Study Of Multidrug Resistance (MDR) Genes By Multiplex PCR And Evaluation Of Some Immunological Parameters In Breast Cancer Patients On Chemotherapy

number: 
2928
English
Degree: 
Imprint: 
Medicine
Author: 
Abdul Rahman Mohammed Geeran Al-Fahdawi
Supervisor: 
Dr. Nidhal Abdul Muhaimen Mohammed
year: 
2012
Abstract:

Breast cancer is the most common cancer in women. The incidence of breast cancer has increased by 0.5% per year over the past decade, whereas the death rate decreased by 1.4% per year during the same period. The decline in mortality is more remarkable in women aged 50 years. The increase in disease-free survival (DFS) and the decrease in overall mortality are most likely a result of increased awareness of breast diseases (Copeland, et al., 2009). Malignant transformation involves genetic and epigenetic changes that derail common regulatory mechanisms and result in uncontrolled cellular proliferation and/or aberrant programmed cell death or apoptosis. These cellular abnormalities are frequently associated with molecular alterations involving certain types of genes, such as proto-oncogenes and tumor suppressor genes, as a result of genetic predisposition and/or exposure to physical, chemical, biological or environmental factors. These biological alterations are reflected in many clinical and pathological aspects of the disease. As an example, the natural history of breast cancer is markedly heterogeneous. Some patients suffer aggressive forms of the disease with rapid recurrences and short survival while others show a good response to current therapeutic modalities and have longer survival rates. Many of the predictive and prognostic factors that are currently known to affect tumor behavior are based on these genomic alterations (Omar, et al., 2003; Jemal, et al., 2007). Many anticancer drugs act by inducing apoptosis. The rapid progress in understanding mechanisms underlying apoptosis may present opportunities to harness the cellular death machinery for the benefit of treating human diseases such as cancer (Dangsheng, et al., 2004). P-glycoprotein (P-gp) is a member of the superfamily of ATP binding cassette (ABC) transporters that mediates the outward movement of a variety of structurally unrelated compounds, therefore contributing to the clinical phenomenon of multidrug resistance. It is nowadays widely accepted that P-gp binds its substrates within the lipid bilayer and exports them from there to the extracellular compartment. The intimate association of both P-gp and its substrates with the membrane suggests that P-gp function may be regulated by the composition of the lipid bilayer (Deeken and Loscher, 2007). Systemic therapy for breast cancer is effective in delaying or preventing morbidity and mortality from this prevalent disease. The most thoroughly studied and undoubtedly one of the more important mechanisms of multidrug resistance is increased expression of the MDR-1 gene. This gene codes for the P-170 membrane glycoprotein, which promotes the efflux of vinca alkaloids, anthracyclines, dactinomycin (actinomycin D), epipodophyllotoxins, and other natural products. This protein occurs constitutively in many normal tissues, including epithelial cells of the kidney, large bowel, and adrenal gland (Fojo et al, 2008). Initial application of systemic treatment to breast cancer involved relatively nontoxic therapies (hormonal) to patients with relatively shorter life spans, limiting the risk of harm. In the 1970s, with the advent of effective systemic chemotherapy, single agent and ultimately combination chemotherapy was introduced largely applied in unselected fashion to patients who were refractory or resistant to hormonal agents. The development of the Cyclophosphamide, Methotrexate ,and 5-Fluorouracil (CMF) regimen was a landmark event in the treatment of breast cancer. Combination chemotherapy was proven to be effective in treatment of advanced disease. Subsequently, it was recognized that the application of effective agents to early stage disease could prevent recurrence and improve survival. The number of chemotherapeutic agents available for use to prevent recurrence (adjuvant indication) has since greatly expanded. The use of chemotherapy has included regimens with agents used singly or in combination, often with additive acute toxicities, such as neutropenia and nausea, and toxicities are increasingly expected as therapeutic agents are combined. AIMS OF THE STUDY The limitation in the resources and shortage of supplements for molecular studies worsen the problem of breast cancer in Iraq .Hence this study will try to start with a clinical, molecular and immunological research on this disease in our country, focusing on the following aims: To study the role of Multidrug Resistance (MDR) genes in drug resistance by Multiplex Polymerase Chain Reaction (MPCR) technique in correlation with the presence or absence of Estrogen Receptors (ER), Progesterone Receptors (PR) and Human epidermal growth factor receptors (Her-2/neu ) markers in breast cancer patients.To assess the immunity of breast cancer patients before and after treatment with adjuvant chemotherapy by studying the immune cells :CD4+, CD8+, CD19+ cells and NK; and the serum markers: IL-3, IL-7, CA 15-3 and Cripto-1 (CR-1).