Author:

Rachel Brazil

Introduction

The importance of platinum-based chemotherapies cannot be underestimated – they are given to about 40% of patients who receive chemotherapy. Much of the research and development leading to the first platinum drug, cisplatin, was carried out in the US, but its discovery launched major research efforts in both the UK and France, producing new generations of platinum drugs with superior properties

Cisplatin – a chance discovery

Cisplatin is a platinum-based chemotherapy drug now used to treat testicular, ovarian, bladder, head and neck, lung and cervical cancer; it was first trialled in the US to treat testicular cancer and in the UK to treat ovarian cancer.

The platinum complex, cisplatin, or in long form, cis-diamminedichloroplatinum (II), was synthesised by Italian chemist Michele Peyrone (1813‒1883) in 1844, when he worked at the University of Giessen, Germany, and became known as Peyrone’s chloride. It played a major role in the development of inorganic chemistry, but it was to be long time before its anti-cancer properties were discovered.

Cisplatin

In the 1960s, physicist Barnett Rosenberg at Michigan State University, US, had seen similarities between the patterns formed during mitosis and those formed by iron fillings around a magnet, and was keen on exploring them further. The discovery of the compound’s anti-cancer properties was famously made by chance, during experiments led by Rosenberg on running an electric current through bacteria.

Rosenberg found that when a current was passed through plates of Escherichia coli bacteria they formed filamentous strand-like growth patterns ‒ similar to what is seen when bacteria stop dividing. It was Rosenberg’s lab assistant, microbiologist Loretta VanCamp, who understood what was going on, says oncologist Hilary Calvert, who was based at London’s Royal Marsden cancer hospital, and who was part of the UK team developing platinum chemotherapy compounds in the 1970s. “VanCamp realised that it was nothing to do with the electricity. It was because the platinum was dissolving off the electrodes and forming platinum compounds in the growth medium, and that was stopping the bacterial division.”

Andrew Thomson (1940‒2021), a chemist at the University of Oxford, was called on to identify the complex involved. After adding ammonium chloride to the growth medium, they soon identified the platinum complex as cisplatin ‒ a square planar molecule containing two chlorines and two amine groups, coordinated with similar ligands next to each other ‒ the ‘cis configuration’. The US lab started to work on the potential for platinum complexes to kill fast-growing cancer cells, and in 1965 the team showed astounding activity in many cancers and in Nature in 1969 described platinum compounds as a new class of potent antitumour agents.

In 1971 cisplatin entered phase I clinical trials in the US, and in 1974 Lawrence Einhorn at Indiana University School of Medicine used cisplatin in a phase II study on testicular cancer in addition to existing drugs, vinblastine and bleomycin. The results were spectacular – there had been no effective therapy before – and the regime soon became the standard therapy.

Platinum complexes quickly caught the attention of European researchers. Pharmacologist Tom Connors (1934‒2002) at London’s Chester Beatty Research Institute in London, which was to become the Institute of Cancer Research started investigating a number of platinum compounds, leading to the first UK trials of cisplatin to treat ovarian cancer. These trials were conducted at the Royal Marsden in 1971, led by medical oncologist Eve Wiltshaw (1927–2008). “She showed that it was the best drug there was for treating ovarian cancer, and it would prolong survival by quite a few years,” says Calvert, who worked for Wiltshaw at the time.

British chemist, Mike Cleare, worked in Rosenberg’s lab for several years, before returning to the UK to work on platinum chemotherapy compounds ‒ including what would later become carboplatin. Explaining the mechanism of action, he said: “Like alkylating agents, platinum drugs are effective in inhibiting the cell division in rapidly dividing cells. There is a direct chemical reaction between the platinum complex and DNA.” Many studies of its mechanism of action suggest the complex loses both its chloride ligands and binds to DNA molecules, creating crosslinks within and between strands, preventing DNA repair and triggering cell death.

One problem with cisplatin is its dose-limiting toxicity. “It has a lot of side-effects,” says Calvert, which include nausea, vomiting, peripheral neuropathy and deafness. “The most prominent one is kidney failure. But it is possible to partly get over the side-effects by giving patients huge amounts of fluid by intravenous infusion and diuretics and flushing them through really quickly while giving the platinum,” he says. This was done using the osmotic diuretic, mannitol. By 1978, US company Bristol Myers gained FDA approval for cisplatin (trade name Platinol), the first platinum anti-cancer drug.

See also this article on cisplatin by Eve Wiltshaw.