Drugs that target topoisomerase action are effective anticancer agents and a number are FDA approved. Anti-topoisomerase therapy is predicated on subverting the endogenous topoisomerase into a genotoxic, DNA damaging agent. A significant problem with such drugs is collateral damage in normal cells. Since all nucleated somatic cells retain some level topoisomerase activity (either type I and/or type II), negative outcome due to DNA damage in normal healthy tissue is unavoidable, unless novel strategies can be crafted to tune down undesirable side effects. In this SBIR, the corporate sponsor (TopoGEN, Inc.) is proposing a combinatorial strategy using `smart pharma' drug design. Potent topoisomerase poisons can be coupled to polyamines (spermine for example) which are processed preferentially by cancer cells based on elevated requirement of exogenous polyamines for cell growth. Evidence is provided that novel anti- topoisomerase/polyamine conjugates induce preferential DNA damage via endogenous topoisomerase poisoning in cells with hyperactive polyamine transport mechanisms. A library of novel polyamine compounds of this sort has been synthesized (and others are being constantly added). In this SBIR, the company will rigorously evaluate these novel compounds for topoisomerase targeting efficacy in vivo using defined model cells lines and in vitro using purified enzymes. This strategy for rational polyamine-topoisomerase drug design will reveal the most effective agents for cancer cell killing while minimizing damage to normal cells.
The development of targeted cancer therapies would be a clear advance in the treatment of cancer. Since cancer costs in the U.S. were nearly 1.4 million lives and $210 billion in 2005, it makes both medical and economic sense to invest in new pharmaceutical technologies. Smart drugs, which can selectively target and kill cancers, would begin to address this important public health issue. ? ? ?
