Experimental studies on high-dose methotrexate with citrovorum factor chemotherapy for 89Sr-induced osteosarcoma murine model.

Experimental chemotherapy using high-dose methotrexate (MTX) with citrovorum factor (CF) was performed on ddN strain mice bearing 89Sr-induced osteosarcoma and the antitumor efficacy was analyzed through autoradiography ([3H]thymidine). The administration was done using sustained infusion via the tail vein using our own device to maintain certain elevated blood levels of the drugs. As the first experiment, MTX was administered to 4 different groups of mice with dose levels of 250, 500, 1,000, 2,000 mg/kg for 6 hours followed by CF 200 mg/kg for 24 hours. It was found that the blood levels of MTX were maintained at 10(-4) M by the dosage of 500 mg/kg, but no higher levels were achieved by increasing dosage. Tissue such as the small intestine and the bone marrow recovered from the toxicity of MTX in about 1 week after the dosage of 500 mg/kg. In tumors, on the other hand, the tissue showed a gradual recovery with time, but the uptake of [3H]thymidine by the tissue was not restored to the pretreatment level. When the antitumor efficacy of a single dosage of 1,000 mg/kg and 2 dosages of 500 mg/kg each with 1 week interval were compared, the latter was definitely more effective. It was, therefore, concluded that the administration of the drugs should be done repeatedly with optimum doses of MTX and CF rather than with ultrahigh doses of MTX and CF all at once.