CELL-KINETICS AND BIOCHEMICAL PHARMACOLOGY OF METHOTREXATE AND 6-MERCAPTOPURINE IN HUMAN-MALIGNANT T-LYMPHOBLASTS

The cell-kinetics and biochemical pharmacology of simultaneous and sequential combination treatment with 0.02-mu-M methotrexate (MTX) and 2-mu-M 6-mercaptopurine (6MP) were studied in MOLT-4 malignant T-lymphoblasts. The results were compared with our data from earlier studies of separate treatment with these antimetabolites. A synergistic effect of combination treatment could be demonstrated, based on the inhibition of purine de novo synthesis by both agents, on DNA and RNA synthesis, on the incorporation of 6-thioguanine nucleotides into DNA and RNA, and on inhibition of cell growth and clonal growth. The synergistic effects of combination treatment with MTX and 6MP will only be available in malignant lymphoblasts, and will be absent in normal bone marrow cells and normal lymphocytes, because the activity of purine de novo synthesis in these cells is absent or low. Based on the synergistic effects of MTX and 6MP and the good penetration of both agents in the cerebrospinal fluid, the Dutch Childhood Leukemia Study Group presently performs a randomized study during protocol M of the BFM/DCLSG-ALL-90 protocol comparing the results of 4 times each two weeks 24 hr intravenous administration of MTX (5 g/m2) versus intravenous MTX, immediately followed by 24 hr intravenous administration of 6MP (1,3 g/m2). The pharmacokinetics and intracellular biochemical pharmacology of 6MP in lymphocytes will be studied, comparing intravenous administration and low dose oral administration.