Platinum compounds are a mainstay of cancer chemotherapy, with over 50% of patients receiving a platinum drug. But there is a great need for improvement. Major features of the cisplatin mechanism of action involve cancer cell entry, formation mainly of intrastrand cross-links that bend and unwind nuclear DNA, transcription inhibition, and induction of cell death programs while evading repair. Recently we discovered that platinum cross-link formation is not essential for activity. Monofunctional Pt compounds like phenanthriplatin, which make only a single bond to DNA nucleobases, can be far more active and effective against a different range of tumor types. Without a cross-link-induced bend, monofunctional platinum complexes can be accommodated in the major groove of DNA. Their biological mechanism of action is similar to that of cisplatin. These discoveries opened the door to a large family of third row transition metal-based drug candidates, including those of Os and Re. The osmium complex [Os(N)Cl<sub>3</sub>(<i>o</i>-phen)] has the remarkable ability to destroy cancer stem cells thought to play a key role in cancer recurrence following conventional chemotherapy and in metastasis. This work was supported by the National Cancer Institute and the Koch Institute for Integrated Cancer Research at MIT.

Platinum and other third row transition metals for treating cancer

249th National Meeting (2015)

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