Tamoxifens Legacy A Menu of Medicines

Chemo Secrets From a Breast Cancer Survivor

Breast Cancer Survivors

Get Instant Access

Tamoxifen became the most investigated anticancer agent over the 40 years of its development. The success of the drug as an adjuvant therapy has been quantified: 400 000 women with breast cancer are alive because of long-term tamoxifen treatment. Most importantly, the development of tamoxifen demonstrated that there was an advantage for patients by targeting the estrogen receptor specifically. This in turn encouraged the pharmaceutical industry to invest in research to discover both safer and more effective drugs. This is best illustrated by comparing treatment options for advanced breast cancer in 1970, i.e., before tamoxifen (Figure 7) with the therapeutic options for all stages of breast cancer in 2005 (Figure 8).

Figure 7 The endocrine options in the early 1970s for the patient with metastatic breast cancer. Surgery to remove endocrine organs (ablative surgery) which secreted estrogenic hormones or their precursors. In the case of postmenopausal patients, additive high-dose estrogens, androgens, or progestins were standard therapy.

Figure 7 The endocrine options in the early 1970s for the patient with metastatic breast cancer. Surgery to remove endocrine organs (ablative surgery) which secreted estrogenic hormones or their precursors. In the case of postmenopausal patients, additive high-dose estrogens, androgens, or progestins were standard therapy.

Gnrh Tumour Removal

Figure 8 The current menu of medicines used to block the exposure and action of estrogens in breast tumors. The ultimate target in all cases is to prevent the formation of the estrogen-estrogen receptor complex within tumor cells. FSH, follicle-stimulating hormone; GNRH, gonadotropin-releazing hormone; LH, luteinizing hormone; SERM, selective estrogen receptor modulation.

Figure 8 The current menu of medicines used to block the exposure and action of estrogens in breast tumors. The ultimate target in all cases is to prevent the formation of the estrogen-estrogen receptor complex within tumor cells. FSH, follicle-stimulating hormone; GNRH, gonadotropin-releazing hormone; LH, luteinizing hormone; SERM, selective estrogen receptor modulation.

The clinical success of tamoxifen encouraged an important re-evaluation of inhibitors for the aromatase enzyme system. In other words, block the synthesis of estrogens from androgen precursors. Early nonspecific inhibitors such as aminoglutethimide had many side effects, especially since there was a necessity to coadminister the drug with a glucocorticoid. Aminoglutethimide faded out of fashion during the 1970s as tamoxifen became the endocrine treatment of choice for breast cancer. However, the development of the suicide inhibitor formestane215 based on Brodie's original laboratory work216'217 created an opportunity for the development of a whole class of new drugs. The process took about 20 years, i.e., throughout the 1980s and 1990s.218 Today aromatase inhibitors are used to treat postmenopausal women with estrogen receptor-positive disease instead of tamoxifen211'219 or after tamoxifen.212'213 In general, there are fewer side effects such as endometrial cancer or blood clots and there are significant improvements in disease control.

Examination of the pharmacology of the drug in great detail taught many lessons. The finding that tamoxifen was a carcinogen in rat liver advanced the development of toremifene that did not induce rat liver tumors. Despite the fact that toremifene was not a complete carcinogen, the drug also increased endometrial cancer to the same extent as tamoxifen.220 No major increase in human liver cancer has been reported with tamoxifen. Additionally, the development of aromatase inhibitors221 for the treatment of breast cancer obviated the need for another SERM for treatment. More importantly, the studies with tamoxifen in rats exposed a weakness in the toxicity testing methods. Had tamoxifen been tested for carcinogenicity 30 years ago, there would have been no tamoxifen, lives would have been lost, and the goal of targeting tumors would have been retarded for perhaps a decade. Tamoxifen became a success story which proved that targeting could save lives.

Interestingly enough, there are those in the research and clinical community that consider that tamoxifen will continue to have a role in treating select patients and will certainly continue to be a useful medicine in underdeveloped countries that cannot afford more expensive medicines such as aromatase inhibitors. It is also fair to say that the pure antiestrogen fulvestrant would not have been discovered at ICI Pharmaceuticals Division in the early 1980s if research on tamoxifen had not been continued. Tamoxifen is a pioneering medicine not a perfect medicine so it was only rational that work on other approaches to breast cancer treatment, targeted to the estrogen receptor, should have started in the hope of exploiting tamoxifen's expanding clinical market in the 1980s. The serendipitous discovery of the pure antiestrogens is an example of drug discovery by talented scientists in industry who discovered a new class of drugs, the estrogen receptor downregulators which not only are useful in the clinic but provided a new insight into regulatory processes in cancer cells.224

Tamoxifen is the first SERM and without the developing pharmaceutical database during the 1980s, raloxifene, originally a failed breast cancer drug called keoxifene (see 8.09 Raloxifene), would not have been reinvented as a treatment and preventive for osteoporosis with breast and endometrial safety.225,226

The discovery of SERM action with tamoxifen227 has opened the door to discovering selective activity for all members of the steroid hormone receptor superfamily. A huge effort is under way to discover agonist and antagonists drugs for the androgen receptor, progesterone receptor, glucocorticoid receptor, thyroid hormone receptor, and the peroxisome proliferator-activated receptor (PPAR).

Overall, the impact of tamoxifen on healthcare, drug discovery, and cancer cell biology has proved to be extremely beneficial but the process took more than 40 years. This story illustrates the real difficulties that industry scientists, often working in a restrictive environment governed by intellectual property rights, have in exploiting the benefits of novel molecules. The development of tamoxifen is unique but its inception depended on individuals, in at the right place at the right time, and a change in the fashions of medical research first from contraception to cancer research and then from cancer research to women's health and preventive care.

Was this article helpful?

0 0
Natural Cures For Menopause

Natural Cures For Menopause

Are Menopause Symptoms Playing Havoc With Your Health and Relationships? Are you tired of the mood swings, dryness, hair loss and wrinkles that come with the change of life? Do you want to do something about it but are wary of taking the estrogen or antidepressants usually prescribed for menopause symptoms?

Get My Free Ebook


Post a comment