TNAG-1981-FCO40-2814-UK-Hong-Kong-Scholarship-Scheme-donation-to-the-UK-Governme-1989 — Page 14

tumours. In the light of this evidence, carboplatin was chosen for clinical development at ICR/RMH.

These events occurred against a background of similar developments elsewhere and three cisplatin alternatives were evaluated in separate clinical centres: carboplatin (at RMH), iproplatin and, a compound called TN06, which was studied because it possessed preclinical activity against cisplatin-resistant leukaemias in mice. TN06 fell at an early hurdle of toxicity, to the kidney, though for some time thereafter carboplatin and iproplatin were close contenders. Eventually, however, it became apparent that iproplatin was more toxic than carboplatin, particularly to the gut, inducing unacceptable diarrhoea and nausea and vomiting. In the RMH studies, carboplatin was shown to be devoid of the major clinical toxicities of cisplatin; at pharmacologically effective doses it did not damage the kidney, nor hearing acuity, nor peripheral nerves and, furthermore, it produced substantially less nausea and vomiting than cisplatin. Its major side effect was to the blood-forming tissues of the bone marrow. However, this toxicity is well understood and managed by clinical oncologists. It became clear that carboplatin elicited broadly the same

antitumour response as did cisplatin, though with substantially reduced toxic risk. Thus carboplatin (JM8, CBDCA) was registered in 1986 for use in the UK by the Bristol-Myers company under the trademark "Paraplatin", in preference to the other two contenders. Notably ICR/RMH data was focal to the UK registration package. They are prominent also in the application for registration currently before the Federal Drug Administration in the United States.

Here in 1988 it is justifiable to enquire of what has been achieved in 20 years of research on platinum drugs. There is no doubt that cisplatin has improved the life-expectancy of patients bearing ovarian and testicular cancers. Equally, there is no doubt that carboplatin can achieve the same results with substantially less toxic risk. What for the future? Clinical and laboratory studies at ICR/RMH suggest that it may be possible now to develop a new generation of platinum drugs which will broaden substantially the scope of platinum-based cancer chemotherapy. Research designed to achieve this objective is now in hand, in collaboration with chemists at the Johnson Matthey Technology Centre.

K.R. HARRAP