Inhibitors of polyamine synthesis were tested for therapeutic effectiveness on transplantable prostate cancer. Inhibition of either ornithine decarboxylase or S-adenosyl-L-methionine decarboxylase (AMDC) by α-difluormethylornithine (DFMO) or methylglyoxal-bis[guanylhydrazone] (MGBG), respectively, was associated with significant antitumor effect. The combination of DFMO with MGBG was not only more effective but no more toxic than MGBG alone. Combination of MGBG with 9-B-D-arabinofuranosyladenine, an indirect effector of SAMDC, failed to increase therapeutic effectiveness of MGBG.
The polyamines, putrescine, spermidine, and spermine, are fundamentally related to both normal and neoplastic cell proliferation. The prostate gland and prostatic tumors in man and rodents contain large amounts of polyamines. This suggests that inhibition of polyamine biosynthetic enzymes, ornithine decarboxylase (ODC) and S‐adenosyl‐methionine decarboxylase (SAMDC) may retard the growth of prostatic cancer. Since alpha‐difluoromethylornithine (DFMO) and methylglyoxal‐bis‐guanylhydrazone (MGBG) are irreversible and competitive inhibitors of ODC and SAMDC, respectively, they were tested as single agents and in combination on a transplantable rapidly growing and hormone‐resistant G subline of the Dunning R‐3327 rat prostatic adenocarcinoma. Groups of rats bearing tumors were treated with various regimens of DFMO, MGBG, and DFMO plus MGBG, daily for 21 days. Analysis of differences in tumor growth between treatment groups and controls showed DFMO had no antitumor effect but was well tolerated, MGBG retarded growth rate significantly but resulted in drug deaths in over 50% of the animals, and the combination of DFMO and MGBG resulted in rapid decline in tumor growth rates after 5 to 9 days of treatment with reduced toxicity. At 21 days, or death, 38 of 60 (63%) rats had no viable tumor on histologic study, whereas tumor was present in each of the animals in the other groups. Alpha‐difluoromethylornithine increased the intracellular uptake of MGBG and potentiated the antigrowth activity of MGBG on a hormone refractory rat prostatic tumor with less toxicity than MGBG alone. Cancer 53:1294‐1298, 1984.
Reduction of one disulfide bond in bovine pancreatic ribonuclease A, which leaves the enzyme with nearly unimpaired biological activity, makes barely perceptible changes in the aqueous Raman spectrum. Reduction of all four disulfide bonds, which inactivates the enzyme, produces serious conformational changes. The spectrum shows a substantial decrease in a-helical content and conversion of all tyrosines to a weakly hydrogen-bonded form. Cleavage of the peptide chain by cyanogen bromide at the three sites of methionine residues (13, 29-30 and 79) makes little alteration in the a-helical content but reduces the proportion of the P-pleated sheet. This structural change is attributed mainly to the chain breaking at residue 79, which occurs in the center of the P-network.
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