Success of Fluoropyrimidines Drugs
Fluoropyrimidines (FPs) are an example of a class of drugs that is widely used for cancer chemotherapy, yet the cytotoxic mechanisms of FPs are not completely understood and clinical response to these drugs is limited. I invented a novel polymeric form of FdUMP, the TS-inhibitory metabolite of 5FU, and have demonstrated the safety and efficacy of the FdUMP polymer in tissue culture and animal models of human cancer.
The results indicate that FdUMP[N] polymers are likely to be highly efficacious for the treatment of human cancer. Further, FdUMP[N] polymers are highly cytotoxic towards cancer cells that are not sensitive to 5FU, such as prostate cancer cells, but are not cytotoxic to normal prostatic epithelial cells.
The increased activity of FdUMP[N] polymers relative to monomeric FPs results from the increased misincorporation of FdUTP into DNA and greater DNA damage. In collaboration with Dr. Yves Pommier (NCI), we showed that exposure of cancer cells to FdUMP results in trapping of topoisomerase I (Top1) cleavage complexes at the site of FdUTP misincoporation. Thus, FdUMP mechanistically resembles the camptothecin class of anticancer drugs. [ATP-levels in drug-treated cells are assessed using a luminescence assay]. In collaboration with Dr. Frits Peters (Free University, Amsterdam) we recently showed that FdUMP retained activity towards TK-null cells while FdU does not implicating cellular degradation to FdU is not essential for FdUMP cytotoxicity.
Current efforts in my laboratory are focused on elucidating the cell death pathways that are activated in human prostate cancer cells following exposure to FdUMP. My laboratory has also demonstrated that FdUMP is a potent radiosensitizer of prostate cancer xenografts in vivo.
Structured DNA Molecules Initiative
A major new initiative in my laboratory in recent years is the development of highly structured DNA molecules that are selectively cytotoxic to cancer cells.
The selective killing of malignant cells remains an important challenge that has not been fully met by the development of monoclonal antibodies and other targeted therapeutics. The “CytotoxamersTM” being developed in my laboratory represent a novel approach to the selective killing of cancer cells.
These structured molecules are less prone to extracellular degradation than linear homopolymers and have the potential to be highly selective anticancer drugs ushering the antimetabolite class of anticancer drugs into the era of targeted therapeutics.