Collaboration Yielded A New Class Of Cancer Drugs

In the mid-1960s, Michigan State University professor Barnett Rosenberg accidentally discovered an unusual effect that platinum compounds had on cell division. After the causative compounds were identified and subsequently tested in tumor cells, one went on to become the anticancer drug cisplatin, or cis-diamminedichloroplatinum (II) (C&EN, June 20, 2005, page 52).

Although the new cancer killer brought tremendously positive changes to the oncology field, cisplatin can cause severe kidney and nerve damage, as well as hearing loss. To remedy against this, researchers came together to create next-generation compounds that have fewer toxic side effects.

Much of what follows is based on the recollections of Chris Barnard, a scientist with the British precious-metals firm Johnson Matthey. Barnard was a member of the Johnson Matthey biomedical group between 1980 and 1995 and specialized in the characterization and chemistry of platinum compounds.

After his discovery, Rosenberg approached various companies with an interest in platinum to help support his work on its anticancer properties. According to Barnard, Rosenberg was looking for scientists who could provide the chemistry expertise to develop a series of compounds with which to study structure-activity relationships. He thought these might provide guidance on lessening the toxicity of cisplatin.

Michael J. Cleare went from Johnson Matthey to work at Michigan State as a postdoctoral fellow in the early 1970s. Barnard says the metals firm Engelhard, now part of BASF, also agreed to place a chemist into Rosenberg's lab. In 1973, Cleare and James D. Hoeschele, who was a postdoc at Michigan State and then worked for Engelhard, published articles that for many years defined the structural rules governing what researchers believed would make an effective platinum drug.

On his return to Johnson Matthey, Cleare set about contacting others in the U.K. who might have had an interest in anticancer applications. Rustenburg Platinum Mines sponsored the group he pulled together, and it became known as the Rustenburg Cancer Group. Key participants included the Institute of Cancer Research (ICR) and the Royal Marsden Hospital (RMH), both in London.

Meanwhile, the development of cisplatin was supported largely by the National Cancer Institute in the U.S. The drug was then licensed to Bristol-Myers Squibb, which got approval and starting selling it in 1978 under the name Platinol.

After the launch, discussions were held between BMS, Johnson Matthey, and ICR regarding further work on analogs of cisplatin, and these resulted in formal agreements. Work focused on altering the ligands, which influence the activity and fate of platinum complexes.

Carboplatin, or cis-diammine(1,1-cyclobutanedicarboxylato) platinum (II), was designed with a bidentate dicarboxylate ligand, instead of chloride ligands. This change slows down reactivity and degradation into potentially toxic derivatives that can cause side effects. Developed as a drug by BMS, it was approved in 1986 in Europe and in 1989 in the U.S.

Picoplatin, or cis-amminedichloro(2-methylpyridine) platinum(II) was another product of the alliance. Here the team added steric bulk to block access to the platinum atom and prevent binding with proteins in the body that can deactivate it and lower its effectiveness.

The third major analog the group designed was satraplatin, or bis(acetato)amminedichloro(cyclohexylamine) platinum (IV). It violated the structure rules by being a Pt(IV) complex, which allows it to have two additional axial acetato ligands. It is significantly more inert to ligand substitution and can work as an orally bioavailable compound.

The alliance was particularly well-balanced and set up in a way that ensured rapid progression of chosen candidates, Barnard says. Johnson Matthey contributed skills for synthesizing and characterizing platinum compounds. Funded jointly by charities, commercial contracts, and the government, ICR specialized in discovery and preclinical development of new anticancer agents and was attached to RMH, which conducts clinical studies.

Meanwhile, BMS provided drug formulation and manufacturing capabilities. It also had the regulatory control and project management expertise to ensure that the results conformed to the standards required for drug registration.

The project came to an end, however, when BMS decided to stop supporting the clinical program for satraplatin and the development program for picoplatin. According to Barnard, the drug company's projections for these programs did not meet its criteria for commercial success.

The rights to satraplatin were returned to Johnson Matthey. With no immediate interest from other major pharmaceutical companies, the compound was eventually licensed to a company now known as Spectrum Pharmaceuticals. It in turn sublicensed satraplatin's development to what is now Agennix.

Without the support of BMS and the withdrawal of other major pharmaceutical partners from Johnson Matthey research programs, Barnard says, the company took the view that these activities could best be continued outside the company. With the venture capital support, it established Anormed in Vancouver and transferred much of its intellectual property in pharmaceutical research, including picoplatin, to that company. Picoplatin now is in the hands of Poniard Pharmaceuticals, which has been conducting clinical trials of the compound.

Barnard says the direction of work at ICR has moved away from small-molecule drugs and toward other approaches to cancer research. "None of the partners has played a major role in platinum anticancer drug development since the last collaborative program was completed," he says.