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be considered to be a low-risk, low-tech way of drug development, but it has produced agents with improved spectra of activity of toxicity that have some clinical advantages (notably carboplatin). However, it does seem unlikely that such a strategy will lead to a significant increase in the potential for cancer cure by the new drug. |
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Initial large scale screening of compounds for anticancer activity was based on the long established mouse P388 leukaemia system. Around 10 years ago it became clear that too few clinically useful agents were emerging from the screen [2]. A new screen has been developed based on a large panel of human tumor cell lines. In tandem, new methods of analysis of data were developed, including COMPARE, which allows drugs to be selected based on differential cytotoxicity for particular groups of tumor cell types, possibly indicating novel mechanisms of action based on tumor specific biochemistry [3]. Many tens of thousands of compounds have now been screened by this system, and many thousands considered worthy of further investigation have been selected. It is usual to subject such compounds to second-level screening using human tumor xenografts in nude mice. A similar, but not identical system, has been adopted in Europe [4]. As yet it is too soon to know if such large-scale screening programs will be cost effective in terms of detecting new, active compounds with novel mechanisms of action. |
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In 1965 Rosenberg reported the chance observation that platinum complexes had potent biological activity. When Escherichia coli organisms were grown in culture containing a platinum electrode, bacterial growth continued but cell division was inhibited, giving rise to long filamentous bacteria. This eventually led to the demonstration of cisplatin antitumor effects in 1968, and hence to clinical development of that compound. |
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This story illustrates the importance of serendipity, but it is clearly not a strategic path that can be followed! Undoubtedly, we will continue to make these types of breakthroughs, and perhaps the message should be that all involved in drug development should be as open minded as possible. In addition, we should recognise that observations made outside our own fields of endeavour may have major importance. Since the very nature of cancer is a derangement of cell growth and behaviour such observations may conceivably arise from almost any branch of the biological sciences, and more particularly from the burgeoning field of molecular biology [5]. |
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