Shining new light on drug design: photoactivated chemotherapy

About 11M cases of cancer are diagnosed each year and there is a pressing need for new anticancer drugs. The world’s leading anticancer drugs are platinum-based compounds such as cisplatin. These types of platinum compounds are not targeted to cancer cells and also kill healthy cells. This can result in severe side-effects and the development of resistance, so that some patients stop responding to treatment. Methods for increasing the selective activation of platinum drugs at the site of the tumour are envisaged which address these problems. We have developed new platinum-based drugs which are non-toxic in the dark, but become highly toxic when activated by light. By shining light only on the area of cancerous tissue, we can target the activation of the drug to just the selected area.
It is vital that we carry out more studies into how these drugs kill cancer cells, which will involve laboratory work and experiments to investigate if they can shrink/treat cancers. We hope that the wavelengths of light for activating these compounds make them suitable for treating surface cancers and that slight changes to the drugs will allow treatment of a wider range of cancers.

With around 25 million people living with a diagnosis of cancer, new anti-cancer therapies are urgently needed. If cancer is to become a manageable disease, then these new therapies need to ensure as few side-effects as possible, and bypass the resistance mechanisms commonly seen with current treatments. In addition, treatments that could be repeated as often as required (unlike current chemotherapy or radiotherapy) would be very useful. Platinum (Pt) drugs are amongst the most successful and commonly prescribed class of anti-cancer agents (44% of 2004 market). Cisplatin and its related prodrug carboplatin have a broad spectra of anti-tumour activity. However, their use is curtailed by the serious dose-limiting side effects that are often responsible for treatment failure. These include extreme nausea and vomiting, ototoxicity and nephrotoxicity. Additionally many tumours have intrinsic or develop acquired resistance to these drugs. The side-effects of Pt drugs could be avoided if a selective activation of a Pt-prodrug could be made to take place only in the tumour tissue. Thus we have developed a series of photolabile Pt(IV) complexes that show equal or greater cytotoxicity than cisplatin tested under identical conditions in cultured tumour cells, but only when they are irradiated with UVA or blue visible light. They are relatively non-toxic in the dark. These photolabile complexes appear to kill the cells by a distinct mechanism and are not simply acting as prodrugs of cisplatin or transplatin. Moreover, they may not require oxygen (O2) for their mechanism of action, thus removing one of the limitations of current, conventional light-activated therapies. Our challenge is to develop Pt-complexes that are selectively taken up by tumour cells, and for which the wavelength of activation can be controlled, making them useful for the treatment of thin walled organs as well as thicker tumours. We also wish to demonstrate antitumour activity without an O2-dependent mechanism. Finally, we want to develop novel methods of light delivery that will optimise the therapeutic benefit of these light-activated Pt prodrugs. Thus the light-activated Pt prodrugs should combine the potent cytotoxic properties of Pt-based drugs, but with the targeting of photodynamic therapy. Success with this project will ultimately lead to more effective and less toxic therapeutics for cancer chemotherapy.