The Use Of Tamoxifen In All Stages Biology Essay

Abstract

Tamoxifen the first targeted anticancer agent for breast cancer patients and its effects on reduction of breast cancer events and improvement in overall survival are undisputed. Hence, it has long been considered an essential part of patient care.

this review, the use of tamoxifen in all stages of breast cancer, it mode of action and another anti-oestrogens anticancer action

Introduction

Breast cancer is malignant tumor developed in the breast. Itis the most common type of cancer in women. It accounts for a tenth of all new cancers and nearly a quarter (1.3 million) of all new female cancer every year. It is also the leading threat to women's health with about 555,000 women dying from it. In the UK, it is first leading causes of cancer deathin women

Years ago, breast cancer treatment was based on surgical procedures which results in continual recurrence of the disease for an indefinite period. Later research found out that some breast cancers required female sex hormones oestrogen and progesteron to grow so the presence of these hormone receptors within a breast cancer resulted in the recurrenceof the disease after surgery. It was hard to imagine a non-toxic targeted treatment for breast cancer which could also reduce in the risk of recurrence.

Over 30 years ago tamoxifen was developed more than as a potential new way of preventing recurring but also inhibiting oestrogen from stimulating the growth of breast cancer cells.It was the first cancer chemopreventive approved by the Food and Drug Administration (FDA) for the reduction of breast-cancer incidence in both pre- and post-menopausal women at high risk.Tamoxifen has been the gold standard for the endocrine treatment of all stages of oestrogen-receptor-positive breast cancer(Markopoulos C, J,. 2010).

Tamoxifen(Nolvadex) belongs to a class of compounds called selective estrogen receptor modulators(SERMs). Chemicallyit resemblesestrogen but unlike estrogen it binds and competitively interacting with the estrogenreceptor andblock the effect of estrogen in breast cancer cells. This prevents ER-mediated transcription through estrogen response elements of various genes.Tamoxifen therapy has recorded a significant reduction of the annual breast cancer death rate of 34%, with an absolute reduction in mortality of 9.2% at 15 years. ( Criscitiello et al, 2010 )

It is found to be a safe and effective for treatment all stages breast cancer with low incidence of side effects. The World Health Organization has estimated that over 400,000 women are alive today as a result of tamoxifen therapy, and millions more have benefited from palliation and extended disease-free survival.Most recent reported indicate that reduction in the annual breast cancer death rate significantly by 34%, with an absolute reduction in mortality of 9.2% at 15 years.

One of the added benefits of tamoxifen is that is can reduce the risk of osteoporosis. A recent review reported the benefit of Tamoxifenon bone mineral density, in post-menopausal women with early breast cancer. Tamoxifenusealoneprotectsthe spinal bone mineral density and tamoxifen plus chemotherapy partially prevent bone loss in the hip.

However tamoxifen treatment hasbeen one of the major obstacles to the successful treatment of breast cancer due to drug resistance.About one-third of early-stage breast cancer patients become resistant to Tamoxifen over the 5-year treatment period.

TREATMENT OF EARLY STAGE BREAST CANCER

There are four stages in breast cancer stages I and II is the primary( early ) , stage III the advance stage and stage IV the metastatic . Each stages takes into account size of tumour and the extent to which the cancer have spread.

Early breast cancer means cancer cell size is relativelysmall with tumor size between 2 to 5 cm and has not spread, can be surgically removed. At this stage breastcancer cellsare relative small and localize.The results of several clinical studies has indicated that tamoxifen, either alone or in combination with chemotherapy can reduce the rate of cancer recurrence and improve survival. . When use in combination tamoxifenworks by eliminate any microscopic tumor cells that might remain in the breast after surgery reducing the risk of remission.(Eisner A and LuohW,S,2011)

A systematic review hasestablished the efficacy of adjuvanttamoxifen treatment in early breast cancer.The review reported asubstantially improvement of survival by 10-year in ER-positive tumours women, with the proportional reductions recurrence and in mortality. Ameta-analysis from the EBCTCG also reports of a reduction in the risk of recurrence (hazard ratio [HR], 0.63; 2 P = .001) and breast cancer mortality (HR, 0.71; 2 P = .00002)1In women younger than 45 years

TREATMENT OF MICROMETASTASES BREAST CANCER

stage III, locally advanced breast cancer(is characterized by the spread of cancer cell to slymph nodes and the chest walls with tumor size larger than 5 cm. Effective treatment requires both local (directed to destroying any cancer cells in the breast ) and systemic therapy ( destroy cells spread outside the breast ). These cancer cells outside the breast are referred to as micrometastases. Tamoxifen is effective in advanced breast cancer to destroy micrometastases that the surgery therapy alone are not able to treat, thereby reducing recurrence. Sometimes these are given before surgery to skink the tumour, in that case, they are called neoadjuvant systemic therapy

TREATMENT OF METASTATIC BREAST CANCER

Historically, metastatic breast cancer has been considered incurable. With cancer cells spreading to other areas of your body, the bones, brain, liver and lungs to goal of treatmentat the stage is to shrink the cancer cells to prolong life, delay the progression of the cancer, relieve cancer-related symptoms, and improve quality of life. However with the development of more active hormonal therapy drugs the risk of death is decreasing by 1%–2% each year

Use of anti-oestrogens in treating breast cancer

Anti-oestrogens are classified into two major groups’ type1 and type II. Type I, which are analogs of tamoxifen, they exhibit a mixture of oestrogens and anti-oestrogens actions in laboratory assays, whereas type II has no estrogen-like properties in laboratory assays. Type I antiestrogens agents such as tamoxifen, and raloxifene are substances that balance the effects of excess estrogens. They binds to oestrogen receptor (ER) preventing activation the receptors and proliferative gene expression and signalling

Mode of action of tamoxifen

A

Figure 4

B

Figure 10

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Estradiol diffuses into all cells and binds to estrogen receptor ER to form a steroid receptor complex estradiol–ER which undergoes conformational changes and dimerizes. Subsequent it binding to specific DNA sequences resulting in transcription target genes. This process requires both functional domains of the ER, activating function-1 (AF-1) and AF-2, to bind to DNA and recruit necessary coactivators of transcription

When the 4-hydroxytamoxifen, the active tamoxifen metabolite binds to the ER, it interacts with the estrogen receptor in a manner similar to estradiol except that AF-2 binding to the coactivator complex is inhibitedwhereas AF1 remains active. Tamoxifen partial agonism is shown in the different effects it has on the two distinct transcriptional activating functions (AF-1 and AF-2). Thus, tamoxifen-like drugs can produce increased cellular levels of ERleading to development of resistant

How another group of anti-oestrogens exert their anticancer action

Fulvestrant is the first of a new type an anti-oestrogens agent unlike no known estrogen agonist activity that downregulates the ER. It wasdeveloped from modifying the long-chain alkyl substitutes in the 7-position of estradiol. Interaction between fulvestrant a pure antiestrogens and the estrogen receptor is fundamentally different from that of Tamoxifen (SERMs).WhenFulvestrantbindstoestrogen receptor monomers it inhibits receptor dimerization, inactivating ofboth 1 (AF1) and AF2. This results to reduction in translocation of receptor to the nucleusand degradation of the estrogen receptor. Thus, fulvestrant block the ability of the ER to regulate transcription and also reduces cellular levels of ER. This suggests that early use in the therapy would reduce the risk of development of cross-resistance to subsequent endocrine therapies.

File:Fulvestrant organic synthesis brazier 2010.svg

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Journal Article (printed)