Naturally occurring polyamines, putrescine, spermidine, and spermine, have been implicated in a variety of cellular processes such as cell division, differentiation, and membrane function. Studies with a number of potent and specific inhibitors of the enzyme ornithine decarboxylase (ODC), the first enzyme involved in polyamine biosynthesis, have established an unambiguous role for e polyamines in cell growth. This trial will investigate diethylhomospermine (DEHSPM) given as a subcutaneous injection daily for five days and to determine the qualitative and quantitative toxicity associated with this polyamine. The increased cellular concentrations of polyamines in growing tissues, the increased uptake of exogenous polyamines into polyamine-starved tumor cells and a relatively specific transport system suggest that appropriate structural analogues of these compounds can serve as antiproliferative agents. Activity by DEHSPM and similar analogues has also been described in U-87MG and SF-126 human brain tumor cells, non- small lung cancer cells, and MAIME-3 melanoma cells. The activity of DEHSPM in these cells support the hypothesis that polyamine analogues that enter cells, deplete intracellular levels of natural polyamines, and replace the natural polyamines from their binding sites on DNA without replacing function should act as antiproliferative agents.
The specific aims of this study are: to determine the maximum tolerated dose of DEHSPM administered as a subcutaneous injection daily for five days; to determine the qualitative and quantitative nature of the toxicities encountered when DEHSPM is administered on this schedule; and to determine the pharmacokinetics/pharmacodynamics of DEHSPM and polyamine changes.
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