Effects of antineoplastic and immunosuppressant drugs on deoxyribonucleic acid-polymerizing enzymes of rat thymus and spleen
Coleman, M.S.; Hutton, J.J.
Molecular Pharmacology 13(1): 122-132
1977
ISSN/ISBN: 0026-895X PMID: 299913 Document Number: 123686
Most drugs used in cancer chemotherapy have antineoplastic and immunosuppressant activities. Inhibition of nucleic acid synthesis and cell division is a common mechanism of action of such drugs, but their effects on DNA polymerases and DNA synthesis in lymphoid cells were not extensively described. Thymus and spleen are major sites of replication of lymphoid cells and play important roles in cellular and humoral immunity, respectively. The time course of changes in the activities per cell of DNA dependent DNA polymerases .alpha. and .beta. (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 was reported. 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 declined to less than half their pretreatment values. By 24 h the weights of the thymus and spleen 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 < 10% of the normal activities of terminal deoxynucleotidyltransferase and < 30% of the normal activities of DNA polymerase .alpha. Treatment with vincristine, 5-fluorouracil, actinomycin D or cyclophosphamide reduced DNA polymerase .alpha. activity per spleen cell to < 30% of normal. Terminal deoxynucleotidyltransferase activity was never found in spleen, drug treated or not. Thymic lymphocytes were separated into density classes on bovine serum albumin gradients and changes in enzyme activities were 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.