It is a minor miracle that tamoxifen overcame a succession of conflicting animal data to find a place in clinical practice. The drug was developed by ICI during the 1960s as an oral contraceptive and in rats tamoxifen can prevent ovulation or terminate pregnancy. (1) In women however, tamoxifen stimulates ovulation and is listed as a treatment for infertility! (2)
Tamoxifen is also used in breast cancer therapy where it works by blocking the action of oestrogen in breast tissue. The drug is therefore called an “anti-oestrogen”. In monkeys, and rats at low doses, tamoxifen also acts as an anti-oestrogen but in mice, dogs, and rats at high doses, the drug has the opposite effect, behaving like an oestrogen.(1) The use of animals to investigate these effects is bedevilled with problems since “significant species variation has been observed in target tissue response to oestrogens and antioestrogens making it hazardous to predict therapeutic activity in the human by extrapolation of effects in experimental animals...”(3)
Animal tests have also given conflicting results in assessing the drug's harmful effects, with tamoxifen producing liver tumours in rats but not mice.(4) Liver cancer does not seem to be a problem for human patients and only two cases have been reported in around 3 million women who have received the drug. Furthermore, tamoxifen is known to be processed differently by rats and people. John Patterson, medical director at ICI, explains that “If this was a new chemical entity those findings in rats would have caused us to stop its development, but the human experience gave us confidence."(5)
Nevertheless the rat data led to a major row between Britain's two biggest cancer charities and the Medical Research Council over trials of tamoxifen for the prevention of breast cancer, in which the drug is given to healthy women. Most proponents of the trial considered the rat experiments nothing to worry about (6,7) but the MRC actually withdrew its support and initiated new animal tests. Embarrassed by the split, one of the cancer charities, the Imperial Cancer Research Fund, stated that "We are going to be in a position where the animal rights people are going to be saying to us 'You ignore animal data when you choose to'."(1)
Ironically, fresh doubt was cast on tamoxifen's preventive role by a subsequent clinical study suggesting an increased risk of womb cancer amongst breast cancer patents being treated with the drug. Whilst questioning whether it should be given to healthy women, the report stressed that for the treatment of breast cancer, the benefits far outweighed the risks.(8)
Overall, tamoxifen has comparatively few serious side effects and according to ICI, the main reason patients stop taking the drug is nausea and vomitting.(1) This must have surprised the company because "None of the toxicological studies produced any evidence of vomitting even though high doses were used in dogs which we consider to be a predictive species for vomitting in man."(1)
1) M.J.Tucker et al in Safety Testing of New Drugs, Eds. D.R.Laurence et al (Academic Press, 1984)
2) British National Formulary, No.26 (BMA & the Royal Pharmaceutical Society of GB, 1993)
3) P.K.Devi in Pharmacology of Estrogens, Ed. R.R.Chaudhury (Pergamon Press, 1981)
4) I.N.H. White et al, Biochemical Pharmacology, 1993, vol.45, 21-30
5) Reported in P.Brown, New Scientist, 1992, February 29, 11.
6) Editorial, New Scientist, 1992, March 21, 9
7) P. Brown, New Scientist, 1992, March 21, 12.
8) F. E.van Leeuwen et al, Lancet, 1994, February 19, 448-452.
|<<Previous||Back to 101 Mislead Results Index||Next>>|