JVriting Committee for the Southeastern Cancer S t u d y Group
Recent studies suggest that a therapeutic advantage with reduced toxicity can b e achieved by the administration of intensive high doses of methotrexate i n malignant disease. The action of methotrexate can be reversed by the administration of folinic acid (Leucovorin) which bypasses the major site of methotrexate action, the binding of dihydrofolic reductase, preventing the formation of tetrahydrofolic acid. Thus, the duration of exposure of sensitive cells to lethal doses of methotrexate can be accurately controlled. Patients with metastatic cancer or acute leukemia were treated with oral rnethotrexate administered in 4 equally divided doses totalling 100, 200, or 300 mg/m2 over a 24-hour period once weekly. Leucovorin, in doses of 5 m g every 6 hours for 6, 9, or 12 doses depending upon the creatinine clearance, was begun on a randomized basis a t 24 or 36 hours after methotrexate to determine if there were any differences in response or toxicity by the delay in "rescue." Objective and/or subjective responses were observed in 25% of 93 patients with metastatic cancer a n d remissions (3 complete a n d 5 partial) in 23% of 35 evaluable patients with acute leukemia. The highest response rates were obtained in head a n d neck carcinomas (22%) and breast carcinomas (45%). Responses were also seen in other carcinomas, including ovary, cervix, and choriocarcinoma. Toxicity was minimal a n d similar in all combinations of schedules of methotrexate and Leucovorin. This approach warrants further study alone or i n combination with other drugs i n carcinoma of the breast a n d head a n d neck, a n d in acute leukemia.
ETHOTKESATE, 1%). IRREVERSIBLY BINDING
M diliytlrofolic reductase, the enzyme necessary for the conversion of folic acid to the reduced and active form, tetrahydrofolic acid, inhibits the methylation of uridylic acid to thymitlylic acid thus interfering with DNA synthesis.19 It has been shown that induction of dihydrofolic reductase activity occursI.2,10