In Tamoxifen’s case, a drug first developed as a potential contraceptive languished for many years before its present application was found. Furthermore, its propensity to cause liver tumours in rats, a toxicity problem that thankfully does not carry over into humans, was not detected until after the drug had been on the market for many years. If it had been found in preclinical testing, the drug would almost certainly have been withdrawn from the pipeline.
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'The drugs Prednisone and Vincristine are often hailed as 'curing' childhood leukemia. Both drugs were rejected by the US National Cancer Institute as 'useless' on the basis of animal tests. Prednisone was developed as a result of clinical observation of the effects of adrenal extract. Vincristine is an alkaloid of 'Vincra Rosea', a type of periwinkle plant, and extracts of periwinkle were used in the Roman Empire to 'dry tumours' (Pliny). They were eventually brought to clinical trials. The children cured of leukemia owe their lives to clinical observations and trials - and not to the animal 'model'.'
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Why the dog was ever considered as an appropriate animal for carcinogenicity testing is also not entirely clear... Despite the obvious problems of study design and interpretation, carcinogenicity tests in the dog, lasting 7 years, were requested by regulatory authorities from the late 1960s...One of the best known examples of the inappropriate use of the dog was the carcinogenicity testing of hormonal contraceptives. It is now understood that mammogenesis in the dog is very different from that in primates; quantitative and qualitative differences exist in the feedback control mechanisms, receptor content and behaviour, and target sensitivity and responsivity. As a result of this biological difference there was a high incidence of mammary tumours in long-term studies in dogs treated with progestagens/contraceptive steroids such as lynestrol. Ultimately pressure from the scientific community led, relatively recently, to the requirement for carcinogenicity studies in dogs being dropped.
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Elsewhere, I have pointed out that overfeeding of rats profoundly influences the incidence particularly of endocrine tumours. Furthermore, endocrine tumours and tumours of tissues, such as the breast and uterus, which are very directly under sex-hormone control, constitute a very high proportion of the tumours observed in most carcinogenicity studies in rats. [Comparing] the incidences of tumours in these categories in men and women with those in male and female rats... [shows] the differences between the two species are sufficiently striking to make one wonder how appropriate the laboratory rat is as a model for man in terms of the spectra of tumours to which they are prone.
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It’s been well known for maybe two decades that many of these preclinical human cancer models have very little predictive power in terms of how actual human beings – actual human tumours inside patients – will respond…Preclinical models of human cancer, in large part, stink…Hundreds of millions of dollars are being wasted every year by drug companies using these [animal] models…
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For example, the control incidence of mouse liver tumour varies between 0 and 58% in 41 NTP [National Toxicology Program] bioassays where these tumours are induced by a test chemical.
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The standard carcinogenicity bioassay, which involves treating two rodent species for a minimum of 2 years, at a range of doses, is acknowledged to be an insensitive tool because of the background `noise' of spontaneous disease. Most strains of rat used in such studies have high incidence of pituitary and mammary tumours; some inbred rat strains frequently develop leukaemia or testicular tumours; mice strains show high incidence of malignant lymphomas and liver tumours.
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Even when there are common target sites for a given carcinogen, there are usually important differences, between man and animals, and between different species and strains of animals. These 'spontaneous' tumours in rats and mice... [vary] widely according to sex, strain, diet, conditions of maintenance, hormonal status, immunological status and latent virus infections.
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'The argument from man is so much more convincing than the argument from mice - which indeed, may be completely misleading, as in the case of urethane, which has some inhibitory action on human tumours, but a marked, though temporary one on chronic human leukemias.'
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It seems sometimes that almost everything we eat, drink or take can cause cancer in rats. That does not necessarily relate to tumours in humans.
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God knows we’ve cured mice of all sorts of tumours. But that isn’t medical research.
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