Methotrexate (MTX) was administered by continual intravenous infusion for 24 hours in doses ranging from 200-800 mg/m2 to 16 patients who had metastatic cancers and normal bone marrows and 11 patients with acute leukemia. Citrovorum factor (CF) was administered every 6 hours for 12-15 doses beginning 36 hours after the start of the MTX infusion. Plasma and urine were collected to measure MTX concentration. Daily bone marrow aspirates were obtained for measuring intracellular MTX concentration, labelling index (LI), mitotic index (MI), grain count distribution, cellular DNA distribution by flow cytometry (FCM), and marrow morphology. The plasma MTX concentration proved to be a function of dose and creatinine clearance. There was a positive correlation between the creatinine clearance and MTX clearance. The intracellular MTX concentration correlated highly with the plasma concentration. The LI, grain count, and proportion of cells in S phase increased on days 2 and 3. The magnitude of the changes on days 2 and 3 was dose related. The MI fell on day 2 and recovered by day 4. Transient megaloblastic changes occurred. The cell cycle perturbations in leukemic marrow were less pronounced than those in normal marrows. These observations are consistent with a transient, dose related, S phase delay.
Cancer 47:215-223, 1981. TUDIES I N ANIMALS bearing transplanted tumors S have shown differences between normal hematopoietic stem cells and neoplastic cells in sensitivity to various chemotherapeutic drugs.4.20.22 This is in part due to differences in the percentage of cells in a drug sensitive phase of the mitotic cycle. The dose of drug is an important variable. A dose-dependent effect of cyclophosphamide on the rates of recovery of bone marrow, gastrointestinal mucosa, and L1210 ascites tumor cells (as measured by tritiated thymidine incorporation) was reported by Rosenoff et al.*l Similar dose-dependent effects of 5-fluorouracil on the recovery of bone marrow, gastrointestinal tract, and P-1534 ascites tumor cells were observed in the mouse.16 Vogler et al. demonstrated that larger doses of methotrexate (MTX) had a greater effect on the committed granulopoietic stem cell than a smaller dose given on the From the