Effects on human peripheral lymphocytes of in vivo administration of 9-beta-D-arabinofuranosyl-2-fluoroadenine-5'-monophosphate (NSC 312887), a new purine antimetabolite.
9-beta-D-Arabinofuranosyl-2-fluoroadenine-5'-monophosphate (NSC 312887) (2-F-ara-AMP) is a new purine antimetabolite with documented preclinical activity against a number of animal tumors. Data from in vitro studies and preclinical animal toxicology trials indicated that 2-F-ara-AMP might be lymphocytotoxic. We studied effects of 2-F-ara-AMP on peripheral lymphocytes of patients receiving the agent in a Phase I clinical trial. Eleven patients received 13 courses given by i.v. bolus daily for 5 days. Mononuclear cells were isolated, and lymphocyte subsets were quantitated by immunofluorescence and flow cytometry 1 day before treatment and 4 hr after the final infusion. Lymphocytopenia developed rapidly (median time to nadir, 6 days) and was reversible. Standard leukocyte counts, differential counts, and percentages of isolated mononuclear cells reactive with monoclonal antibodies were used to calculate numbers of peripheral cells in each major lymphocyte subpopulation. Total T-lymphocyte counts fell during all treatment courses, with calculated mean absolute T-cell counts decreasing by 90%. Decreases were observed in all major T-lymphocyte subsets. By contrast, calculated B-lymphocyte counts decreased an average of 50% and were noted to increase during two treatment cycles. We also compared in vitro recoveries of cells from each major lymphocyte subpopulation before and after administration of 2-F-ara-AMP. Recoveries of total mononuclear cells, total T-cells, and non-T-, non-B-cells all were reduced substantially by 2-F-ara-AMP, but B-cell recovery was not reduced. These in vivo data, the first in human subjects, are in agreement with in vitro studies of halopurine nucleotide analogues which have demonstrated that T-cells are more sensitive than are B-cells to the cytotoxic effects of these compounds.
D000328:Adult; D000368:Aged; D001088:Arabinonucleotides / Q000627:therapeutic use*; D001402:B-Lymphocytes / Q000166:cytology* / Q000187:drug effects; D004341:Drug Evaluation; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D007958:Leukocyte Count; D007962:Leukocytes / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D013601:T-Lymphocytes / Q000166:cytology* / Q000187:drug effects; D001084:Vidarabine Phosphate / Q000031:analogs & derivatives / Q000627:therapeutic use*
D001088:Arabinonucleotides; D001084:Vidarabine Phosphate; C042382:fludarabine phosphate