Tamoxifen is an anticancer agent used for treatment of breast cancer patients who are estrogen receptor positive. Tamoxifen (ICI46,474 compound developed by Imperial Chemical Industries Ltd, London, England) was initially discovered to be contraceptive in animal models such as rats, but however failed to prove anti-fertility in human females. ICI46,474 in females worked opposite to induce ovulation. Therefore instead of using for birth control, it was used in fertility treatment for induction of ovum in sub fertile females. Because of the ovulation effect, ICI46,474 was used in females who had the problem with ovulation. Due to the genotoxic side effect of tamoxifen, it was less used as an ovulating drug. Further studies revealed that tamoxifen was found acting as antagonist to estrogen receptor alpha in selected tissues, especially in Breast Tissue. One of the important factor which was prevalent in breast cancer was the over expression of estrogen receptor and its pathway. Due the antagonist activity of tamoxifen against estrogen receptor alpha, it found a new role as drug for treatment for breast cancer. Tamoxifen drug has similar binding affinity for both estrogen receptor alpha and estrogen receptor beta transcription factors.
Breast cancer has turned to be one of the most common cancer affecting females. The occurrence of breast cancer increases with the age of the women and females near menopausal cycle are the most affected. The treatment of breast cancer varies from surgical removal mammary gland to hormone therapy. The success of tamoxifen as a drug for breast cancer has resulted in life saving of billion females around the globe. Breast cancer patient who are estrogen receptor alpha positive can be benefited from the treatment of tamoxifen and better outcome of the treatment of tamoxifen was seen with patients who consumed the drug for more number of years.
Estrogen receptor is a transcription factor which belongs to the nuclear receptor families. The ligand estrogen binds to the receptor, which induces the conformational changes and dimerization of the transcription factor and also translocation to the nucleus from cytoplasm, thereby enhancing the expression of the estrogen receptor dependent genes. There are two members in the estrogen receptor family as estrogen receptor alpha and estrogen receptor beta genes. Endocrine therapies are either targeted to block the synthesis of estrogens or block the signaling pathways mediated with estrogen receptor molecules. Hormone therapy is the most successful method to manage breast cancer patients with estrogen receptor positive.
The development of Mammary gland depends on the estrogen receptor signaling. Estrogen receptor alpha is key regulator of estrogen signaling culminating in cell proliferation of mammary gland cells and is a vital gene necessary for ductal growth and elongation. Estrogen receptor beta, another member of estrogen receptor family also regulates proliferation and differentiation of the mammary gland cells. Estrogen has a role in breast cancer risk as the estrogen metabolic products are genotoxic which might cause increased risk of DNA damage and estrogen mediated cell proliferation might lead to increased risk of mutations due to increased DNA replication. Hence Estrogen receptor alpha has been considered as prognostic marker and clinical target in breast cancer.
Tamoxifen inhibits estrogen receptor alpha activity reducing the risk of recurrence of invasive breast cancer which is positive for estrogen receptor alpha. For the past 30 years, Tamoxifen has been used to treat estrogen receptor alpha positive breast cancers and reduced the mortality in the breast cancer patients. Tamoxifen is known to reduce the risk of breast cancer in patients who are in high risk to develop breast cancer. Tamoxifen drug has antitumor effect may be due to competitively inhibition of the estrogen binding with estrogen receptor alpha which results in inhibition of expression of estrogen dependent genes such as growth and angiogenic factors that are secreted by tumor tissue. Tamoxifen treatment blocks the G1phase of the cell cycle and slows the cell proliferation process. The slow cell proliferation coupled with tumor cell loss might results in the regression of mammary gland tumor tissue of patients who are treated with tamoxifen.
Tamoxifen treatment also has adverse effect during pregnancy due to the genotoxic effect of tamoxifen and its metabolites. Tamoxifen treatment affects developing embryos hence patients who plan for child should stop tamoxifen treatment before conceiving. Tamoxifen and its metabolites are have a long half life in the human body, therefore a minimum of 2 to 3 months gap should be given after the withdrawn of tamoxifen drug to allow the body to completely eliminate tamoxifen and its metabolites before conceiving. The tamoxifen drug has been associated with relatively higher frequencies of severe congenital fetal abnormalities hence during tamoxifen drug treatment a highly reliable method of birth control is necessary.
The tamoxifen metabolism in humans is a complex procedure and several enzymes are involved. The primary site of tamoxifen is in the liver and cytochrome P450 system is involved in the metabolism of tamoxifen. It has observed that the few of the metabolites of tamoxifen are even more effective antagonist to estrogen receptor alpha that tamoxifen itself. N-demethylation is the major pathway which results in N-desmethyltamoxifen by enzymes CYP3A4 and A5. N-desmethyltamoxifen is hydroxylated to endoxifen by the action of CYP2D6 enzyme. Endoxifen has a very high antiestrogenic activity compared to tamoxifen and also found in high levels in blood plasma. The alternative pathway in the tamoxifen metabolism is hydroxylation tamoxifen which results in 4-hydroxy tamoxifen by the action of CYP2D6 enzyme. The 4-hydorxy tamoxifen is nearly 30 to 100 times more antiestrogent than tamoxifen. The plasma level of 4-hyroxy tamoxifen is comparatively lower than the endoxifen. Both 4-hydroxy tamoxifen and endoxifen have good affinity for estrogen receptor alpha and are effective antiproliferative agents and also inhibits estrogen dependent gene expressions. Metabolism of Tamoxifen requires several CYP enzymes such as CYP3A4, A5 and CYP2D6. Patients with variations in the enzyme genes might influence the outcome of tamoxifen therapy. Patients with normal enzymes results in high plasma levels of the endoxifen and hydroxyl metabolites of tamoxifen which might results in the tamoxifen treatment success.
Tamoxifen drug has few unwanted side effects such as hot flashes .Tamoxifen usage results in the increased risk of endometrial cancer due to its agonistic activity in the endometrium. The prolonged used of the tamoxifen has been associated with few gynecological complications like development of endometrial cancer and polyps, adenomyosis and adnomyomatous polyp, leiomyoma, ovarian cysts, and cervical polyps. Due to the cancer inducing phenomenon of tamoxifen drug, it has been listed as a human carcinogen in 1996 from the International Agency of Research on Cancer. Despite of side effects of tamoxifen drug, the control of breast cancer and preventing relapse of breast cancer are the benefits of tamoxifen treatment, which has been considered for approval of this drug for treatment in breast cancer by US Food and Drug Administration (FDA).
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