Cancer remains one of the most feared and deadly diseases of the world. According to WHO, cancer affects one person out of three and it caused a quarter of deaths among those affected in the year 2000. Like any other cancer type, breast cancer develops when a normal functioning cell loses it self-control mechanism used in the modulation of its growth (division and control). This type of cancer can develop from internal breast tissues such as those from the ducts or the milk supplying lobules of the breast. Breast cancer emanating from the ducts is referred to as Ductal Carcinomas while those emanating rom the lobules of the breast is called Lobular Carcinomas (Graham, 2009). The chemotherapy management of patients with breast cancer keeps evolving from use of more conventional cytotoxic substance to a more effective targeted therapy. Unlike the conventional cytotoxic therapy, targeted therapy is highly selectively in that they can target a cellular pathway (targets) involved in the proliferation and development of breast cancer (Hobday and Perez, 2005). Previous research shows that 95% of breast cancer cases are dependent hormones (Jorge and Gerrat, 2005).
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Targeted therapy aim to inhibit and suppress the growth of cancerous cells by preventing the action of natural molecules that are needed by the breast cancer cells to grow (FDA Orange Book, 2011). Variety of breast cancers has also been linked to elevated level of oestrogens in the body and with increase in the level of cancer biology; more molecular targets associated to breast cancer are being identified (Alex and Nixon, 2009; Graham, 2009). Molecular targeting drugs include; selective oestrogen receptor modulators, aromatase inhibitors, signal transduction modulator. Targeted therapy is highly safe and effective strategy to combat cancer cells. The use of this strategy is specific for a type of breast cancer patients in that the drugs are given to only patients with likelihood of benefiting form the treatment. However, more research on cancer management should be carried out so as to identify more targets and develop novel agents to modulate the activity of the targets (Hobday and Perez, 2005).
MOLECULAR BASIS OF BREAST CANCER
All normal living cells undergo check-ups in other to detect any form of damage to cell DNA or irregularities during cell cycle. Any form of abnormalities in the gene or irregularities in cell cycle leads to different form of cellular defects in the breast. Combination of this cellular defect forms leads or can initiate a malignant cell of the breast. This is characterized by loss of control over cell growth that leads to continuous growth of the malignant cells. Cellular defects related to breast cancer include loss of insensitivity of breast cell receptors to growth signal factors, abnormalities in the growth signalling pathway and cell cycle regulation, unlimited or uncontrolled cell division and evasion of apoptosis by cells of the breast. Tumour cells can be developed from mutation in the various genes that codes for different enzymes and other proteins that control different phase of cell cycle. Many cancerous cells of the breast can produce growth factors such as VEGF AND FGF-2 on their own to stimulate their receptor and can also develop abnormal receptor in other to multiply their growth (Graham, 2009).
BREAST CANCER DRUGS
The primary breast cancer drugs used in the management of breast cancer are cytotoxic in nature. These cytotoxic drugs help in combating cancerous cells of breast by killing the tumour cells directly. The commonly cytotoxic breast cancer drugs used include;
Alylating Agents such as cisplatin, Oxaliplatin and Idarubicin. They disrupt the activity of DNA by form intrastrand cross-linking between duplex DNA.
Antimetabolites such as Methorexate, Cytarabine that work by blocking the synthesis of DNA.
Antibiotics such as Epirubicin, Daunorubicin and Amascarine. They have multiple effects on nucleic acid.
Although conventional cytotoxic drugs remain an integral part of chemotherapy for breast cancer patients, their non-specificity, toxicity and resistance by cancerous cells limit their usage. They can kill both cancer and normal cells; as a result, normal cells are damage during treatment (Rang et al., 2007).
MOLECULAR TARGETED CHEMOTHERAPY
Breast cancer chemotherapy has now entered a new era, which can be described as molecular target anticancer agents. Molecular pathways involved in the development of breast cancer can signify the major targets for chemotherapeutical approaches. Over the last few years, the use of targeted drug design approach has become more sophisticated thereby providing lots of breast cancer drugs for variety of molecular targets. Use of drugs that can act on molecular targets provides an effective strategy for treatment of breast cancer. Molecular targeting anticancer agents are highly selective in nature by their ability to recognise specific abnormalities within cancer cells.. On the basis of target selectivity, anticancer agents can be classified into Hormonal target drugs and Non-Hormonal target drugs (Cristofanilli and Hortobagyi, 2002).
HORMONAL TARGETS DRUGs
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They target drugs hormones that are associated and involved on the development of breast cancer. Drug in this category either selectively inhibit the synthesis of a particular hormone such as oestrogen, progesterone etc. or indirectly blocking their synthesis (Krishna, 2001). Steroid hormones such as oestrogen can induce the protein involved in DNA synthesis; thereby instigate the proliferation of both malignant cells and normal. Through receptor-facilitated processes, these hormones can also activate growth-regulating genes. Breast cancers cells which have are hormone receptor positive are likely to respond to hormonal anticancer agents than those with hormone receptor negative. Anticancer agents that target hormones includes the following:
Selective Oestrogen Receptor Modulators (SERMs) such as Tamoxifen, Reveratrol and Raloxine (Shoko et al., 2008). These drugs produce oestrogen antagonistic effects in the breast by inhibiting receptor activities. Based on ther result of clinical trials, Tamoxifen is the only SERM approved for reduction of breast cancer in patients with high risk of breast cancer (Janes, 2010).
Aromatase Inhibitors (AI) such as Letrozole, Anastrozole, Fadrazole, Formestane, Vorozole and Exemenstane. These agents selectively inhibit Aromatase, which catalyse the rate-limiting step in the biosynthesis of oestrogen from Androgens (Cristofanilli and Hortobagyi, 2002)..
Estrone Sulfatase Inhibitors (ESI) such as Estrone-3-O-sulfatase, 4-methylcoumerin-7-O-sulfamate, Medrogesterone, Dehydrogesterone and Promegestone. These agents target Oestrone sulfatase which catalyses the conversion of oestrogen to a more stable Oestrogen Sulfotransferase (Krishna, 2001; Nicola and Atul, 1993).
NON-HORMONAL TARGET DRUGS
Vital processes associated with the pathogenesis of breast cancer that do not involve activation of hormone receptor are targets for drugs that belong to this category.
Some drugs in this category also work by disruption or inhibition of process involve in DNA synthesis (Graham, 2009). Anticancer agents that are non-hormonal targets pa include the following;
Signal Transduction Modulators (STMs) such as Geftinib, Eriotinib, Trastuzumab, and Lapatinib (approved 2007). Drugs in this category target signal transduction pathways associated with breast cancer proliferation and development. Sunitinib inhibits PDGF-R, VEGF-Rand other tyrosine receptor kinase. Sorafeni and Vatalinib are inhibitor of MTK receptor. Other targets include for STMs drugs includes; Tyrosine Kinases receptor, Platelet-derived growth factor receptor (PDGF-R), epidermal growth factor receptor (EGF-R), Ras protein and other pathways.
Angiogenesis Modulators such as Merimastat, Prinomastat and CGS. Drugs that belong to this category inhibit angiogenic factors (VEGF and bFGF). Other targets include inhibition of MMPs and up-regulation of thrombospondin and angiostatin (Graham, 2009; Ferdinando, 2006).
Cell Cycle and Apoptosis Modulators such as Flavopiridol, which inhibit expression of Cyclin D1 and D3 expersiom. Roscivtinine selectively antagonise CDK 3 receptor. Other targets for drugs in this category include tyrosine kinase, tumour necrosis factor and Bcl protein (Graham, 2009).
Limitations of Breast Cancer Agents
There are still drawbacks to this use of these agents despite the unarguable success of chemotherapy (anticancer agents) in the treatment of Breast cancer. These draw backs includes;
Unacceptable toxicity that might limit the long-term use of these agents and reduce patient compliance.
Drug resistance may be developed
Ineffectiveness of the drugs for all subsets of patients.
Hence, there is need to design and develop novel agents which are needed to increase survival of patients, delay the cancer progression and improve patients tolerability to the treatment (FDA Orange Book, 2011). There is need for intensive laboratory and clinical research to provide information about various forms of drug resistance to anticancer agents. This information will aid the development of new therapeutic approach for the prevention and treatment of breast cancer.
Progress and Future Perspective
Knowledge of pathophysiological mechanism and other developmental processes of breast cancer have provided opportunities for more molecular targeted approaches for treatment and prevention of cancer. With increases in the number of years and cost of design and development of drugs, it will be a good practice for pharmaceutical industry and research groups to focus on the design of drugs, which selectively targets a pathway associated with the proliferation of breast cancer. The use of Computational drug design approach such as ligand docking can be use to facilitate the design and discovery cancer agents with high selectivity for a particular molecular target. Also, combination of old existing drugs as well their optimisations can provide new agents for combating breast cancer. Combination such as SERM drug with ESI drug to target a dual or multiple pathways can prove effective against cancerous cell. Through the testing of new drug combination, researcher will be able to know if certain breast cancer is more susceptible to a specific drug combination. However, there is continuous need to keeping researching on targeted therapy because it holds promises and benefits to cancer patients.
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