Professor Ken Harrap and the formula for carboplatin
In the latest in Our Milestones series, we go back to the 1970s to look at how Cancer Research UK scientists played a role in a global quest to develop and fine-tune one of the world’s most successful cancer drugs.
Sometimes the greatest medical advances are found in the most unlikely of places.
Fifty years ago, US-based physicist Barnett Rosenberg and microbiologist Loretta Van Camp wanted to find out whether electrical fields affected the growth of bacteria. So they dunked metal electrodes into the bugs’ nutrient broth. The bacteria failed to grow – forming long strands rather than neat little cells.
But, after much excitement, and a lot of head scratching, it turned out that the reason had nothing to do with electricity. Instead, the effect was due to the electrodes they were using, which happened to be made of a metal called platinum.
This raised an intriguing question: if platinum could kill fast-growing bacteria, could it also kill similarly fast-growing cancer cells?
It was those curious minds that would turn this serendipitous discovery into the development of cisplatin – the first platinum-based cancer drug.
And Cancer Research UK’s scientists would play a part in taking platinum-based drugs from lab bench to patient bedside, and refine them into some of the most effective cancer treatments to date.
Meet the super-group
While The Beatles and Led Zeppelin were enjoying their platinum-selling record successes, the 1960s weren’t a swinging picture for all. For anyone diagnosed with cancer at this time, it was mentioned in whispered tones, – back then, only one in four people survived ‘The Big C’ past the 10 year mark.
While early trials of combination chemotherapy in childhood leukaemia brought (premature) hopes that the end was in sight, further cures for other types of cancer failed to materialise. The need to develop new and better treatments was ringing loud and clear.
One of the people on the hunt for novel drugs was Sir Alexander Haddow, then Director of London’s Chester Beatty Research Institute (funded by one of the founding charities that merged to form Cancer Research UK). He heard about Rosenberg’s results at a meeting in the USA and immediately knew this was something special.
Rosenberg had discovered a number of platinum-containing chemicals that could kill bacteria and cancer cells, but it wasn’t clear which of these –if any – was the most suitable for use as a drug to treat patients. But Haddow he knew he had the right people and the right instruments in his chemistry department to turn the bug-killing effects of platinum into new therapies for cancer.
Back in London, Haddow put a young and ambitious pharmacologist – Dr Tom Connors – in charge of sifting through this huge number of platinum-based-hopefuls, to find the best candidate to take forward into clinical trials. Connors was the right man for this large-scale job: he took a thorough approach to testing all possible molecular combinations, searching for the best compromise between toxicity and effectiveness.
Eventually they struck it lucky with a compound known as cis-[PtCl2(NH3)2] – or cisplatin, as we now know it – and by 1971 it was ready to go into clinical trials. At the Royal Marsden Hospital, a team led by Dr Eve Wiltshaw gave cisplatin to patients for the first time in the UK.
Despite challenging side effects, Wiltshaw saw promising results in women with ovarian cancer.
Alongside parallel research in the USA, their work showed the astounding activity of cisplatin to treat many types of cancer, and quickly established it as the ‘gold standard’ treatment for a range of tumours.
And so, in 1978, cisplatin was approved by the US Food and Drug Administration for use in cancer patients. This international super-group of researchers had delivered a hit, and the life-saving promise of the drug was music to doctors’ and patients’ ears.
An unexpected duet
Seven years after cisplatin became widely available, 25-year-old Tim Parkes was getting ready for a Christmas party. He pulled on some tight trousers as part of his fancy dress costume, and was shocked to notice an unusual swelling between his legs.
He put it down to an earlier incident with a cricket ball, but went back to the doctor to get it checked out again just in case.
It turned out to be much more than a sporting injury, and Tim found himself on the operating table by Boxing Day.
As a fit young man, with 2-year old daughter Becky keeping him busy, he was shocked to be diagnosed with testicular cancer, which had spread to his lungs and the lymph nodes in his stomach. He remembered visiting his grandmother in hospital back in the 60s, fading away from the dreaded ‘Big C’ with radiotherapy as her only treatment option.
But this was 1985, and cisplatin was now available.
Tim was told: “Hopefully you’ll be okay when you’re on it – it’s relatively new but it looks to be working” .
Without treatment he was only given eight months to live, so he started cisplatin chemotherapy straight away.
Cisplatin treatment in the 1980s was tough. After a few courses, Tim only needed to see the drip coming towards him down the corridor to trigger aggressive and relentless vomiting. But despite feeling terrible while on cisplatin, Tim was encouraged when his first scan revealed the tumours had reduced in size by an astonishing 50 per cent. More chemotherapy and radiotherapy followed, leading ultimately to the sweetest sound for any patient: his doctor told him he was cured.
Over the following 25 years, Tim has played a range of sports, had an extremely successful career taking his business to America and, against all the odds, had a second daughter – Maddi.
He says, “Before I had cancer I was a bit wild and crazy, and in a way I’m lucky. I had a second lease of life, I did a masters degree, and wanted promotions. I really felt like I wanted to do something with my life.”
But the treatment took its toll. The human body isn’t able to defend itself from heavy metals like platinum, leading to toxic effects to kidneys, nerves and hearing. Tim remembers his oncologist warning him: “This is hammering your system so much that when you get to 50 you are going to have to look out for your kidneys.”
Unfortunately, he was right: Tim now only has part of one kidney still functioning, and is likely to face dialysis or a transplant in the future, alongside a cocktail of medicines that he takes daily, from hormone replacement therapy to drugs that support his pancreas and bowel.
It was long-term side-effects such as these that spurred researchers on. Could they to develop even better, kinder platinum drugs, or find ways to offset their downsides?
By the early 80s, as Tim’s story shows, cisplatin was having a huge impact on patient survival – but it was just the beginning. The pressure was on to make a killer follow-up hit.
Firstly, they needed to unpick the instrument and figure out just how it was working. They discovered that cisplatin was impressively able to interact with and bind to DNA – the instruction manual in every cell – triggering cancer cells to commit suicide. Knowing these mechanisms set the scene for improvements to be made.
This task fell to Professor Kenneth Harrap at The Institute of Cancer Research, who remembers a significant moment when a doctor colleague told him: “I don’t know why you think you’re so fantastic; you need to do something about the toxicity of cisplatin. It is destroying my patients.”
And so the journey began to find a modified version of the drug that retained its effectiveness but without the side effects. Kidney damage was the major issue – so Harrap and colleagues, in collaboration with chemists at the Johnson Matthey company, focused switching parts of the drug’s molecular structure around until they found versions with less harmful effects.
Eventually their work led to the development of a second drug – carboplatin – licensed in the UK in 1986 and still widely used today to treat thousands of patients. And other platinum-based drugs, such as oxaliplatin, have followed on its heels.
A global hit album
These drugs are still used in the treatment of a wide range of cancers, including lung, breast, bladder, cervical and ovarian cancers, and are prescribed for up to one in five of all cancer patients. And thankfully today more powerful anti-sickness tablets and other treatments can help control the side effects they may cause.
From his perspective, Tim is eternally grateful that cisplatin was available, despite the side effects.
The drug has revolutionised testicular cancer treatment: the death rate from the disease has fallen by around 80 per cent since the early 1970s and today, with surgery and combination chemotherapy treatment, 98 per cent of men are cured.
As a result of his experience, he’s a huge advocate for cancer research. “It’s incredible to see what’s been done, where we’ve got to, and the determination to beat it,” he says. “Everyone has a part to play; it touches everyone. We will be successful in beating it.”
We agree. And it’s fair to say this suite of drugs have been a platinum hit, thanks to the many scientists and doctors who worked tirelessly over the years to turn those first inklings of effectiveness into lifesaving drugs.
One of the key players in the story deserves particular recognition. Tom Connors dedicated his whole career to cancer research, but in a cruel twist of fate, it was to be the disease that took his life – Tom died from prostate cancer in 2002. But he left an incredible legacy.
For many people at Cancer Research UK, he was an adviser, a supporter and a friend for over 30 years. He played a huge role in honing our process for clinical trials, ensuring that the best drugs are brought to patients in the quickest time.
We have a duty to continue his life-saving work, striving every day towards new milestones.
Connors TA, Jones M, Ross WC, Braddock PD, Khokhar AR, & Tobe ML (1972). New platinum complexes with anti-tumour activity. Chemico-biological interactions, 5 (6), 415-24 PMID: 4652593