Cancer is uncontrolled growth and abnormal proliferation of cells in the body. Most cancers form a tumor but some cancers, like leukemia do not. The branch of medicine which concerned about study, diagnosis, treatment and prevention of cancer is known as oncology. Cancer metastasis is a process where tumor cells leave the primary tumor and travels through lymph and blood circulatory system and establishes secondary tumor in other body organs. Carcinogens are a class of substances responsible for the damaging DNA, and causes mutations. It's very difficult to determine what causes cancer. Proto-oncogenes are normal genes coding for proteins that helps in cell proliferation and regulation. Whenever there are mutations in the proto-oncogene, it will trigger uncontrolled cell proliferation. There are two types of tumor suppressor genes that always maintain the integrity of genome and it reduces the probability of converting normal cell in to tumor cell (Philip W. Hinds and Robert A. Weinberg, 1994).
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Care taker genes are p53, Rb1 and APC (adenomatous polyposis coli)
Gate keeper genes are BRCA1, BRCA2 and MSH2 MLH1
Cancer is classified by the site of origin and tissue type
Carcinoma: cancer originates from the epithelial cells that forms lining on external parts of body and internal body organs most common type of cancers as breast, lung, liver and prostrate.
Sarcoma: cancer originates from the connective and supportive tissues like cartilage, bones and muscles.
Myeloma: originates from the plasma cells of bone marrow, myeloma is a type of blood cancer.
Leukemia: cancer affects the bone marrow in the site of blood cell production.
Lymphoma: they are like solid cancers and effects in the sites of stomach, brain and intestine (T.R. Golub et al., 1999).
1.1 BREAST CANCER
According to American Cancer Society, breast cancer is the most common type of cancer in women. Breast cancer originates from the tissue of the breast; it can be invasive and non-invasive.
It is classified into two different types based upon the origin of tumor, ductal carcinoma and lobular carcinoma. Ductal carcinoma starts in the ducts that help in moving milk from the breast to nipple. Most of the breast cancers are ductal carcinoma. Lobular carcinoma originates in the lobules of the breast where milk produces. Invasive breast cancer means it spreads from the ducts and lobules to other breast tissue whereas non-invasive condition it has not yet invaded other tissue in breast region. Based upon the receptor status four types are present.
Group1 (luminal A): Tumors are positive for estrogen and progesterone and negative for HER-2.
Group 2 (luminal B): Tumors are positive for estrogen, negative for progesterone and positive for HER-2.
Group 3 (HER-2 positive): Tumors include estrogen negative, progesterone negative and HER-2 positive. . HER2 gene helps the breast cells to grow faster, divide and also repair themselves. When cells have too many copies of the HER 2 gene it leads to high risk factor of breast cancer.
Group 4 (basal like): It is also called as triple negative breast cancer (TNBC). TNBCs are negative for progesterone, estrogen and HER-2 receptors (Lisa A. Carey et al., 2006).
1.2 BREAST CANCER STAGING
Cancer staging is a process that explains about whether cancer has spread within the breast or other parts of the body. Staging process also reveals the severity of the disease and to plan treatment. There are mainly three different ways to spread cancer with in the body. One is through tissue of the body, where cancer invades surrounding normal healthy tissue. Second is through the lymph system, where cancer cells invades lymph system and travels to other body system through lymph vessels. Last one is through blood circulation, where cancer cells enters in to the veins and capillaries and travels to other body organs. Cancer cells separate from the breast tumor and travels to other body organ through blood or lymph vessels and starts secondary tumor. This process is known as metastasis. Stages of breast cancer are stage I, II, IIIA, IIIB, IIIC & IV. Stage I cancer was divided in two parts stage IA and IB. In stage IA, tumor will be 2cm or less than 2cm and tumor has not spread yet outside the breast tissue and in stage IB small lump of breast cancer cells are found in the lymph nodes and size is not greater than 0.2 millimeter. Stage II again divided in to two stages IIA and IIB. In stage IIA, no tumor or tumor size of 2cm are found in axillary lymph nodes near the breast bone. In stage IIB, tumors are larger than 2cm but smaller than 5cm and are found in the lymph nodes. In this stage, tumor cells are also spread to 1 to 3 axillary lymph nodes near the breast bone. Stage IIIA tumor will be of any size or no tumor and cancer was found in 4 to 9 axillary lymph nodes near the breast bone sometimes also seen in lymph nodes and size of tumor will be larger than 5cm and small lumps of breast cancer will be found in lymph nodes, stage IIIB tumors will be of any size and will spread to skin and chest. Swelling will be seen and cancer cells are spread up to 9 axillary lymph nodes. In stage IIIC, no tumors will be seen or tumors of any size are spread to skin, chest, and also more than 10 axillary lymph nodes near breast bone, above or below collar bone. Final stage is stage IV where metastasis is seen and tumors are spread to other organs of the body, mostly to liver, bones, lungs and brain.
1.3 RISK FACTORS
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A risk factor is anything that affects your chance of getting disease. Various types of cancers have different types of risk factors. Having risk factor, it doesn't mean that the person gets the cancer but chances of getting cancer will be higher. In most cases, breast cancer will occur even in the absence of any risk factors. There are different types of risk factors like gender and age which cannot be changed and some related to personal habits such as alcoholism, smoking, diet which can be changed.
Women have very higher percentage of risk factor in developing breast cancer compare to men.
Risk of developing breast cancer increases in older age. Women more than 55 age have high chance of getting breast cancer than the young women.
Genetic risk factor:
About 5 to 10% of patients normally develop breast cancer because of heredity and mutations in the genes. There are several genes like BRCA1, BRACA2 which are tumor suppressor and DNA repair genes. Normal function of these genes is protecting cells from abnormal proliferation and repairing the damaged DNA. Mutations in these genes can be transferred from one generation to another. If person inherit one copy of mutated gene from parents then the person is having high probability of getting cancer in life time and they also have high rate of developing other cancers like ovarian cancer. There are other gene mutations which are also responsible for causing breast cancer but lesser rate than the BRCA1 and BRCA2 genes. Mutated or defected genes of ATM, TP53, CHEK2, PTEN, CDH1, and STK11 will also cause breast cancer.
Life style related factors:
Conceiving children after the age of 35, defective birth control methods, hormone therapy after menopause, alcohol consumption, overweight or obese and lack of physical activity.
Family history of breast cancer (William D. Dupont, PH.D., and David L.Page, 1985), personal history of breast cancer, race and ethnicity, dense breast tissue, certain benign breast condition (non-proliferative lesions and proliferative lesions without atypia, lobular carcinoma in situ, irregular menstrual periods, previous chest radiation, diethylstilbestrol exposure). Diet, vitamin intake, antiperspirants, induced abortion, chemical environment, tobacco smoke etc are other unproven factors.
The first symptom in the breast cancer person may develop lumps in their breast tissue but 9 out 10 women these lumps are benign. Most of these benign lumps are breast cell changes, cysts and fibro adenoma.
Most of the breast cancers patients have a lumps or thickening of the breast area, hardening of breast skin, changing of breast shape, and a blood stained discharge from the nipple, itchiness, rashes around the nipple and presence of lumps near the arm pit area.
Even though presence of all this symptoms most of the tumors are benign they are not cancerous.
A rare type of a cancer called inflammatory breast cancer was seen with different types of symptoms the whole breast will look in red color, inflammation will be seen and very sore and skin will be hardened.
Another very rare type of breast cancer was seen it is known as Pagets disease it will be red, scaly rash and sometimes itchy. In many breast cancer women breast pain will be present but in some women it is absent.
Biopsy is a process of collecting sample of tissue cells from the breast and testing them to see whether they are cancerous or not.
Mammogram is an x-ray of breast. Diagnostic mammograms are used to detect breast diseases which have symptoms related to breast cancer. It shows the area of abnormal tissue and usually it takes in two different angles. If mammogram shows any lumps in the breast a biopsy is required to confirm the tumor.
MRI was used along with the mammograms to screen women who have high chances of developing breast cancer.
Breast cancer treatment can be done in four different ways.
Breast cancer surgery is removal of tumor and surrounding normal healthy tissue and conserving as much of the breast tissue possible. There are different types of breast cancer surgery treatments are present. The type of surgery differs depending upon the amount of healthy breast tissue that removed from the tumor, tumor characteristics and whether tumor has metastasized. Types of breast cancer surgery include lumpectomy, partial or segmental mastectomy, total mastectomy, modified radical mastectomy and radical mastectomy.
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Radiation therapy typically involves delivering precise amount of high radiation energy to kill cancer cells. Radiation stops the tumor cells regeneration and minimizes the damage of healthy tissue. Radiation therapy for breast cancer used after lumpectomy or mastectomy, hormone therapy and chemotherapy, to decrease the risk of cancer re-growing. Radiation therapy is painless. However, patients experiences side effects after treatment.
1.6.3 Hormone therapy
There are certain types of hormones that can attach to the breast cancer cells and affects their ability to multiply. The main aim of hormone therapy is to block, or remove hormones. In breast cancer, estrogen and progesterone hormones promote the growth of cancer cells. Hormone therapy is given to block the naturally producing estrogen hormone from the body to stop or slow the cancer's growth.
Women who are estrogen- positive are more likely to responds to hormone treatment than the women who are estrogen-negative. Hormone therapy drugs used to treat breast cancer are Tamoxifen, Fareston, Arimidex, Aromasin, Femara, Zoladex/ Lupron, Megace and Halotestin.
Chemotherapy refers to use of anti-cancer drugs (chemicals) to kill the breast cancer cells. The US food and drug Administration approved the use of combinational chemotherapeutic drugs, FEC- 5FU, epirubicin and cyclophosphamide. Combinational treatment has significant risk of bruising and bleeding, anemia, diarrhea and risk of blood clots side effects. Chemotherapy used for three main different purposes.
Adjuvant therapy: Used to prevent or postpone the cancer from coming back after the surgery and radiation therapy.
Neo-adjuvant therapy: Sometimes tumors are very big that can be shrinking it first with chemotherapy and make it easier to do surgery.
To treat metastatic diseases: If the cancer shows up in different parts of the body other than breast and lymph nodes.
Apoptosis is the process of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes include blebbing, loss of cell membrane asymmetry and attachment, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation. Apoptosis differ from necrosis, in which the cellular debris can damage the organism. German scientist Carl Vogt was first to describe the principle of apoptosis in 1842. In 1885, anatomist Walther Flemming delivered a more precise description of the process of programmed cell death. However, it was not until 1965 that the topic was resurrected. While studying tissues using electron microscopy, John Foxton Ross Kerr at University of Queensland was able to distinguish apoptosis from traumatic cell death. Apoptosis process is controlled by diverse range of cell signals, which may originate either extracellular (extrinsic inducers) or intracellular (intrinsic inducers) (Roberto R. Rosato et al., 2003). Extracellular signals may include toxins, hormones, growth factors, nitric oxide or cytokines that must either cross the plasma membrane or transduce to affect a response. These signals may positively (triggers) or negatively (repress or inhibit) affect apoptosis.
Curcumin is the key principal curcuminoid of the popular indian spice Curcuma longa (turmeric), which is the member of family Zingiberaceae (Guido Shoba et al., 1998). There are three different types of curcumins are present, curcumin I, II and III, and other two curcuminoids are desmethoxycurcumin and bis-desmethoxycurcumin. The curcuminoids are polyphenols, in which phenols are connected by two Î±, Î²-unsaturated carboxyl groups. Polyphenols are responsible for the presence of yellow color in turmeric.
Figure: 1 structure of Curcumin
Curcumin can exist in two different tautomeric forms, one is keto and other one is enol. The enol form is more stable in the solid and solution phases. Curcumin in
1.8.1 BIOSYNTHESIS OF CURCUMIN
The biosynthetic route of curcumin was proven to be very difficult for researchers to determine. In 1973 Roughly Whiting scientists proposed two different mechanisms for curcumin biosynthesis. The first mechanism of synthesis involved a chain extension reaction by cinnamic acid and 5 malonyl-CoA molecules both eventually arylized into a curcumioid. The second mechanism of synthesis involved two cinnamate units coupled together by malonyl-CoA. Cinnamic acid is the starting point for both the mechanisms, which is derived from the phenylalanine amino acid. This is not worthy process because the plant biosynthesis employing cinnamic acid as a starting point was rare compared to the more general use of p-coumaric acid. Only a limited identified compounds, such as anigorufone and pinosylvi, use cinnamic acid as their start molecule. This proposed biosynthetic route follows together the first and second mechanisms suggested by Roughly and Whiting. Though, the first mechanism model in which 5 malonyl-CoA molecule reacts with cinnamic acid and forms curcumin. However, functional groups, the alcohol and the methoxy, introduce themselves onto the curcuminoid seem like to support more strongly than the second proposed mechanism.
5-FU is a rationally designed anti-metabolite drug by Charles Heidelberger in 1957. It is a pyramidine analog (which mimic the structure of metabolic pyrimidine) and thymidylate synthase inhibitor.
Figure: 2 structure of 5-FU
5-Fu has been used as anti-cancer drug for about 40 years; against colorectal cancer, pancreatic cancer and breast cancer (Daniel B. Longley and Patrick G. Johnston, 2007). It acts in several ways, but principally as thymidylate synthase inhibitor. Thymidylate synthase enzyme methylates deoxyuridine monophosphate (dump) converts into thymidine monophosphate (dtmp). DTMP plays very crucial role in the DNA synthesis and repair mechanism. 5FU inhibits the Thymydylate synthase, prevents the formation of thymidine results no DNA replication and cells will go thymidine less death. In combination of Curcumin and 5FU they sensitize the breast cancer cells and induce apoptosis.
1.9.1 MODE OF ACTION
5-FU is a pyramidine analogue, it transformed in to the cell in different cytotoxic metabolite and incorporated into DNA and RNA. 5-FU induces cell cycle arrest and apoptosis by inhibiting the DNA synthesis. 5-FU active during certain cell cycle because it is S-phase specific drug. In addition to being incorporated into DNA and RNA it also inhibits the activity of exosome complex (exoribonuclease complex) which is essential for cell survival. 5-FU shows severe side effects includes;
1.10 SYNERGESTIC EFFECT
Synergetic effect was defined as the interaction of two or more agents so that their combined effect is greater than the sum of their individual effects. Drug synergism occurs when drugs can interact in ways that enhances or magnify one or more effects of those drugs.
1. BOOK REFERENCES
Daniel B. Longley, Patrick G. Johnston (2007). Apoptosis, Cell Signaling, and Human Diseases 2007. Volume 2. Humana Press, pp 263-278.
2. JOURNAL REFERENCES
T.R. Golub, D.K. Slonim, P.Tamayo, C.Huard, M.Gaasenbeek, J.P.Mesirov, H.Coller, M.L.Loh, J.R.Downing, M.A. Caligiuri, C.D.Bloomfield, E.S.Lander (1999). "Molecular classification of cancer: Class Discovery and Class prediction by Gene Expression Monitoring".sciece.286.5439.531.
Lisa A. Carey, MD; Charles M. Perou, PhD; Chad A. Livasy, MD; Lynn G. Dressler, PhD; David Cowan, BS; Kathleen Conway, PhD; Gamze Karaca, MSc; Melissa A. Troester, PhD; Chiu Kit Tse, MSPH; Sharon Edmiston, BS; Sandra L. Deming, PhD, MPH; Joseph Geradts, MD; Maggie C. U. Cheang, MMedSci; Torsten O. Nielsen, MD; Patricia G. Moorman, PhD; H. Shelton Earp, MD; Robert C. Millikan, DVM, PhD,. (2006). "Race, Breast Cancer Subtypes, and Survival in the Carolina Breast Cancer Study".jama.295.21.2492.
William D. Dupont, PH.D., and David L.Page, M.D. "Risk Factors for Breast Cancer in women with Proliferative Breast Disease". N Engl J Med 1985; 312:146-151.
Philip W. Hinds, Robert A. Weinberg, "Tumor suppressor genes". Current Opinion in Genetics & Development [1994, 4(1):135-141].
Roberto R. Rosato, Jorge A.Almenara, Yun Dai and Steven Grant. (2003). "Simultaneous activation of the intrinsic and extrinsic pathways by histone deacetylase(HDAC) inhibitors and tumor necrosis factor- related apoptosis-inducing ligand (TRAIL) syngergistically induces mitochondrial damage and apoptosis in human leukemia cells". Mol Cancer Ther December 2003 2;1273.
GuidoÂ Shoba, DavidÂ Joy, ThangamÂ Joseph, M.Â Majeed, R.Â Rajendran, P.Â S. S. R.Â Srinivas. (1998). "Influence of Piperine on the Pharmacokinetics of Curcumin in Animals and Human Volunteers". Planta Med 1998; 64(4): 353-356.