Effect of inhibitors of ornithine and adenosylmethionine decarboxylases on the synthesis of deoxyribonucleic acid in Ehrlich ascites cells in vivo [laboratory animals]

An inoculation of mice with Ehrlich ascites cells induced a rapid enhancement of polyamine synthesis in the tumor cells. The activities of L-ornithine decarboxylase and S-adenosyl-L-methionine decarboxylase were substantially stimulated already 4 h after the intraperitoneal inoculation. The first peak of tumor DNA synthesis occurred around 20 h after the inoculation and was accompanied by significant increases in the concentration of cellular spermidine and spermine. Inhibition of increased ornithine decarboxylase activity after the inoculation by repeated doses (every 4 h) of 1,3-diaminopropane prevented any increases in tumor polyamines and likewise depressed the synthesis of DNA 20 h after the inoculation. The inhibition of DNA synthesis by diamino-propane was further increased when the amine treatment was continued for 40 h. DL-alpha-Difluoromethylornithine when given every 4 h produced a more rapid decrease in the concentration of cellular spermidine than did diamino-propane but increased cellular spermine and only insignificantly inhibited the synthesis of DNA. Less frequent injections of the compound (every 10 h) led to a marked decrease in spermidine content with only small increases in tumor spermine and clearly inhibited the synthesis of DNA in the ascites cells. A combination of diaminopropane of 1,3-diamino-2-propanol with N, N'-bis(3-aminoguanidino)-propan-1,2-diimine produced a striking synergism in decreasing the synthesis of DNA. The potentation of the antiproliferative effect of diaminopropane or diaminopropanol by N, N'-bis(3-aminoguanidino)propan-1,2-diimine appeared to be specific to the diamines since no such synergism was found when difluoromethyl ornithine and N, N'-bis(3-amino-guanidino)propan-1,2-diimine were injected together. Furthermore, the latter compound clearly slowed down the degradation rate of the diamines in the tumor cells.