Platinum anticancer drugs action mechanism

The minor perturbation of the DNA structure caused by cis-platin may well not be detected in a cell which has a deficiency in the repair mechanism, whereas a normal cell might have a more selective repair mechanism. Whether this is the mechanism of action of the platinum anticancer drugs still has to be established, but it is the first model which satisfactorily accounts for all the known chemical and structural restraints. In addition, it suggests further modeling experiments with the more effective second generation drugs. 

In general terms, both steric effects and electronic factors are expected to play a role in determinating the reactivity of square-planar platinum complexes. The presence of planar amine ligands in cis- or /ran.y-Pt(anion )2 complexes and their orientation with respect to the coordination plane, as well as their substituents, can reduce the rates of DNA binding or thio binding compared to aliphatic ammine and amine complexes. Especially, substituents close to the coordination site should be expected to slow down axial substitution reactions at Pt. As there is now little doubt that DNA platina-tion is a key event (or THE key event) in the mechanism of action of platinum anticancer drugs, attention to the process of formation of the major adduct (GG) as an intrastrand cross-link between N(7) atoms of two adjacent guanine (G) residues, will remain important. 

Dhar, S. Lippard, S. J. Current Status and Mechanism of Action of Platinum-Based Anticancer Drugs. In Bioinorg. Med. Chem. 79-95 (Wiley-VCH Verlag) (2011). 

Biochemically important platinum complexes. - Since the mechanism of action of anticancer drugs like ds-platin, cis-PtCl2(NH3)2, implies N-guanosine-binding... 

While transplatin is not an active anticancer drug some trans platinum complexes, however, are highly cytotoxic. In the search for active trans platinum compounds several complexes with triphenylphosphine or dimethylphenylphos-phine ligands have been studied (Fig. 13.5), and found to be active on various cancer cell lines, with no cross resistance to cisplatin observed [22]. Apoptotic cell death with no G1 and G2/M accumulation in the cell cycle, typical for the cisplatin, was observed indicating a non-classical mechanism of action. 

H. Harder, then in our laboratory but now at George Washington University, was responsible for these studies. He also checked that the synthesis of precursor molecules for DNA, and the transport of these across membranes was not responsible for the inhibition. He has more recently shown that the ability of the DNA to act as a template for new synthesis is strongly inhibited by the platinum drug. These results can be most reasonably explained by the hypothesis that the anticancer activity of the platinum drugs arises from a primary attack on DNA. The battle to discover the molecular mechanism of action was, therefore, joined on the field of metal complex interactions with DNA, and numerous other laboratories entered the fray. The booty has been rich, embarrasingly so. 

---