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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The fundamental problem in drug discovery for cancer is that the model systems are not predictive at all. ancer research at Merck Research Laboratories in West Point, Pennsylvania…Researchers blamed the failures on the fact that the drugs were being tested against mouse, not human, tumors… the xenograft tumors don't behave like naturally occurring tumors in humans – they don't spread to other tissues, for example. Thus, drugs tested in the xenografts appeared effective but worked poorly in humans.
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Since its inception 25 years ago, EPA [the US Environmental Protection Agency] has applied the same logic to hundreds of other substances, extrapolating from high levels in animal studies to arrive at acceptable levels for humans. But that approach, say scientists both inside and outside the federal government, may no longer be the best way to safeguard public health...EPA's new emphasis on molecular data is based on a growing body of evidence that extrapolations from megadoses can provide a misleading picture of the effects of low-level exposure. Chloroform is a good example. EPA's current strict standards were derived from a study in which mice developed liver tumors after exposure to massive daily doses of chloroform pumped into their stomachs over several months. However, those findings may not be relevant to human exposures, according to a paper picked by the Society of Toxicology as the best published last year in its journal.
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The use of inbred strains as test animals can be further questioned on the basis that they often develop spontaneous tumors in organs where cancers are not frequent in humans. For example, incidences of mouse liver tumors in 2-yearold B6C3F1 mice has ranged from 17.8 to 46.9 percent. In contrast, the death rate from liver cancer in the United States is about 0.005 percent.
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