Hydroxylamine-containing inhibitors of polyamine biosynthesis and impairment of colon cancer cell growth

Polyamine synthesis (by the action of ornithine decarboxylase [ODC] and S-a denosylmethionine decarboxylase [SAMDC]) and polyamine content are high in colon cancer. In addition, colonic lumen is rich in polyamines synthesised by colonic microflora; for this reason, polyamine depletion in colon cancer may be a logical approach to impair growth of colon cancer cells. We evalu ated highly specific and reportedly non-toxic hydroxylamine-containing inhi bitors of ODC (1-aminooxy-3-aminopropane, APA) and SAMDC (S-(5'-deoxy-5'-ad enosyl)-methylthioethyl-hydroxylamine AMA) in human colon cancer cells (Cac o-2 and HT-29) in culture. APA depleted ODC activity within 24 hr, more rap idly than did difluoromethylornithine. APA and AMA in combination (100 muM each) reduced ODC and SAMDC activities to undetectable levels within 24 hr and intracellular polyamines to 8-23% of control. The resulting growth arre st could be reversed only by twice as much spermidine as is physiologically present in the colonic lumen. In concentrations sufficient to deplete grow th, APA and AMA were not toxic. Simultaneous treatment with APA, AMA, and 5 -fluorouracil reduced colon cancer cell survival more potently than treatme nt with 5-fluorouracil alone. The hydroxylamine-containing ODC and SAMDC in hibitors APA and AMA are potent inhibitors of colon cancer cell proliferati on and might be therapeutically promising in colon cancer. (C) 2001 Elsevie r Science Inc. All rights reserved.