Temozolomide: the brain tumour superstar

Temozolomide was synthesised by Professor Malcolm Stevens and his team at the University of Aston, and was an early success for the Phase I/II Clinical Trials Committee, a predecessor of the Centre for Drug Development’s New Agents Committee. Now the international standard of care for treatment of glioblastoma, in 2008 sales figures exceeded $1 billion. Here, Malcolm reflects on the work that led to his team’s discovery.

“We didn’t have any particular idea where we were going – it was unfettered interesting research that eventually led to something very worthwhile. But we didn’t know what that ‘worthwhile’ was going to be when we gathered at Aston in the 1970s.

There was no particular moment in time when temozolomide was ‘discovered’ – there was work that I did as a PhD student, serving my apprenticeship, and my early days as a lecturer up in Edinburgh where we investigated the properties of molecules that were rich in nitrogen. That was the secret of our ultimate success – making compounds with multiple nitrogen atoms. They tend to be rather easy to make, which is a good thing, and they have interesting properties from a chemical and from a biological perspective.

We realised when we’d made the family of compounds that eventually became temozolomide that they were likely to have some exciting biological properties. Up to that time, all the compounds we’d made were biologically inert, and it was only around that time – the early 1980s – when we were making interesting molecules.

And because of funding from the Cancer Research Campaign (a predecessor charity to CRUK), we had the ability to test the compounds. We were able to do the synthetic chemistry, the toxicology work, and could manufacture formulations of the drug.

When we were researching temozolomide, we weren’t supported by any major pharmaceutical companies, so the obvious place to go to was the Cancer Research Campaign’s Phase I/II Committee. Exciting early work convinced the committee of the potential for the treatment, so they decided to fund the clinical trials on temozolomide.

I don’t think there was ever a ‘eureka’ hats-in-the-air moment, but I guess we expected that something was going to work. After all, we’re scientists, we think that we’ve done our side of the bargain – the preclinical work – and why should we be surprised if something beneficial happens in the clinic?”