29 October 2010
Inactive platinum complexes can be transformed into exciting anticancer compounds by coupling them with testosterone using a quick and simple method, claim UK scientists. This could pave the way for new target specific anticancer drugs.
Platinum compounds cisplatin, carboplatin and oxaliplatin are commonly used to treat cancer. But these drugs can only treat a limited number of tumours and some types of cancer are now showing resistance. The drugs are also highly toxic and cause unwanted side effects. Drugs that target the site of disease without harming healthy tissue are better and have been explored by using the sex hormone oestrogen attached to a Pt compound. These target oestrogen receptors which are over-expressed in most breast cancer tumours.
Now, Carlos Sanchez-Cano, Michael Hannon and colleagues at the University of Birmingham,UK, have used testosterone to create a metallodrug that targets the androgen receptor, the predominant sex-steroid receptor over-expressed in all prostate tumours as well as many breast and ovarian tumours.
Testosterone delivers the platinum warheads resulting in interesting effects on the activity and properties of the drug
By attaching steroidal testosterone to inactive platinum compounds, the team show that targeted drugs have enhanced cell uptake and anticancer activity levels compared to non-steroidal cisplatin. Further investigation on a small library of testosterone-coupled platinum complexes shows that testosterone serves not only as a delivery agent for the compounds but modifies the types of DNA binding formed. The testosterone-based complexes cause the DNA helix to undergo significant unwinding and bending.
'To date, nobody has used testosterone for targeting,' says Sanchez-Cano. 'We have shown that drug delivery agents are not only the mere transporters of warheads; instead, they can have an interesting effect on the activity and properties of the carried drug,' he adds.
Terry Jenkins, a medicinal chemist at the University of Greenwich, UK, comments: 'This design strategy has great significance as the approach offers prospects for a worthwhile increase in drug activity together with a reduced burden for patients through toxic side-effects resulting from inefficient, untargeted delivery.'
The team are now exploring the effects of linking different metallic units to steroidal molecules. 'More work needs to be carried out to fully understand the mode of action these compounds have once inside the cell and to see how they would work in more complicated systems presenting target and non-target cells at the same time, to see the real potential of this kind of strategy,' concludes Sanchez-Cano.