Michelle Holtorff's Research Abstract

POLYAMINE ANALOGS IN CANCER SUPRESSION

The polyamines (putresine, spermine and spermidine) are essential for the growth and proliferation of all cells. Further, quickly dividing cells especially cancer cells, synthesize and absorb large amounts of polyamines. Thus high polyamine levels have been shown necessary for tumor cell growth. Ornithine decarboxylase (ODC) is the rate-limiting enzyme in polyamine biosynthetic pathway. This enzyme, in turn, is under the regulation of a small 24.0 kDa protein named antizyme. In normal cells a high cellular concentration of polyamines causes antizyme synthesis. Antizyme binds to ODC and causes its degradation by a 26S proteosome. This causes the inhibition of polyamine biosynthesis, thus lowering the levels of polyamines in the cell. But in addition to regulating ODC, antizyme is also responsible for the control of the polyamine uptake into the cell. For these reasons, antizyme is considered the key regulatory enzyme for polyamine levels in the cell. Limiting cancer cell growth through drug-induced polyamine depletion has clinical application. DFMO, for instance, is useful as a chemopreventive agent because it inhibits ODC and consequently polyamine synthesis. But a major drawback of DFMO and other polyamine analogs is that they limit polyamine biosynthesis but have no effect on polyamine uptake into the cell. Therefore it would be useful to find a polyamine analog that induces the synthesis of antizyme. That way, polyamine synthesis and transport into the cell would both be limited. Furthermore, it is desirable to have an analog that would starve cancer cells of polyamines without inducing cell death; this would allow these analogs to be used chemopreventively.

Purpose: To find polyamine analogs, which deplete polyamine levels and arrest cancer cell growth. Compounds of this type would be used as cancer suppression drugs, which could be given to a patient after chemotherapy or in the early stages of cancer cell differentiation.

Research to be done: Several attributes of an effective chemoprevenative analog need to be deciphered. First, it should be determined which analogs are most effective at inducing the synthesis of antizyme. Preliminary studies have shown that some analogs are more effective at inducing synthesis of antizyme than others. Second, since different analogs cause different amounts of antizyme to be produced, one needs to know how different levels of antizyme synthesis affect cell growth. What levels of antizyme would be necessary to slow cell growth without affecting cell viability? How much antizyme synthesis can be stimulated before it kills the cell? Third, is there a correlation between polyamine uptake from media and the induction of antizyme synthesis? Antizyme has been shown to inhibit polyamine transport when polyamine levels are high but does the transporter itself have any affect on the level of antizyme synthesis? Fourth and finally, in order to be an effective chemopreventative agent, an analog should inhibit polyamine synthesis and uptake into the cell without having any adverse secondary effects such as interference with normal mitochondria function.