Polyamines are considered to play an important, yet undefined, role in regulating cell proliferation and growth. Researchers have investigated various methods of depleting intracellular polyamine pools as a potential approach to the discovery of new anticancer agents. One such method has investigated the use of inhibitors of polyamine synthesis. Compounds that have reached clinical trials include difluoromethylornithine (DFMO) and methylglyoxal-bis (MGBG). Although these and other polyamine inhibitors have demonstrated antiproliferative effects in vitro, their clinical application as anticancer agents has been largely unsuccessful. The reason for this is most likely due to the existence of efficient homeostatic mechanisms that serve to restore intracellular polyamine pools through compensatory mechanisms, thereby maintaining functionality. An alternate approach to polyamine depletion has been proposed. In principle, the concept is similar to the well-established use of dysfunctional analogs of endogenous substances as cytotoxic agents. Synthesized polyamine analogs are able to be taken up by cells using the polyamine transporter, recognized by cells as a naturally occurring polyamine and are incapable of substituting for the natural polyamine in those yet unidentified functions required for cell growth. A pseudo-polyamine excess is created in cells, thereby down-regulating the enzyme responsible for polyamine synthesis. In addition, some of these analogs are potent inducers of spermidine, an enzyme responsible for intracellular polyamine catabolism. If successful, this approach could result in antiproliferative effects mediated through depletion of functional polyamine pools. This is a Phase I, open label, non-randomized dose-finding study to determine the dose-limiting toxicity and the maximum tolerated dose of diethylnorspermine (DENSPM).
Showing the most recent 10 out of 459 publications