asta-z-7557 and Carcinoma--Ehrlich-Tumor

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.

Topics: Acetylation; Acetyltransferases; Animals; Butyrates; Butyric Acid; Carcinoma 256, Walker; Carcinoma, Ehrlich Tumor; Cells, Cultured; Cyclophosphamide; DNA Repair; Electrophoresis, Polyacrylamide Gel; Histone Acetyltransferases; Mechlorethamine; Saccharomyces cerevisiae Proteins

ASTA Z 7557 is a stabilized cytostatic metabolite of cyclophosphamide which forms crystals at room temperature and releases 4-OH-cyclophosphamide in aqueous solution. The LD50/30 in mice after push injection is 417 mg/kg, after fractionated administration (q 6 hours X 4) 794 mg/kg. Daily treatment times 5 gives a LD50/30 value of 200 mg/kg. Depression of nucleated bone marrow cells and of leukocytes in the peripheral blood is observed after treatment. Recovery is slow. This holds true for push and fractionated administration. ASTA Z 7557 is a powerful cytostatic drug for treatment of an Ehrlich ascites tumor, a Lewis lung and a mammary carcinoma. Of two human tumor xenografts a malignant amelanotic melanoma responded with slight growth delay, whereas a gastric cancer did not.

Topics: Animals; Carcinoma, Ehrlich Tumor; Cell Division; Cyclophosphamide; Drug Evaluation, Preclinical; Humans; Lethal Dose 50; Lung Neoplasms; Male; Mammary Neoplasms, Experimental; Melanoma; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Neoplasm Transplantation; Neoplasms, Experimental; Stomach Neoplasms; Transplantation, Heterologous