Andrew Thomson

Professor Andrew Thomson FRS OBE was a founding member of the IBDG. Andrew is an acclaimed spectroscopist and pioneer of metalloprotein research in the UK and internationally. In the monologue below, Andrew gives a fascinating insight into his contributions to the CisPlatin story, 50 years after the seminal JBC paper describing the inhibition of cell division by platinum complexes, and how he subsequently turned his attention towards metalloproteins.

CisPlatin – Recollections and Reflections Fifty Years On

ajt1My involvement in the CisPlatin story began as I was completing my D. Phil. under the supervision of R.J.P. Williams at Oxford, studying the polarised optical spectra of crystals of platinum(II) salts. Bob Williams knew Barney Rosenberg through their shared interest in electron transfer in proteins. Rosenberg had discovered that certain platinum species, formed by electrolysis of the electrodes, caused E. coli cells, in liquid culture, to grow as filaments.

Bob drew this intriguing problem to my attention. Barney was seeking his help in identifying the chemical state of platinum that was the causative agent. It struck me as a fascinating discovery that might allow me to broaden my experience in biology and biophysics. On completion of my D. Phil. degree in 1965, I took up a postdoctoral post with Barney Rosenberg at Michigan State University, a far cry from Oxford. I synthesized a range of platinum complexes to test their filamenting activity guided by electrophoretic data that pointed to a neutral complex as the likely active species.

ajt2The first paper reporting the identity of two platinum complexes that caused filamentation, written by Rosenberg, L. Van Camp, E. Grimley and A.J. Thomson, appeared in 1967 in the Journal of Biological Chemistry, 242, 1347. It was entitled “The Inhibition of Growth or Cell Division in Escherichia coli by different ionic species of Platinum (IV) complexes”. Although the title referred only to a Pt(IV) complex, the paper also reported that both cis-[PtIV(NH3)2Cl4] and the Pt(II) complex  cis-[PtII(NH3)2Cl2],  were  effective in causing E. coli. cells to grow into long filaments by inhibiting cell division. Remarkably only the cis but not the trans stereo-isomers were active. On diluting out the platinum complex the filaments developed cross walls forming bacterial cells of normal size and shape. The cis isomer of Pt(II) was shown by Van Camp and myself to be the more highly effective at filamenting E. coli. This led Rosenberg, in a major leap, to test the efficacy  of cis-[PtII(NH3)2Cl2] to inhibit eukaryotic cells undergoing uncontrolled cell division. Using materials synthesized by me the anti-tumour activity was tested against an experimental tumour, sarcoma 180, in mice causing the tumour to disappear within eight days. Further tests against L1210 leukaemia cells growing in culture at the National Cancer Institute (NCI) in Washington were also promising. These results were published by B. Rosenberg, Van Camp, J.E. Trosko and V.H. Mansour in Nature in 1969, 222, 385. A preprint sent to me was inscribed on the front in Barney’s handwriting “Hang on to your hat, Andy, this may be the best anti-tumour drug yet!”

This report did not immediately lead to an explosion of interest from clinicians. There was reticence by the NCI who considered all heavy metals to be toxic. Serendipitously, Sir Alexander Haddow, the then director of the Chester Beatty Institute in London, was intrigued by the Nature article. He suggested to his clinical colleagues, Eve Wilshaw and David Galton, that CisPlatin (as cis– [PtII(NH3)2Cl2] later became known) may be a new class of alkylating agents with unexpected results because it contained a metal. So in 1971 testing began in patients. At that time no ethical permissions were required, the Hippocratic oath being sufficient, so Eve chose to treat a group of patients with stage III ovarian carcinoma this being the only adenocarcinoma known to respond to alkylating agents. The results deeply impressed her. Several patients showed dramatic regression of tumour mass despite the fact that most were seriously ill before treatment. By 1972/3 there were also some six groups in the US also conducting clinical trials with CisPlatin. Those led by D.J. Higby and L.H. Einhorn demonstrated in 1974 major activity against testicular cancer. Using combination therapy with vinblastine and bleomycin they obtained complete remission rates of ~70%, never before seen. The daunting and severe side effects of nephrotoxicity and bone marrow suppression could be largely overcome by hydrating patients before therapy. However, vomiting was so severe some patients withdrew from treatment. Thus CisPlatin became a driver in the search for anti- emetics that was to lead to the development of antagonists of the 5HT3 (5-hydroxytryptamine) receptor. [1]

In Rosenberg’s lab a search for analogues superior to CisPlatin, undertaken by M. J. Cleare, on secondment from Johnson Matthey, produced Carboplatin, the second platinum drug to be approved. It had reduced side effects, particularly the elimination of nephrotoxic effects. Nausea and vomiting are less severe and more easily controlled. It has proved highly successful against ovarian carcinoma. But chemotherapy with CisPlatin in combination remains the preferred treatment for testicular cancer. This is the most common tumour in men between ages of 15 and 35 years with an incidence of 3/100,000 that has doubled over the past 50 years in the USA and Europe. Until the introduction of CisPlatin fewer than 10% of patients enjoyed long term survival. Today it is >95%. Over the 20 years from 1979 patents on these two drugs earned more than $200M for Michigan State University alone.

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The development of CisPlatin marked a watershed in the treatment of cancer. Three major classes of anti-cancer agents then available were antimetabolites, alkylating agents, anthracyclines that were standard in the treatment of leukaemia. CisPlatin was remarkable for its success against solid tumours. More than 30 years later CisPlatin and its close congener Carboplatin continue to play central roles in the management of solid tumours. It has also stimulated a new research discipline of inorganic drugs, the search for new biological activities and studies of biological function.   Third generation, platinum drugs are in the clinic, including Oxaliplatinum and the first Pt(IV) cis complex, Iproplatin.

I left Rosenberg’s lab in 1967 to take up a faculty post in the new School of Chemical Sciences at UEA, Norwich. There I continued to work on the mechanism of action of CisPlatin particularly its interaction with DNA the likely target. Since the pair of cis chloride ions are labile CisPlatin is a bi- functional reagent subject to attack by nucleophiles such as the bases of nucleotides. N8 of guanine, facing into the wide groove of DNA, was a known the target for alkylation by the nitrogen mustards, and, indeed, proved to a major site of platination. I continued this work for several years as part of an interdisciplinary consortium in the UK funded by Rustenberg Platinum Mines but my research interests were shifting.

ajt5I had already begun developing the application of variable temperature, variable field Magnetic Circular Dichroism (MCD) spectroscopy to the study of transition metal cofactors in proteins. This had been in my mind since my days in the Inorganic Chemistry Laboratory, Oxford, as a graduate student where I became friends with Philip Stephens, a very bright man, a theoretician working for his D. Phil. degree with David Buckingham. He was developing ways of analysing magnetically induced circular dichroism that arose from the Faraday Effect. No MCD spectra had ever been measured at that time. From discussions with Philip it became clear that this technique might provide an optical, and hence, a selective, probe of the ground state magnetic properties of paramagnetic metal centres in proteins especially those containing multiple centres. At UEA I had acquired a superconducting magnet with optical access to the sample (see photo above) to install in a circular dichroism spectrometer to develop this idea.

ajt6I chanced to meet Colin Greenwood (see photo right), a faculty member in the School of Biological Sciences at UEA.  He was using flash photolysis to measure the kinetics of reactions of oxygen with cytochrome c oxidase, the terminal electron acceptor of the mitochondrial respiratory chain. He told me that, although this membrane-bound protein contained two haems and two copper centres, curiously only one copper and one haem gave rise to EPR signals. It had been suggested, by Helmut Beinert, that EPR silent haem and copper ion were magnetically coupled implying they must be close together. At once I told Colin that I had a new technique, MCD, that would be able to measure the strength of that coupling and confirm or refute the hypothesis. Thus began many years of close collaboration between us that was to lead to the establishment of the UEA Centre for Metalloprotein Spectroscopy and Biology (CMSB) between the Schools of Chemistry and Biology [2].  But that is a story for another time.

I am grateful to my former students and postdocs who have journeyed with me parts of the way and taught me much. As a founding member of IBDG I take pleasure in its continued success and wish it well in the future.

Further details of these histories are available in the following publications.

[1] “The Discovery Use and Impact of Platinum Salts as Chemotherapy Agents for Cancer”. Wellcome Witness to Twentieth Century Medicine. Edited by DA Christie and EM Tansey. Volume 30. [ISBN 978 085484 1127]

[2] “Andrew Thomson and the Centre for Metalloprotein Spectroscopy and Biology at the University of East Anglia” by Michal T Wilson. Transactions of Biochemical Society. (2008) 36, part 6. 1103-1105.

Acknowledgement. Sketch of Andrew Thomson by Les Dutton

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