Molecular Pharmacology, Vol 13, 122-132, Copyright © 1977 by the American Society for Pharmacology and Experimental Therapeutics

Effects of Antineoplastic and Immunosuppressant Drugs on Deoxyribonucleic Acid-Polymerizing Enzymes of Rat Thymus and Spleen

¹ Departments of Biochemistry and Medicine, University of Kentucky Medical Center, Lexington, Kentucky 40506, and Veterans Administration Hospital, Lexington, Kentucky 40507

Most drugs used in cancer chemotherapy have both antineoplastic and immunosuppressant activities. Inhibition of nucleic acid synthesis and cell division is a common mechansim of action of such drugs, but their effects on DNA polymerases and DNA synthesis in lymphoid cells have not been extensively described. Thymus and spleen are major sites of replication of lymphoid cells and play important roles in cellular and humoral immunity, respectively. We report the time course of changes in the activities per cell of DNA-dependent DNA polymerases and (DNA nucleotidyltransferase, EC 2.7.7.7), terminal deoxynucleotidyltransferase (nucleoside triphosphate:DNA nucleotidylexotransferase, EC 2.7.7.31), and adenosine deaminase (adenosine aminohydrolase), EC 3.5.4.4) in rat thymus and spleen following administration of vincristine, 5-fluorouracil, actinomycin D, cyclophosphamide, cytosine arabinoside, or dexamethasone. Ten hours after administration of drug, only dexamethasone treatment was associated with a significant (p < 0.001) loss of thymic weight and enzyme activity. Terminal deoxynucleotidyltransferase and adenosine deaminase activities per cell in thymus had declined to less than half their pretreatment values. By 24 hr after drug, the weights of the thymus and spleen had significantly (p < 0.001) decreased in all animals. As calculated on the basis of activity units per cell, thymocytes remaining after vincristine or dexamethasone treatment contained less than 10% of the normal activities of terminal deoxynucleotidyltransferase and less than 30% of the normal activities of DNA polymerase . Treatment with vincristine, 5-fluorouracil, actinomycin D, or cyclophosphamide reduced DNA polymerase activity per spleen cell to less than 30% of normal. Terminal deoxynucleotidyltransferase activity was never found in spleen, whether drug-treated or not. Thymic lymphocytes were separated into density classes on bovine serum albumin gradients, and changes in enzyme activities are reported for cells of different densities. DNA-metabolizing enzymes in spleen and thymus responded differently to drug treatment. These differences may be related to differences among drugs in their relative suppression of humoral as opposed to cellular immunity.