced
macrocytic anemia and the degree of protection was not dose-related.
Leucovorin protection against cecal enteropathy was associated with increased
DNA synthetic rates and higher mitotic activity of cecal epithelium than those in rats administered TMX alone. Importantly, the combination of daily administration of high dose TMX for 4 weeks with protective coadministration of
leucovorin did not result in target organ toxicities that differed from TMX alone.