1. Sacred cows & Golden geese, C. Ray Greek, MD and Jean swingle Greek, DVM. Continuum 2000.
2. Specious Science, C. Ray Greek, MD and Jean swingle Greek, DVM. Continuum 2002.
3. Pietro Croce, Vivisection or Science?: An Investigation into Testing Drugs and Safeguarding Health, Zed Books.

The extent to which inadequate concealment of allocation might introduce bias in animal experiments is uncertain. However, it is easy to imagine how bias could arise. For example, weaker animals may be easier to catch than healthy animals, and this could result in systematic differences between the intervention and control groups on baseline prognostic factors.

"The fundamental problem in drug discovery for cancer is that the model systems are not predictive at all." says Alan Oliff, executive director for cancer research at Merck Research Laboratories in West Point, Pennsylvania.

Pharmaceutical companies often test drug candidates in animals carrying transplanted human tumors, a model called a xenograft. But not only have very few of the drugs that showed anticancer activity in xenografts made it into the clinic, a recent study conducted at the National Cancer Institute (NCI) also suggests that the xenograft models miss effective drugs.

Researchers blamed the failures on the fact that the drugs were being tested against mouse, not human, tumors, and beginning in 1975, NCI researchers came up with the xenograft models, in which investigators implant human tumors underneath the skin of mice with faulty immune systems. Because the animals can't reject the foreign tissue, the tumors usually grow unchecked, unless stopped by an effective drug. But the results of xenograft screening turned out to be not much better than those obtained with the original models, mainly because 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.

"We had basically discovered compounds that were good mouse drugs rather than good human drugs," says Sausville.

The xenograft models may also have missed effective drugs. When Jacqueline Plowman's team at NCI tested 12 anticancer agents currently used in patients against 48 human cancer cell lines transplanted individually into mice, they found that 30 of the tumors did not show a significant response-defined as shrinking by at least 50% to any of the drugs.

So far, the results from these mouse models [transgenic mice] have been mixed, however. One mutant mouse strain, for example, lacks a working APC gene, a tumor suppressor that leads to colon cancer when lost or inactivated. This mouse seems to do well at re-creating the early signs of colon cancer. But in the later stages of the disease, the type of mutations in the tumors begin to diverge from those in human colon cancer, and the disease manifests itself differenrly as well. It spares the liver, for example, unlike the human cancer.
Other new mouse models have fared even worse. Take the one in which the retinoblastoma (RB) tumor-suppressor gene was knocked out. In humans, loss of RB leads to a cancer in the retina of the eye. But when the gene is inactivated in mice, the rodents get pituitary gland tumors. And BRCA1 knock-outs, which are supposed to simulate human breast and ovarian cancer-don’t get tumors at all.

“one might expect that these animals would also mimic human symptoms, not just the genetic mutations,” says molecular biologist Tyler Jacks of the Massachusetts Institute of Technology. “In fact, that is usually the exception, not the rule.”