Between 1970 and 1994, cancer claimed the lives of about 0.5 million Americans every year. According to the most recent statistics, it is estimated that approximately 1.3 million new cases of cancer will be diagnosed and 555,500 people will die from cancer in the United States in the year 2002. Despite these statistics, 5-year survival rates following diagnosis stand at around 55%, and for some specific cancers such as breast and prostate cancer this figure is very much higher. The number of cancer related deaths is however improving only very slowly (around 1% per decade) and not surprisingly therefore, analysis of pharmaceutical development databases suggests about 25% of all drugs in preclinical development are targeted towards cancer. Topoisomerases catalyze ATP-independent breakage of one of the two strands of DNA, passage of the unbroken strand through the break, and rejoining of the broken strand. Inhibitors of topoisomerase I and topoisomerase II act as cellular poisons, and represent a key area of cancer therapeutics. At present 34 topoisomerase I and 115 topoisomerase II inhibitors are in development or on the market, and perhaps even more exciting is the small number of dual inhibitors that are emerging. Representatives dual inhibitors are particularly promising since they appear to be able to avoid the problem of drug resistance that limits the usefulness of inhibitors that target only one isoform. One of the leading dual inhibitors, Xenova's XR11576 has just entered phase I trials and has been the focus of a licensing agreement with Millennium Pharmaceuticals. The therapeutic profile of XR11576 is described in a recent publication. The molecule exhibited similar potency for both topoisomerase I and topoisomerase II. The compound stabilized enzyme-DNA cleavable complexes indicating that it acted as a topoisomerase poison. However, the DNA cleavage patterns obtained with XR11576 were different from those induced by camptothecin and etoposide, which are topoisomerase I and II poisons, respectively. XR11576 demonstrated potent cytotoxic activity against a variety of human and murine tumor cell lines (IC50=6-47 nM). Moreover, XR11576 was unaffected by multidrug resistance (MDR) mediated by overexpression of either P-glycoprotein or MDR-associated protein, or by down-regulation of topoisomerase II. The latter property supports the dual inhibitory mechanism of action of the compound and is particularly interesting in view of previous data showing that some topoisomerase I inhibitors might be capable of increasing sensitivity to topoisomerase II active drugs. XR11576 exhibited a similar pharmacokinetic profile in mice and rats after either i.v. or p.o. administration. In vivo XR11576 showed marked efficacy against a number of tumors including sensitive (H69/P) and multidrug-resistant (H69/LX4) small cell lung cancer and the relatively refractory MC26 and HT29 colon carcinomas following i.v. and p.o. administration. The efficacy of XR11576 was at least comparable to that of TAS-103, originally proposed as a dual inhibitor of topoisomerase I and II. These results suggest that XR11576 is a promising new antitumor agent with oral and i.v. activity, supporting the further development of this and similar molecules.

Link to journal abstract:

Interested in collaborating with this group? Contact leaddiscovery@bioportfolio.co.uk