Cancer is the second leading cause
of death in the US, exceeded only by heart disease. In the US, I
of every 4 deaths is from cancer. Since 1990, there have been approximately
5 million cancer deaths. Despite the advances made in cancer chemotherapy
in recent decades, many anticancer drugs display relatively poor
selectivity for cancer cells. Solid tumors are particularly resistant
to radiation and chemotherapy. Prodrug approach has been applied
to alleviate toxicity of the anticancer drugs and to improve their
target specificity. This proposal is designed to explore new sulfurcontaining
amsacrine derivatives with a particular emphasis on the modulation
of cytotoxicity by the use of the S/SO/SO2 redox system to achieve
improved selectivity against cancer cells: 1. A series of sulfur-containing
amsacrine derivatives will be designed and synthesized as intercalating/topoisomerase
inhibitory agents with a bioreductive potential to achieve selectivity
against solid tumors. 2. The proposed compounds will be evaluated
for their potential cytotoxicity against established tumor cell
lines in vitro. 3. Mechanism(s) of activation/cytotoxicity will
be examined by using several techniques. In addition, studies will
be conducted on the structure-activity relationship (SAR) through
the use of a molecular modeling technique. |
