Improved anti-cancer drugs
Researchers in New Zealand have found a radical way to help develop anti-cancer drugs.
Many slow-growing solid tumours are resistant to radiotherapy and some anti-cancer drugs, which is partly due to low oxygen concentrations (hypoxia) in the cancerous cells.
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Tirapazamine, a drug currently undergoing clinical trials, is known to be activated in the hypoxic parts of tumours. This is because it is transformed into a radical species by a pathway which is inhibited by oxygen. This radical species can kill cells by inducing strand breaks in DNA.
Robert Anderson and colleagues from the University of Auckland have now found strong evidence that the active species is the benzotriazinyl radical, and not the OH radical, as previously suggested.
Anderson's group made a number of analogues of tirapazamine, and measured the reduction potentials of radicals derived from each.
They found a strong correlation between the reduction potentials of the benzotriazinyl radicals and their cytotoxicity under hypoxic conditions.
This means that the effectiveness of the drug can be controlled by adding substituents to the tirapazamine 'core'.
To help future research, Anderson's group has defined a set of kinetic and thermodynamic parameters that should be applied to potential drugs. Anderson suggests that satisfying these criteria, as well as other pharmacological aspects, should lead to 'the successful development of an improved analogue of tirapazamine'. David Barden