The Cross-Border Biotech Blog

Biotechnology, Health and Business in Canada, the United States and Worldwide

Friday Science Review: June 15, 2012

Cisplatin was the first platinum based chemotherapy and remains the most widely used. Through an alkylating-like mechanism of action, cisplatin kills cells by binding, cross linking and damaging their DNA, thereby stimulating apoptosis through failed DNA repair attempts.

Platinum based chemotherapy is a standard first line therapy following surgery for many of the most common cancers (e.g. lung, ovarian, cervical). While cisplatin is able to produce positive responses in many patients, with time many will suffer from disease progression due to the development chemoresistance. While targeting cancer stem cells may prove to be a successful (and topical) approach, other approaches that seek to overcome the mechanisms of chemoresistance are important. These mechanisms will depend upon the agent to which resistance is conferred, but include increased efflux, mutation in the therapeutically target enzyme, decreased drug activation, increased drug metabolism, drug inactivation, enhanced DNA repair and mutation of the apoptosis pathway.

In this weeks post, the Lu lab at the University of Waterloo sought to boost the DNA-damaging activity of cisplatin. Based upon the authors’ previous studies, where they demonstrated the importance of a dissociative electron-transfer mechanism for reductive DNA damage by cisplatin, the authors proposed that addition of a biological electron donor to cisplatin treatment would increase its activity and potentially overcome resistance. N,N,N’,N’-tetramethyl-p-phenlenediamine (TMPD) is one such donor and in combination with cisplatin it was shown to increase plasmid DNA double strand breaks (a simple measure for DNA-damage activity); increase cisplatin sensitivity in both HeLa cells and in the cisplatin resistant ovarian cancer cell line NIH:OVCAR-3. A key feature of the combination is that it led to synergistic rather than additive effects. Furthermore, the authors proposed that the presence of TMPD actually suppressed the mechanism conferring cisplatin resistance to the NIH:OVCAR-3 cells, however, demonstration of that will require further work.

Indeed, much remains to be done to demonstrate the broad applicability and robustness of the results, but cisplatin’s immense importance in the formulary and its frontline use in a wide range of cancers means that the rapid development of a TMPD adjunctive therapy is one to be hoped for.

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