Cancer is a disease characterized by a loss in the normal control mechanisms that govern cell survival, proliferation, and differentiation Katzung et al., 2011. Cancer is caused by changes in a cell's DNA - its genetic "blueprint" (American Cancer Society, 2012).Some of these changes may be inherited from our parents, while others may be caused by outside exposures, which are often referred to as environmental factors (National Cancer Institute, 2010). Environmental factors can include a wide range of exposures, such as lifestyle factors that are nutrition, tobacco use and physical activity, naturally occurring exposures like ultraviolet light, radon gas, and infectious agent, workplace exposure, household exposure, pollution and last but not least medical treatment which include chemotherapy, radiation, immune system-suppressing drugs (American Cancer Society, 2012). These causal factors may act together or in sequence to initiate or promote carcinogenesis. The development of most cancers requires multiple steps that occur over many years. Certain types of cancer can be prevented by eliminating exposure to tobacco and other factors that initiate or accelerate this process. Other potential malignancies can be detected before cells become cancerous or at an early stage, when the disease is most treatable (National Cancer Institute, 2010).
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A report from American Cancer Society (2012), approximately 1,690,000 new cancer cases will be diagnosed and 577,000 Americans will ultimately die of cancer. National Cancer Registry (2007) stated a total of 18,219 new cancer cases were diagnosed in that year and registered. It comprises of 8,123 (44.6%) males and 10,096 (55.4%) females.
Breast cancer was the most common cancer in females and also the first most common cancer among population regardless of sex in Malaysia. According to NCR (2007), there were 3,242 female breast cancer cases diagnosed in 2007 which accounted for 18.1% of all cancer cases reported and 32.1% of all are female's. The incidence of breast cancer was highest among Chinese where the age-standardised rate (ASR) was 38.1 per 100,000 population followed by Indian and Malay with the ASR of 33.7 per 100,000 population and 25.4 per 100,000 populations respectively. The percentage of breast cancer detected at stage I and II was 58% (NCR ,2007).
Estrogen is a natural steroid hormone found in our body. Estrogen comprises estradiol, estrone and estriol. The most active estrogen which is estradiol is produced by ovaries. Estradiol also, plays a major role in the advancement of breast cancer, and a majority of the human breast cancers start out as estrogen dependent and express the estrogen receptor (ER). The biological effects of estrogen are mediated by its binding to one of the structurally and functionally distinct ERs which are ERÎ± and ERÎ² (Saha Roy & K. Vadlamudi, 2012).
The main good effects of estrogen include its roles in development of vagina, uterus and fallopian tube as well as secondary sex charecteristics, development of uterine lining, enchancing coagulatibilty of blood, (Katzung et al., 2011), controlling cholesterol production in ways that limit the buildup of plaque in the coronary arteries, and preserving bone strength by helping to maintain the proper balance between bone buildup and breakdown (National Cancer Institute, 2010).
Regardless all these important beneficial effects, estrogen can also be harmful. Estrogen is able to promote the proliferation of cells in the breast and uterus in which way it is the most serious problem. In spite of the fact that estrogen does not appear to directly cause the DNA mutations that induce the development of human cancer, its ability to stimulate cell proliferation in its normal roles, can also increase a woman's chance of developing breast or uterine cancer (National Cancer Institute, 2010). There are three mechanisms that have been considered to be responsible for the carcinogenicity of estrogens. They are 1) receptor-mediated hormonal activity, 2) a cytochrome P450 (CYP)-mediated metabolic activation, which elicits direct genotoxic effects by increasing mutation rates, and 3) the induction of aneuploidy by estrogen (Russo et al., 2003).
An estrogen receptor is a protein molecule found inside the cells that are targets for estrogen action. Estrogen receptors contain a specific site to which only estrogens (or closely related molecules) can bind (National Cancer Institute, 2010).
When estrogen molecules circulate in the bloodstream and move throughout the body, only cells that contain estrogen receptors are affected. Estrogen receptors normally reside in the cell's nucleus, along with DNA molecules.
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When the estrogen molecules are absence, these estrogen receptors are inactive and have no influence on DNA . But once an estrogen molecule enters a cell and passes into the nucleus, the estrogen binds to its receptor, thereby causing a conformational change to the receptor. Later, this estrogen-receptor complex then binds to specific DNA sites, called estrogen response elements, which are located near genes that are controlled by estrogen (National Cancer Institute, 2010).
After it has become attached to estrogen response elements in DNA, this estrogen-receptor complex binds to coactivator proteins and more nearby genes become active. The active genes produce molecules of messenger RNA, which guide the synthesis of specific proteins. These proteins can then influence cell behavior in different ways, depending on the cell type involved (National Cancer Institute, 2010).
ERÎ± is the major subtype in the mammary epithelium and plays an important role in mammary gland biology as well as breast cancer development. ERÎ± is a ligand-dependent transcription factor that modulates gene transcription via recruitment to the target gene chromatin (Mann et al., 2011). Recent mechanistic studies have highlight a role of estrogen estrogen-induce rapid ERÎ± extranuclear signaling in facilitating the metastatic process (Saha Roy and K. Vadlamudi, 2012).
Emerging evidence suggests that ERÎ± signaling has the potential to contribute to epigenetic changes. Several histone modifications at the ERÎ± target gene promoters which are acetylation, phosphorylation and methylation via dynamic interactions with histone modifying enzymes are due to estrogen. Deregulation of enzymes involved in the ERÎ± - mediated epigenetic pathway could play a vital role in ERÎ± driven neoplastic processes. Unlike genetic alterations, epigenetic changes are reversible, and hence offer novel therapeutic opportunities to reverse ERÎ± driven epigenetic changes (Mann et al., 2011).
Estrogen receptor negative (ER -)
ER-negative breast cancers are often considered to be the result of tumor progression from ER-positive premalignant lesions or ER-positive breast cancers by genetic alteration such asgene instability, loss of heterozygosity, and exon deletion epigenetic alteration such as promoter methylation or ER protein degradation in proteasome after hypoxia in non-vascularized tumor (Rochefort et al., 2003). It does not or less likely to respond to hormone (Kumar et al., 2005).
How to treat cancer?
Cancer can be treated by radiotherapy, chemotherapy, surgery and immunotherapy. The treatment can be curative or palliative intent and to control the disease.
Radiotherapy specifically acts against cells that are reproducing rapidly.. Normal cells are programmed to stop reproducing (or dividing) when they come into contact with other cells. When there is a tumor, this stop mechanism is missing then it causes cells to continue to divide over and over. The main culprit for that particular cells capable of reproducing is the DNA of the cell. This therapy uses high energy x-rays to penetrate and damage the DNA cells, thus killing the cancer cells, or at least stopping them from reproducing. Radiotherapy can damage cancer cells as well as normal cells but because normal cells are growing slowly, they are able to repair this radiation damage than that cancer cells (Abramson Cancer Center of University of Pennsylvania, 2006).
Chemotherapy is the use of drugs or medicines to treat cancer (American Cancer Society, 2012). The RNA or DNA of a cell tell it how to replicate itself, and classic chemotherapy (which excludes immunotherpeutics and biological response modifiers) works by destroying this RNA or DNA. The more rapidly the tumor cells are replicating, the better chemotherapy is able to kill the cells (Abramson Cancer Center of University of Pennsylvania, 2010).
There are few types of chemotherapy drugs. They are 1) alkylating agent which is directly damage DNA from reproducing that is a non specific phase, example, ifosfamide, 2) antimetabolites which interfere with the growth of DNA or RNA. These agents damage the cells during S phase in cells cycle, example, 5-fluorouracil (5-FU), 3) antitumor antibiotic which interfere with enzymes involved in DNA replication, example, Doxorubicin, 4) topoisomerase inhibitor which interferes topoisomerase, an enzyme that helps to separate the strands of DNA so they can be copied. Example of this agent is topotecan, last but not least 5) mitotic inhibitor which inhibit mitotic division or inhibit enzymes that make protein needed for cell reproduction. Example of this type of agent is paclitaxel which will be discussed further later (American Cancer Society, 2012).
Surgery can be done for various reasons. They can be preventive (prophylactic) surgery, diagnostic surgery, staging surgery, curative surgery, debulking (cytoreductive) surgery, palliative surgery, supportive surgery, and restorative (reconstructive) surgery.
Preventive surgery is done to remove body tissue that is likely to become cancer. Diagnostic surgery is done to check present of cancer or what type of cancer is present. Staging surgery is done to find out how far the cancer has spread or whether it has metastasis or not. Curative surgery as the name suggest is a surgery to cure when the cancer is found in only one area and probably all the cancer has been removed. Debulking surgery is done to remove some of the cancer cells but not all of the cancer cells are removed. Palliative surgery is done to treat problems caused by advanced cancer. It can also to overcome problems causing discomfort or disability. Supportive surgery is done to help with other treatments. Last but not least, reconstructive surgery, is done to restore the major function of an organ or body parts after surgery (American Cancer Society, 2012).
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In the case of immunotherapy, it is designed stimulate that particular person who is having cancer natural immune systems to recognize and attack cancer cells. It is often categorized by two types which are passive and active. Passive immnunotherapy rely on immune system components that is created outside of human body while active immunotherapy stimulates its own immune system to fight against disease. Example of passive immunotherapy is monoclonal antibody therapy such as rituximab. BCG is an example of active immunotherapy that is able to boost immune response (American Cancer Society, 2012).
Chemotherapy and anticancer drugs
Chemotherapy is presently used in three main clinical settings: (1) primary induction treatment for advanced disease or for cancers for which there are no other effective treatment approaches, (2) neoadjuvant treatment for patients who present with localized disease, for whom local forms of therapy such as surgery or radiation, or both, are inadequate by themselves, (3) adjuvant treatment to local methods of treatment, including surgery, radiation therapy, or both.
Dose is a major determinant of the antitumor activity and toxicology for many chemotherapeutic agents. The effect of dose for biotherapeutic agents and hormones is complex (KIII & Antman, 2000). The dose response curve in biologic systems is usually sigmoidal in shape, with a threshold, a linear phase, and a plateau phase (Katzung et al., 2011). There are few factors affecting dose effects. They are : 1) classes of chemotherapy drugs, 2) tumor factor and , 3) host factor (KIII & Antman, 2000).
For chemotherapy, therapeutic selectivity is dependent on the difference between the dose-response curves of normal and tumor tissues. A positive relationship between dose intensity and clinical efficacy has been portrayed in solid tumor such as breast, lung, and colon cancers. Recently, there are three main strategy to dose-intense delivery of chemotherapy. The first one is dose escalation, by increasing the doses of the several anticancer agents. The second strategy is administration of anticancer agents in a dose-intense manner by reducing the interval between treatment cycles, while the third approach involves sequential scheduling of either single agents or of combination regimens. Each of these strategies is being applied to a wide range of solid cancers, including breast, colorectal, and nonsmall cell lung nowadays, and in general, dose-intense regimens have significantly improved clinical outcomes (Katzung et al., 2011).
Paclitaxel and chemotherapy
Paclitaxel is a naturally occurring diterpenoid (Iqbal et al., 2011), extracted from the bark of Pacific Yew Taxus brevifolia trees. It has been reported to be the first compound with a taxane ring and possessing anti-tumor activity (Javeed et al., 2009).
Paclitaxel as promising anticancer drugs
Anticancer mechanisms of paclitaxel
Paclitaxel binds to specific pockets within Î²-tubulin in Î±/Î²-tubulin dimers , that are incorporated within preformed microtubule polymers. Once paclitaxel binds, it will increase microtubule polymerization and stability as well as trigger mitotic arrest of cycling cancer cells which later followed by apoptosis (Ahmed et al., 2011). Subsequent arrest at the mitotic checkpoint results in apoptosis presumably through G2/M arrest and subsequent apoptosis through the mitochondrial pathway. Paclitaxel can also cause disruption of microtubules during interphase, thereby interfere with growth and metabolism (Murray et al., 2012).
Some of the most well characterized mechanisms of molecular action include (Figure 2.2.2).
activation of cell division control-2 kinase (cdc-2),
stabilization of cyclin B-1,
activation of the spindle assembly checkpoint,
induction of apoptosis through phosphorylation of bcl-2,
inhibition of cell proliferation.
There are few fundamentals of paclitaxel resistance. The first one, mutation outside the paclitaxel-binding site increases the fraction of unstable microtubules in the cell. Second, overexpression of Î² 3-tubulin or overexpression of depolymerizing microtubule-associated proteins results in a disproportionate increase in free tubulin dimers. Third a consequent reduction in paclitaxel binding sites. Finally, loss of the extracellular matrix protein transforming growth factor, beta-induced (TGFBI) which results in decreased focal adhesion kinase activation, decreased microtubule stability, and an increase in unstable microtubules resulting in significant paclitaxel resistance (Ahmed et al., 2011).
Clinical dosage form
Intravenous (i.v) injection administration
Consequently paclitaxel is currently administered via i.v. infusion in which the drug is solubilized in a 1:1 (w/w) mixture of ethanol and Cremophor EL. Patients have to hospitalize for infusion administration which is time consuming and requires infusion equipment, nursing aid and strict aseptic conditions. Moreover, an irrational fear of needles (belonephobia) makes infusion therapy distressful and unacceptable in many cases (Iqbal et al., 2011)