Platinum Anticancer Drug Chemistry and Biology

A major area of work is to understand and improve platinum anticancer drugs. cis-Diamminedichloroplatinum(II), cis-DDP or cisplatin, is an anticancer drug currently in widespread clinical use. We are studying the mechanism of action of cis-DDP in order to be able to design more effective agents in the platinum family of therapeutics. There are four main steps in the molecular mechanism: cell entry; activation of the platinum complex for DNA binding; binding to DNA in the cell nucleus; and the subsequent biological consequences that arise from the damaged genome, specifically, transcription inhibition and repair of the damaged DNA. X-ray and other structural studies of cis-DDP and related platinum anticancer drugs coordinated in a site-specific manner to synthetic double-stranded DNAs, both alone and in complex with proteins that bind or process the platinated DNA, have revealed important features about the stereochemical features. Among the complexes under investigation are the nucleosome core particle and RNA polymerase II in complex with site-specifically platinated DNAs and an RNA leader strand. The information gained in these studies is used to guide the synthesis of novel anticancer drug candidates.

A strategy under active investigation is to devise platinum(IV) pro-drugs in which two additional, axial ligands are employed to attach cis-DDP and its analogues to nanomolecular constructs, such as single-walled carbon nanotubes, gold nanoparticles, and linear polymers, for preserving the lifetime of the platinum payload after administration, for targeting cancer cells, and/or for taking advantage of the unique metabolism of cancer cells to improve the efficacy and selectivity of the prodrug. The redox properties of the compounds are adjusted to release the platinum(II) warhead in the cells and not prematurely in blood, which carries the construct to the tumor site. Animal studies are currently in progress with collaborators to evaluate several platinum(IV) pro-drugs having these characteristics.

We have identified a family of cellular proteins that bind to DNA platinated by cis-DDP. Several genes that encode these proteins have been obtained from both human and yeast cDNA libraries. We demonstrated that the major adducts of cisplatin are removed by excision repair in human cell extracts and that HMG-domain proteins can shield cisplatin-DNA adducts from repair. The resulting adducts block replication and transcription, one possible mechanism for which being to sequester one or more factors that are essential for transcription. Other proteins such as PARP-1 interact with platinated DNA. Knowledge about these interactions is being used in conjunction with chemical synthesis and gene therapy strategies to obtain better platinum-based molecules and protocols for cancer chemotherapy.