PT - JOURNAL ARTICLE AU - ALAN C. SARTORELLI AU - SHIRO TSUNAMURA TI - Studies on the Biochemical Mode of Action of a Cytotoxic Methylhydrazine Derivative, <em>N</em>-Isopropyl-α-(2-methylhydrazino)-<em>p</em>-toluamide DP - 1966 Jul 01 TA - Molecular Pharmacology PG - 275--283 VI - 2 IP - 4 4099 - http://molpharm.aspetjournals.org/content/2/4/275.short 4100 - http://molpharm.aspetjournals.org/content/2/4/275.full SO - Mol Pharmacol1966 Jul 01; 2 AB - N-Isopropyl-α-(2-methylhydrazino)-p-toluamide inhibited the incorporation of thymidine-3H, deoxycytidine-3H, formate-14C, adenine-8-14C, and 4-amino-5-imidazolecarboxamide-2-14C into DNA, and the utilization of orotic acid-6-14C and leucine-1-14C for the synthesis of RNA and protein, respectively, in L5178Y lymphoma cells. The site of the drug-induced blockade of the formation of DNA did not appear to reside at the level of thymidine kinase (ATP:thymidine 5'-phosphotransferase, EC 2.7.1.21), thymidine monophosphate kinase (ATP:thymidine monophosphate phosphotransferase, EC 2.7.4.9), or DNA nucleotidyltransferase (deoxynucleosidetriphosphate:DNA deoxynucleotidyltransferase, EC 2.7.7.7). Furthermore, treatment of cells with N-isopropyl-α-(2-methylhydrazino)-p-toluamide did not influence the rate of loss of thymine-3H from prelabeled DNA. Possible metabolic alterations which might explain the observed results are discussed. The inhibitions of the syntheses of nucleic acids and proteins that were measured were followed by a period during which most of the cell death occurred; this period corresponded with the development of a metabolic imbalance that was characterized by an accumulation of RNA and protein and an increase in cell volume. ACKNOWLEDGMENTS The authors wish to thank Dr. W. E. Scott, Hoffmann-La Roche, Inc. for a generous supply of MIH and Miss Sheila J. Feld for excellent technical assistance. This investigation was supported by USPHS Research Grant CA-02817 from the National Cancer Institute and by Grants ACS IN-31E-806 and ACS IN-31F-905 from the American Cancer Society. One of us (S.T.) gratefully acknowledges postdoctoral support from the Anna Fuller Fund.