levoleucovorin and Sarcoma-180

Currently, biochemical modulation for 5-fluorouracil (5-FU) by leucovorin (LV) and cisplatin (CDDP) seems one of the most successful chemotherapy for gastro-intestinal tract cancers. The mechanism of the modulation is thought to increase intracellular 5, 10-methylenetetrahydrofolate (CH2-H4 folate) levels. The purpose of this study is to examine the effect of LV and CDDP as a modulator of 5-FU. Either 10, 200, 400 mg/kg of LV or 2, 4, 6 mg/kg of CDDP were administered intravenously to mice bearing Sarcoma-180. Two hrs. later, CH2-FH4 folate levels were measured in tumor, muscle and intestine by thymidylate synthase (TS) binding assay. As the results, after administration of 200, 400 mg/kg of LV or 4, 6 mg/kg of CDDP, CH2-H4 folate level was elevated. This elevation was dose-dependent in LV. In contrast, no more elevation was observed after 6 mg/kg of CDDP injection. There was much smaller increase of CH2-H4 folate level was observed in the muscle and intestine. We conclude that the elevation of CH2-H4 folate levels depends on the organ and this leads to the tumor specificity in these chemotherapy.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Dose-Response Relationship, Drug; Drug Synergism; Fluorouracil; Leucovorin; Mice; Sarcoma 180; Tetrahydrofolates; Thymidylate Synthase

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.

Topics: Animals; Calcium; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Female; Leucovorin; Leukemia L1210; Methotrexate; Mice; Mice, Inbred Strains; Sarcoma 180; Time Factors

Topics: Animals; DNA; DNA, Neoplasm; Drug Therapy, Combination; Intestine, Small; Kinetics; Leucovorin; Leukemia L1210; Methotrexate; Mice; Neoplasms, Experimental; Sarcoma 180; Time Factors

The 5-arylpyrimidine antifolate DDMP showed appreciable therapeutic activity against an ascitic form of Sarcoma 180 in BD2F1 mice. Antitumor effects were highly schedule and dose dependent at a limited number of doses within the range of 8--40 mg/kg. The best results (increased lifespan = 112%) were obtained with two doses of DDMP at 40 mg/kg given 4 days apart. The incorporation of citrovorum factor rescue in dose schedules with DDMP appeared to improve the therapeutic index. In multiple-dose schedules with citrovorum factor allowing an average of eight doses of DDMP at a maximum level of 16 mg/kg, increases in median lifespan were greater than 158% with a number of long-term survivors.

Topics: Animals; Antineoplastic Agents; Drug Therapy, Combination; Female; Leucovorin; Mice; Pyrimidines; Sarcoma 180

Topics: Amides; Animals; Carbon Radioisotopes; Cells, Cultured; Depression, Chemical; Folic Acid; Glycine; Leucovorin; Mice; Pentosephosphates; Ribosemonophosphates; Sarcoma 180

Topics: Animals; Antimalarials; Antineoplastic Agents; Biguanides; Boron Compounds; Carcinoma, Ehrlich Tumor; Dogs; Folic Acid Antagonists; Hematopoiesis; Leucovorin; Leukopenia; Mice; Rabbits; Rats; Sarcoma 180; Species Specificity

Topics: Animals; Biological Transport, Active; Calcium; Cell Membrane Permeability; Dinitrophenols; Hydrogen-Ion Concentration; In Vitro Techniques; Leucovorin; Methotrexate; Riboflavin; Sarcoma 180; Temperature; Tetrahydrofolate Dehydrogenase