Alkylating antitumor agents reduce histone acetyl-transferase activity.
N-Mustard depresses the acetylation of histones in Ehrlich ascites and Walker carcinoma cells. It is demonstrated that this effect is not caused by an accelerated deacetylation but is due to an inhibition of the acetyl-transferase reaction. Employing 4-sulphonatoethylthio-cyclophosphamide it is demonstrated that the alkylating agent affects predominantly the acetylation of a chromatin fraction which is soluble in 0.1M NaCl after digestion with micrococcal nuclease. After removal of the alkylating agent, the recovery of histone acetylation is relatively slow and--in contrast to the repair of DNA cross-links--characterized by a 4-hr lag period. The reduction of histone acetylation by N-mustard is much less expressed in cells which are resistant to the drug than in the sensitive parental lines. This is in contrast to DNA-interstrand cross-links in Walker cells where both N-mustard sensitive and resistant cells inhibit the same cross-link frequency and identical repair rates. Based on these data it is concluded that the inhibition of histone acetylation may be an important part of the mechanism by which alkylating agents inhibit tumor growth.
D000107:Acetylation; D000123:Acetyltransferases / Q000378:metabolism*; D000818:Animals; D002087:Butyrates / Q000494:pharmacology; D020148:Butyric Acid; D002279:Carcinoma 256, Walker / Q000201:enzymology; D002286:Carcinoma, Ehrlich Tumor / Q000201:enzymology; D002478:Cells, Cultured; D003520:Cyclophosphamide / Q000031:analogs & derivatives / Q000494:pharmacology; D004260:DNA Repair / Q000187:drug effects; D004591:Electrophoresis, Polyacrylamide Gel; D051548:Histone Acetyltransferases; D008466:Mechlorethamine / Q000494:pharmacology*; D029701:Saccharomyces cerevisiae Proteins
D002087:Butyrates; D029701:Saccharomyces cerevisiae Proteins; D020148:Butyric Acid; D008466:Mechlorethamine; C037933:Asta Z 7557; D003520:Cyclophosphamide; D000123:Acetyltransferases; D051548:Histone Acetyltransferases