An analysis of dose and schedule dependence of
calcium leucovorin rescue during high-dose
methotrexate therapy of ascitic forms of
l1210 leukemia and
Sarcoma 180 is reported. Schedules with very delayed "low-dose"
leucovorin rescue following lethal doses of
methotrexate were highly effective in preventing toxicity and achieved a pronounced antitumor effect in both
ascites tumor models. Best results were obtained on a schedule of
methotrexate (400 mg/kg s.c.) followed 16 to 20 hr later by
calcium leucovorin (12 mg/kg s.c.) given once every 2 hr for a total of 5 doses. Progressive increases in the
calcium leucovorin dosage on any schedule reduced both toxicity and the antitumor effect of
methotrexate in each model. Following a single course of
therapy, essentially no toxicity was observed, and the antitumor effects were 2-fold (
L1210 leukemia) and 4-fold (
Sarcoma 180) greater than a single, maximally tolerated dose (24/kg s.c.)
methotrexate alone. An increase in the
methotrexate dosage to 800 mg/kg s.c. with or without an increase in
calcium leucovorin dosages on the same schedule did not appreciably increase the antitumor effect observed. Two courses of high-dose
methotrexate (400 mg/kg s.c.) with
leucovorin rescue (24 mg/kg s.c. 16, 20, and 24 hr after
drug) given with an 8-day interval between courses doubled the total antitumor effect in each model with no substantial increase in toxicity and gave long-term survivors with
Sarcoma 180. The results, overall, are in close agreement with prior prediction for schedule and dose dependence made on the basis of related pharmacokinetic and biochemical studies in murine
tumor models reported from this laboratory.