Marimastat, a matrix metalloproteinase inhibitor (MMPI) developed by British Biotech (Oxford, UK), has failed yet again in late-stage clinical trials, this time as part of a combination therapy for ovarian cancers. The failure adds to a long list of clinical disappointments for this class of drugs and emphasizes the need to be discerning when choosing suitable targets for drug development. The use of MMPIs in cancer treatment is now questionable, and observers think any future for MMPIs could lie in the treatment of more acute illnesses requiring a more limited exposure to this class of drug.
MMPs are relatively unbiquitous enzymes, which maintain and degrade the extracellular matrix in many tissues. Several companies had high hopes for MMPIs as a breakthrough in cancer treatment, thinking MMPs were ideal targets because of their causal involvement in metastasis and angiogenesis, and therefore tumour growth. MMPs, expressed at high levels in advanced tumours, help to degrade the cellular matrix of surrounding tissues and allow the tumour to spread. Knowing that a number of MMP subtypes were likely to be involved, British Biotech chose the non-selective route, but its broad spectrum antagonist Marimastat was associated with side effects such as severe joint pain. The company minimized this by reducing the dose, but seemingly at the expense of efficacy. Marimastat has now failed in trials for glioblastoma, pancreatic, gastric, breast, and ovarian cancers.
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