Change is needed. Thirty years of experience with subcutaneous xenografts, human tumors implanted under the skin of the mouse, have satisfied few because so many drugs that cure cancer in these mice fail to help humans. A 2004 analysis in the Journal of the American Medical Association showed that only 3.8% of patients in phase I cancer drug trials between 1991 and 2002 achieved an objective clinical response — and the response rate is declining. Almost all drugs tried in humans work against subcutaneous xenografts in mice. “How many more negative data do you want? It’s very depressing.”
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In summary, mouse xenograft models should not be viewed as ideal models for cancer drug development. Altered, nonhuman host stroma, poor predictive value when applied in an empirical sense, and questionable relation to the naturally occurring human disease are but a few features, which temper enthusiasm for their use.
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[Regarding tamoxifen, an anti-cancer drug] 'Experimentally, tamoxifen has carcinogenic potential. In some strains of rat, but not mouse or hamster, tamoxifen can cause liver cancers at doses as low as 5mg/kg per day... However, there are doubts about the correlation of [the results] with the risk of malignant disease even in rats, let alone in other rodents, mammals, or human beings. There are many uncertainties in extrapolating these experimental data from rats to women. The effect depends on bioavailability, hepatic [liver] blood flow, and hepatic [liver] metabolism to active genotoxic carcinogens, all of which differ enormously between rat and man.
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