Our milestones: Cisplatin – the story of a platinum selling lifesaver – Cancer Research UK

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In the last in Our milestones series, we go back to the 1970s to look at how scientists from Cancer Research UK played a part in a global quest to develop and refine one of the world’s most successful cancer drugs.

Sometimes the greatest medical advances are found in the most unlikely places.

Fifty years ago, the American physicist Barnett Rosenberg and microbiologist Loretta Van Camp wanted to know whether electric fields influence the growth of bacteria. So they dipped metal electrodes into the insects’ breeding ground. The bacteria didn’t grow and formed long strands instead of 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: because of the electrodes they used, which happened to be made of a metal called platinum.

This raised an intriguing question: If platinum could kill fast-growing bacteria, could it kill equally fast-growing cancer cells?

It was those curious minds who would turn this accidental discovery into the development of cisplatin – the first platinum-based cancer drug.

And the scientists at Cancer Research UK are said to have a role in taking platinum-based drugs from the lab bench to the patient’s bedside, refining them into some of the most effective cancer treatments to date.

Meet the supergroup

While The Beatles and Led Zeppelin enjoyed their platinum-selling record successes, the 1960s weren’t rocking for everyone. For everyone diagnosed with cancer at the time, it was whispered – at the time, only one in four people survived ‘The Big C’ after 10 years.

While early trials of combination chemotherapy childhood leukemia brought (premature) hope that the end was in sight, further cures for other cancers were not forthcoming. The need to develop new and better treatments was loud and clear.

One of the people on the hunt for new drugs was: Sir Alexander Haddow, then director of London’s Chester Beatty Research Institute (funded by one of the founding charities that merged into Cancer Research UK). He heard about Rosenberg’s results at a meeting in the US and knew right away that this was something special.

Rosenberg had discovered a number of platinum-containing chemicals that could kill bacteria and cancer cells, but it was not clear which of these, if any, was most suitable for use as medicine for patients. But Haddow knew he had the right people and the right tools in his chemistry department to turn platinum’s insecticidal effects into new cancer therapies.

Back in London, Haddow put a young and ambitious pharmacologist – Dr Tom Connors – responsible for sifting through this huge number of platinum-based hopefuls, to find the best candidate to move forward with clinical trials. Connors was the right man for this large-scale job: he thoroughly tested all possible molecular combinations, looking for the best compromise between toxicity and effectiveness.

Possibly they got lucky with a compound known as cis-[PtCl2(NH3)2] — or cisplatin, as we know it today — 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 in the UK for the first time.

Despite challenging side effects, Wiltshaw . saw promising results in women with ovarian cancer.

In addition to parallel research in the US, their work demonstrated the amazing activity of cisplatin for treating many types of cancer, quickly making it the ‘gold standard’ treatment for a range of tumors.

And so, in 1978, cisplatin was approved by the US Food and Drug Administration for use in cancer patients. This international supergroup of researchers had delivered a hit, and the drug’s lifesaving promise was music to the ears of doctors and patients.

An unexpected duet

Seven years after cisplatin became widely available, 25-year-old Tim Parkes was gearing up for a Christmas party. He put on tight pants as part of his fancy dress costume and was shocked to see an unusual swelling between his legs.

Tim Parkes and his daughter Maddic

Tim Parkes and his daughter Maddic

He attributed it to a previous cricket ball incident, but went back to the doctor for a re-examination just in case.

It turned out to be much more than a sports injury, and by Boxing Day, Tim was on the operating table.

As a fit young man, with 2-year-old daughter Becky keeping him entertained, he was shocked when he was diagnosed testicular cancer, which had spread to his lungs and the lymph nodes in his stomach. He recalled visiting his grandmother in the hospital in the 1960s, where she left the dreaded ‘Big C’ with radiotherapy as her only treatment option.

But this was 1985 and cisplatin was now available.

Tim was told, “Hopefully it’ll be fine when you get on with it – it’s relatively new, but it seems to be working”.

Without treatment, he had only eight months to live, so he immediately started chemotherapy with cisplatin.

The treatment with cisplatin in the 1980s was tough. After a few courses, all Tim had to do was watch the IV move toward him down the hallway to induce aggressive and relentless vomiting. But despite feeling awful while taking cisplatin, Tim was encouraged when his first scan revealed that the tumors had decreased by as much as 50 percent. More chemotherapy and radiotherapy followed, eventually leading to the sweetest sound for any patient: His doctor told him he was cured.

Over the next 25 years, Tim played various sports, had an extremely successful career bringing his business to America and, against all odds, had a second daughter – Maddi.

He says, “Before I got cancer, I was a little wild and crazy, and in a way I’m lucky. I got a second life, I did a master’s, and wanted promotions. I really felt like I wanted to do something with my life.”

But the treatment took its toll. The human body cannot defend itself against heavy metals such as platinum, leading to toxic effects on kidneys, nerves and hearing. Tim remembers his oncologist warning him, “This is so hammering on your system that when you turn 50, you have to watch your kidneys.”

Unfortunately, he was right: Tim now only has part of one kidney that is still functioning and will likely undergo dialysis or a transplant in the future, as well as a cocktail of drugs he takes daily, from hormone replacement therapy to drugs that support his pancreas and gut.

It was such long-term side effects that spurred researchers. Can they develop even better, friendlier platinum drugs or find ways to make up for their drawbacks?

Focus

As Tim’s story shows, cisplatin had a huge impact on patient survival in the early 1980s, but this was just the beginning. The pressure was on to make a great follow-up hit.

First they had to detach the instrument and figure out how it worked. They found that cisplatin was impressively able to interact with and bind to DNA – the manual in every cell – and prompted cancer cells to commit suicide. Knowing these mechanisms forms the basis for improvements.

This task stood out Professor Kenneth Harrap at The Institute of Cancer Research, who recalls a key 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 destroys my patients.”

And so began the journey to find a modified version of the drug that kept its effectiveness, but without the side effects. Kidney damage was the biggest problem — so Harrap and colleagues, in collaboration with chemists at the Johnson Matthey company, focused on switching parts of the drug’s molecular structure until they found versions with less harmful effects.

Ultimately, their work led to the development of a second drug – carboplatin – licensed in the UK in 1986 and still is much used today to treat thousands of patients. And other platinum-based drugs, such as: oxaliplatin, are hot on their heels.

A worldwide hit album

cisplatin

Cisplatin is still used today flicker/haukeland through CC-BY 2.0

These drugs are still used to treat a wide variety of cancers, including lung, breast, bladder, cervical and ovarian cancer, and are prescribed to up to one in five of all cancer patients. And thankfully, today more potent anti-disease tablets and other treatments can help control the side effects they can cause.

From his perspective, Tim is eternally grateful that cisplatin was available despite the side effects.

The drug has revolutionized the treatment of testicular cancer: the death rate from the disease has fallen by about 80 percent since the early 1970s and today, with surgery and combination therapy with chemotherapy, 98 percent of men are cured.

His experience has made him a strong supporter of cancer research. “It’s incredible to see what has been done, where we need to be and the determination to beat it,” he says. “Everyone has a role to play; it affects everyone. We will manage to beat it.”

We agree. And it’s fair to say that this line of drugs has been a platinum hit, thanks to the many scientists and doctors who have worked tirelessly over the years to turn those early suspicions of effectiveness into life-saving drugs.

One of the protagonists in the story deserves special recognition. Tom Connors devoted his entire career to cancer research, but in a cruel twist of fate, it would be the disease that took his life – Tom died of prostate cancer in 2002. But he left an incredible legacy.

For many people at Cancer Research UK he was an advisor, supporter and friend for over 30 years. He played a big roll sharpening our clinical trial process to ensure the best drugs are delivered to patients as quickly as possible.

We have a duty to continue his life-saving work and strive for new milestones every day.

– Lucy

References

Connors TA, Jones M, Ross WC, Braddock PD, Khokhar AR, & Tobe ML (1972). New platinum complexes with antitumor activity. Chemical-biological interactions, 5 (6), 415-24 PMID: 4652593

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