Studies Published by Scientists at ICI Pharmaceuticals Division

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The focus of the fertility control research program at ICI Pharmaceuticals Division was to investigate the physiology of reproduction in laboratory animals, use interesting antihormonal agents to block the reproductive process and to propose possible clinical evaluations of novel compounds.45,46,61-77

The work of others, testing compounds from competing pharmaceutical companies, established the activity and potential value of antiestrogens for the induction of ovulation in subfertile women.12,13,24,26,78-80 Cancer therapy was a remote possibility as the treatment strategy at the time for advanced (metastatic) breast cancer was either endocrine ablation or additive high-dose hormonal therapy.81 Although additive hormonal therapy was cheap, only one in three patients responded and the average response duration was 1 year. Nevertheless, a few unsuccessful attempts to test antiestrogens had occurred (Table 1).

Walpole's team of endocrinologists concentrated exclusively on the study of ovulation so that it could be prevented. 'No egg no pregnancy,' to quote Gregory Pincus, the Director of the Worcester Foundation, when describing how oral contraceptives worked. Additionally, the team at ICI Pharmaceuticals Division studied implantation so that the process

Table 1 Preliminary clinical trials of antiestrogens for the treatment of metastatic breast cancer

Compound

Reference

Daily dose (mg)

Total patients (% response)

Toxicities

Triparanol

Kraft (1962)22

250-1000

8(11)

Nonea

MER25

Kistner and Smith (i960)12

500-4500

4(25)

Acute psychotic episodeb

Clomiphene

Herbst et al. (1964)27 Hecker et al. (1974)28

100-300

56(34)

None reported or mildc

Nafoxidine

Legha et al. (1976)44

180-240

198(31)

Bilateral cataracts, ichthyosis Cutaneous photophobia

Tamoxifen

Cole etal. (1971)87

20-40

114(31)

Transient thrombocytopeniae

aWithdrawn from the market by the William S. Merril Co. in cooperation with the Food and Drug Administration in April 1962.

b Does not include patients treated by Dr Roy Hertz when therapy was stopped due to hallucinations.7 cVisual symptoms.30 dAffecting 80-100% of patients.44

e "The particular advantage of this drug is the low incidence of side effects''87; "The side effects were usually trivial.''88

could be prevented to avoid pregnancy. Walpole, Harper, and subsequently Labhsetwar all published extensively throughout the 1960s on the physiology of reproduction and the use of inhibitory compounds, discovered through a screen in vivo, to dissect the mechanisms of the reproductive process in animals.

The compound ICI46,474 was discovered in the screening process for antifertility agents in the rat. Many of the laboratory studies with ICI46,474 focused on the application of an antiestrogen to confirm that the implantation of the blastocyst in the rat requires an estrogen surge on day 4 following mating.67'68 In other words, an understanding of reproductive mechanisms was the primary goal of the research group. ICI46,474 was subsequently shown to be an antiestrogen in the rat but an estrogen in the mouse (Figure 4). The cis geometric isomer ICI47,699 (Figure 4) was an estrogen in the rat and the mouse.45 Only at the end of Walpole's career at ICI Pharmaceuticals Division did interest turn to the interaction of compounds with the estrogen receptor. The geometric isomers of tamoxifen and clomiphene all inhibited the binding of tritiated estradiol to rat and mouse estrogen receptor derived from uterus and pituitary gland.69 Unfortunately, no firm conclusion could be drawn to explain estrogen/antiestrogen action in different species. This species difference in the pharmacology of antiestrogens also raised the question of whether ICI46,474 would be an estrogen or an antiestrogen in humans. Estrogens were already used in the treatment of breast cancer but an antiestrogenic compound would be of value clinically because there may be fewer side effects. Nevertheless, based on the earlier experience at Merrill in the USA, only compounds that did not cause an increase in desmosterol could be used for long-term treatment in humans.

The reproductive endocrinology team advanced clinical testing in several areas primarily endocrinology and gynecology. Indeed in 1972, Walpole reviewed all of the progress in advancing ICI46,474 to become a clinically useful drug. These data were either just published at the time or subsequently published a few years later.

There was, at the time, an ever-expanding literature on the use of clomiphene for the induction of ovulation in subfertile women.82 ICI46,474 was successfully tested as an agent for the induction of ovulation83,84 and was approved for use in clinical practice in 1975 in the UK and several other countries around the world. Additionally, ICI46,474 was noted to block the uptake of 3H-estradiol in the human uterus in vivo85 and had some benefit in diminishing bleeding for patients with menometrorrhagia.86 As noted earlier, Walpole was interested in cancer therapy and had connections at the Christie Hospital in Manchester.59 A small preliminary study using ICI46,474 to treat late breast cancer showed some benefit in 10 of 46 patients87 and in a preliminary dose response study88 found that 12 out of 33 (33%) of patients receiving 10 mg twice daily and 14 out of 35 (40%) of patients receiving 20 mg twice daily had definite responses.

At that time, in 1973, there was little or no enthusiasm at ICI Pharmaceuticals Division to pursue a major program of drug development for the treatment of breast cancer. Walpole, in contrast, was optimistic about exploiting ICI46,474 as a breast cancer drug and agreed not to take early retirement if the antiestrogen was supported for clinical approval. This was achieved in the UK through the Committee for Safety of Medicines in 1973 and in December 1977 by the Food and Drug Administration (FDA) in the United States.

The reasons for the reluctance to pursue global development of ICI46,474 were the perceived vulnerability of the product in the absence of a patent in the US market and the assessment, which was correct at the beginning of the 1970s, that there was virtually no market. Only one in three patients with advanced breast cancer would respond to endocrine therapy for about a year. This market would amount to no more than £50 000 of sales per annum and the competitor products of high-dose estrogen or androgen cost only pennies per dose whereas the new antiestrogen ICI46,474 would, by necessity, have to cost 10-20 times more per dose. The only advantage for ICI,46,474 was a reduction in adverse side effects (Table 1).

The scientists at ICI Pharmaceuticals Division did not conduct any systematic study of the mechanism of action or antitumor properties of ICI46,474. These studies were conducted outside ICI Pharmaceuticals Division with academic collaborators (the process was advanced through the good offices of Walpole who remained as a consultant for ICI after his retirement in the early 1970s). Laboratory programs were established at the Worcester Foundation for Experimental Biology in Shrewsbury, MA (1972-74) in collaboration with ICI Americas (Stuart Pharmaceuticals) and subsequently at Leeds University, UK (1974-79) with a formal Leeds University/ICI joint research scheme. Tamoxifen was to be reinvented as a pioneering targeted antihormonal treatment for breast cancer by using appropriate laboratory models to create a scientific basis for pursuing rational clinical trials.

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