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According to WHO, "Cancer is the uncontrolled growth and spread of cells that may affect almost any tissue of the body" (WHO, 2010). Next to cardiovascular disorders, cancer is now the second major cause of death in the western world, and the most feared disease. Despite significant progress in the area of cancer treatment, there is also increasing awareness of the importance of early detection and diagnosis of malignant disease. Predicting the clinical course of the individual patient is necessary to provide the basis for rational treatment. The traditional gold values for such assessment, namely histopathological typing and grading of the malignancy and clinicopathological staging, are subjective and often inaccurate, therefore a new and objective technique of tumor detection and prognosis needs to be developed (Trojani et al., 1987).
Cancer causes 6 million deaths every year or 12% of the deaths world wide. Cancer claimed twice as many lives as AIDS in 2004. About 43% of cancer deaths are due to tobacco, diet and infection. Lung cancer kills more people than any other cancer (Sasco et al., 2007).
The world's inhabitants are expected to increase 8.9 billion during the next 50 years with Africa and Asia practice the greatest population growth. Since gastric cancer diminish there slowly, is expected an increased number of new cases in developing countries and Asia. The challenge of calculating the disease in these areas can not obviously resolved by endoscopic screening for early detection or sophisticated staging with subsequent tailored multidisciplinary approaches which appear completely unrealistic now or in the near future. A rethinking about effective treatment strategy of the disease is needed (Dimitrios, 2002).
Because of a lot of inadequacy involved in the classical approach to tumor diagnosis, some new methods are being developed. These are based on monitoring changes in cell biology and biochemistry which occur during the process of tumor development and progression. Immunological markers, detecting either the absence of tissue-specific or the presence of tumor-associated antigens, have been developed for breast and colorectal cancers (Trojani et al., 1987). Flow cytometry illustrates percentage of cells in the proliferative phase of the cell cycle, which is usually high in tumor tissue. A particularly accurate technique for detecting gene mutation, polymerase chain reaction (PCR), has also been used in cancer diagnosis, and its variant, mutant-allele amplification can aid conventional histological staining for colorectal micro metastasis detection in lymph nodes (Lauren, 1965).
Cell division is a physiological procedure that occurs in almost all tissues and under any circumstances. Usually the balance between proliferation and cell death is tightly regulated to ensure the integrity of organs and tissues. Mutations in DNA that show the way to cancer disrupt these orderly processes (Tsai, 2004).
à¤šà¤¿à¤¤à¥à¤°:Normal cancer cell division from NIH-2.svg
Normal Cell Division, B) Cancer Cell Division
Apoptosis, 2) Cell damage- no repair
Fig.1: Normal and cancer cell division
Novel cells appearance when the body does not need them and aged cells do not pass on when they should. The additional cells form a group of tissue named a growth or tumour. All tumours are not cancerous.
Table 1:Â Cancer cells versus normal Cells
Do not undergo apoptosis
No contact inhibition
One organized layer
1.2. TYPES OF CANCER
Cancer is not one single disorder but a multipart of many diseases. About two hundred different types of cancer have been documented. The term neoplasm is defined as new and diseased form of tissue growth.
Tumours can be 'benign' or 'malignant' (Rang et al., 2003).
Cell in benign tumour do not extend to other parts of the body. Most imperative, benign tumours are rarely a danger to life.
Table 2: Examples of benign tumours
Brenner tumour of ovary
Carcinoid tumour of lung
Malignant tumours are cancerous. Cells in malignant tumours are irregular and split without control or order. Cancer cells attack and demolish the tissue around them. Cancer cells can also rupture away from a malignant tumour and enter the blood stream or lymphatic systems.
These can be grouped in to four major types: carcinomas, lymphomas, sarcomas and leukemias.
The examplars of carcinomas are the solid tumours in nerve tissue and in tissues of body surfaces, or their attached glands,
Sarcomas are solid tumours budding from connective tissue cartilage, bone and muscle, they comprise only concerning 2 percent of human cancers.
Lymphomas are cancers in which there is an extreme creation of lymphocytes. Hodgkin's disease is an exemplar of a lymphoma. It comprises about 5 percent of human cancers.
Leukemias are neoplastic growth of leucocytes (W.B.C) and are differentiated by unwarranted production of the cells. They comprise about 4 percent of human cancers.
Table 3: Examples of malignant tumours
Neoplasm is growsly heterogeneous in respect to certain important characteristics namely structure, karyotype, speed of metastasis and growth, immunogenicity etc. Naturally it is rather difficult to develop antineoplastic agents for specific neoplastic conditions affecting the human body. Earlier cancer drugs were discovered through large scale screening of synthetic chemicals and natural products. These agents interacted with DNA or its precursors, inhibiting the synthesis of new genetic material or causing irreparable damage to DNA itself (cancer, 2010).
Subsequently, natural products like paclitaxel and semisynthetics such as etoposide, which target the proliferative processes were developed.
However, the newly developed compounds are based on new knowledge about cancer biology.
Interleukins-2, which regulates the proliferation of tumour killing T-lymphocytes and the natural killer cells and has induced remissions in some patients with malignant melanoma and renal cell carcinoma where conventional anticancer drugs are not effective.
All trans-retinoic acid elicits differentiation and will promote remissions in acute promyelotic leukemia, even after failure of conventional therapy.
1.3. THE CELL CYCLE
An understanding of cell cycle kinetics is important for the proper use of current generation of antineoplastic agents. The majority of cytotoxic agents perform by damaging DNA. Cell cycle regulation is a basic mechanism underlying cell fate that is proliferation, differentiation or death. Thus one of the main hallmarks of cancer is uncontrolled cell proliferation, and tumor cells acquire damage in genes that are directly involved in regulation of the cell cycle (Cell cycle, 2010).
Fig.2 Life cycle of cell
1.3.1. Parts of Interphase
Interphase of the cell life occupies most of the cells "life".
This part of the cell cycle is where the cell spends mainly of its functional life. In this time the cells are performing their assigned tasks, metabolizing, and synthesizing etc. at some point in the cycle; something triggers the cell to start a cell division event. There are lots of stimuli, which can cause the cell to have need of a cell division:
To substitute dead or dying cells
To produce more cells to make bigger the organism (growth and development)
Reproduction, i.e. to boost the amount of unicellular organisms.
To reduce the surface to volume ratio- when the cell develops into too large its surface area grows slower than its volume consequently it becomes less able to absorb sufficient nutrients. Then it divided itself into two and these two new daughter cells are each much smaller and they tends to grow.
This is known as the synthetic phase. Here the DNA molecules are replicated; consequently it is go from single stranded DNA in G1 phase to double stranded DNA in G2 phase.
Gap2 or G2 Phase:
Here the cells are getting ready for the actual division events (much protein synthesis). For paradigm tubulin, the protein of which microtubules are created is synthesized. This tubulin will be used to construct the microtubules of the spindle apparatus in prophase of mitosis. G2 completes interphase and the cell is prepared for mitosis (Maddika et al., 2007).
The mitosis part of the cycle may last only 10-20 hours though some cells can exist for days or week.
It is a continuous process but can be considered to consist of four stages.
Prophase: The duplicated chromosomes (which have up to this point formed a tangled mass filling the nucleus) condense, each now consisting of two daughter chromatids (the original chromosome and a copy). These are released in to the cytoplasm as the nuclear membrane disintegrates.
Metaphase: In metaphase chromosomes are aligned at the equator.
Anaphase: A specialized device, the mitotic apparatus, captures the chromosomes and draws them to opposite poles of the dividing cell.
Telohase: A nuclear membrane forms round each set of chromosomes. Finally, the cytoplasm divides between the two forming daughter cells. Each daughter cell will be in G0 phase and will remain there unless stimulated in to G1 phase (Rang et al., 2003).
1.3.2. Control of the cell cycle
Control of the cell cycle is essential for a normal cell division. It is accomplished by two groups of proteins
Proto-oncogenes - stimulate cell division
Tumor suppressors - inhibit cell cycle, prevent uncontrolled growth.
Cancers are caused by variance in genetic material of the transformed cells. (Michelle, 2001).
Genetic abnormalities found in cancer characteristically affect two general classes of genes. (Mader, 2003).
The causes of cancer may be broadly classified as either 'environmental' or 'genetic', although these may be interrelated and the causes of some cancers are multifactorial.
1.4.1. Environmental factors
More than three quarters of human cancers are thought to have an environmental cause, e.g. exposure to ionising radiation or carcinogens such as asbestos and specific chemicals. Around 30% cancer deaths are attributable to tobacco use. Smoking causes 90% of all lung cancer deaths and smaller percentage of lung tumours (Baghurst et al., 1992)).
1.4.2. Genetic factors
A number of rare tumours are known to be associated with an inherited predisposition. Examples include Wilm's tumour and bilateral retinoblastoma, a rare cancer of the eye in children, where the presence or absence of a specific gene is associated with an 80 to 90% chance of developing the cancer.
Cancer is caused and driven by mutations in DNA that take control the signal transduction pathways that normally operate to regulate life and death in healthy cells. The procedure of malignant progression is driven by the activation of tumour suppressor genes. About 291 cancer causing genes were identified recently and it represents around 1% of the latest prediction of 20-25,000 genes that are encoded in human genome. Twenty seven of these cancer genes encode protein kinase domains, as compared to the six genes predicted by random selection. Kinases are now readily accepted to be druggable as exemplified by the efficacy regulatory approval of the small molecule catalytic inhibitors like imatinib, mesylate, gefitinib and erlotinib (Czene et al., 2002).
Fig.3 Cancers are caused by a sequence of mutations..
Cancer is a disease of regulation of tissue growth. Alteration of genes which regulate cell growth and differentiation is needed. Genetic changes can occur at many levels, from gain or failure of entire chromosomes to a mutation
1.4.4. p53, a tumor suppressor gene
Fig.4 Involvement of p53 in carcinogenesis
Tumour suppressor genes help to prevent the uncontrolled growth of cells. When it may mutate and contribute to cancer. Mutation of p53 is in most human cancers. p53 protein is inactivated by the Human papillomavirus (HPV) encoded by protein, E6, which binds to it. HPV infection is an essential factor in the development of nearly all cases of cervical cancer (Mader, 2003).
Apoptosis or programmed cell death (PCD) is the built-in self-destruct mechanism of the cell, consisting of a genetically programmed sequence of biochemical events leading to cell death. (Sharma et al., 2007). Cells can die in two ways:
Cells are killed by injurious agents.
Cells are encouraged to commit suicide.
1.5.1. Death by injury
Cells undergo characteristic changes. The cells and their orgenelles like mitochondria swell up and the cell contents leak out..
1.5.2. Death by suicide or apoptosis
Cells that are induced to commit suicide:
It develop bubble like blebs on their surface;
Have chromatin in their nucleus degraded.
It will have mitochondria breakdown with release of cytochrome C.
Break in to small, membrane wrapped fragments.
The phospholipid phosphatidyl serine, which is normally hidden inside the plasma membrane, is exposed on surface.
The phagocytic cells can inhibit inflammation by secreting cytokines
'Programmed Cell Death (PCD)' is the pattern of orderly events in death by suicide. (Fan et al, 2005).
1.5.3. Reasons for apoptosis
1. Programmed cell death is as needed for appropriate development as mitosis.
2. Programmed cell death is should required to obliterate cells that characterize a danger to the honesty of the organism.
Viruses infected the cells
The method by which cytotoxic T-lymphocyte will kill virus infected cells by inducing apoptosis.
Cells with DNA damage
DNA damage can cause a cell to disrupt appropriate embryonic development leading to birth defects or it can cause a cell to become cancerous (Apoptosis, 2010).
1.5.4. The mechanism of apoptosis
The cell is experiencing a cascade of events that ultimately result in nucleus condensation and DNA fragmentation during apoptosis. Therefore induction of apoptosis is an efficient method of treating cancer. A cell which can commits suicide by apoptosis by three different mechanisms
One produce by signals arising within the cell..
Fas ligand (FasL)
The third that may be triggered by dangerous ROS (Reactive oxygen species) (Brouckaert et al., 2005).
The intrinsic or mitochondrial pathway
In healthy cell mitochondria express the protein Bcl2 on the outer membranes of their surface. Internal damage to a cell causes Bcl-2 to release Apaf-1 and a related protein named Bax, to penetrate mitochondrial membranes, causing cytochrome c to leak out. There by form a complex of cytochrome c, Apaf-1, caspase-9 and ATP is called the apoptosome. Caspase 9 cleaves and further activates other caspases. (Marsoni and Damia, 2004).
The extrinsic or death receptor pathway
Binding of the complimentary death activators like FasL and TNF respectively broadcasts signal to the cytoplasm that leads to commencement of caspase 8. Caspase 8 (caspase 9) can start a cascade of caspase activation foremost to phagocytosis of the cell (Chen and Goeddel, 2002).
Example: Cytotoxic T cells produce more FasL when it recognizing their target. It will binds with the FasL on the surface of the target cell leading to its death by apoptosis.
Apoptosis inducing factor (AIF)
The inter membrane space of mitochondria is normally located with a protein Apoptosis inducing factor (AIF). migrates in to the nucleus, and binds to DNA, which triggers the destruction of the DNA and cell death (Susin et al., 1999).
1.5.5. Apoptosis and cancer
Some viruses are linked with cancers by means of tricks to stop apoptosis of the cells they have distorted (Lowel and Lin, 1999).
Cervical cancer has been caused by several human papilloma viruses (HPV). The cancer cells may have tricks to stay away from apoptosis even shaped without the contribution of viruses. Melanoma cells avoid apoptosis by inhibiting expression of gene.
.Â More than 30% of cancer is preventable via avoiding risk factors including:Â Â overweight or obesity, low fruit and vegetable intake,Â tobacco, alcohol, physical inactivity, sexually transmitted infection and air pollution. This is accomplished by avoidingÂ carcinogens (Biesalski et al., 1998).
1.6. CANCER TREATMENT
Cancer treatment can include radiation therapy, surgery, hormone therapy, biological therapy and chemotherapy. Doctors possibly will use one technique or a mixture of methods, depending on the type and site of the cancer. Since the action for cancer also damages healthy cells as well as tissues, it often causes side effects (Dholwani et al., 2008).
Surgery is a procedure to remove the cancer. The surgery will depend on many factors including the size and location of the tumour, the type of operation and the patient's general health.
1.6.2. Radiation therapy
This uses high-energy cells to kill the cancer cells in a targeted area. A machine that aims radiation at the tumour area can give radiation externally. It can also give internally; radioactive substance in a small container implanted near the cancer. Radiation treatment is a painless one.
Chemotherapy is the therapy by use of drugs to kill the cancer cells throughout the body. Usually doctors use one or a combination of drugs. Healthy cells also will affect because the drug travels throughout the body. The side effects of chemotherapy will depend mainly on the drugs and dose, the patient receives. The aim of cancer chemotherapy is to bring about a cure or to provide symptomatic relief to the patient if the cancer cannot be cured (Barrett and Blanc, 2009).
Antitumour drugs act in many ways. They can react with the nuclei of cells, on cell membrane and in some cases with other cell organelle. Some drugs are better in killing cells by interfering with DNA synthesis and suppress active cell division.
The use of chemical agents or chemotherapy to destroy the cancer cells is a mainstay in the treatment of malignancies.
1.6.4. Hormone therapy
Hormone therapy is used to treat certain cancers which depend on hormones for their growth. Hormone therapy keeps the cancer cells from using hormones they need to grow. This treatment includes the use of drugs that stop the production of certain hormones or that change the way hormones work. Surgical procedure to remove the organs that make hormones is another type of hormone therapy. For exemplar, the ovaries are removed to treat breast cancer. The testicles may be removed to treat cancer of prostate (Makar, 2000).
1.6.5. Biological therapy
Biological therapy is used to stimulate the body's immune system to fight disease and can lessen some of the side effects of cancer treatment. Interferon, interleukin-2, colony stimulating factors and monoclonal antibodies are some types of biological therapy (Bernardi et al., 2006).
1.7. ADVERSE EFFECTS OF CYTOTOXIC DRUGS
The quantity ofÂ drugsÂ used for the treatment of different types of cancers is constantly increasing and in fact exceeds 100 distinct chemical formulations. The majority of theÂ cytotoxicÂ agents are associated with potential hypersensitivity reactions, and the constant increase of their administration has caused a raise in incidence of theseÂ adverse effects, thus becoming a relevant problem for clinicians. The mechanism underlying these hypersensitivity reactions involves IgE-mediated hypersensitivity reactions, non allergic hypersensitivity reactions, and a few pathogenetically unclear reactions (Pagani, 2010).
Cytotoxic drugsÂ have to improve the survival and to decrease the morbidity, by reducing the requirement for corticosteroid therapy. The basic mechanism of action of cytotoxic drugs is to cause immunosupression by toxic effects to limphocytes. The degree of toxicity for T cells and B cells varies with each and every drug. They also are toxic to rapidly dividing cell. This toxicity causes many of the well-known adverse side effects, such as bone marrow suppression with accompanying increased incidence of infection, gastrointestinal complaints, teratogenic effects, and sterility. The other acute adverse effects occurring most frequently include nausea, vomiting, mucosites, anorexia and alopecia. Cardiotoxicity, nephrotoxicity and pulmonary toxicity, which are specific to the chemotherapeutic agent or class, may depend on total drug exposure, the schedule of administration and previous therapy. Loss of fertility can happen to some patients (Silvis, 2001).
1.8. ROLE OF ANTICOAGULATION IN CANCER
The process of coagulation occurs via a cascade of sequential reactions requiring several enzymes and other molecules known as coagulation (or clotting) factors. Two separate pathways lead to the production of the Stuart-Power factor (factor Xa where "a" represents an activated factor): the intrinsic pathway and the extrinsic pathway. Factor Xa then participates in the final common pathway that results in the fibrin clot by activating prothrombin (factor II) to thrombin (factor IIa). Thrombin, the final enzyme in the coagulation cascade, in turn converts soluble fibrinogen into insoluble fibrin monomers (Leo et al., 2005).
A "hypercoagulable state" is often also associated with cancer. Patients with malignancy are, therefore, at risk of developing thromboembolic disorders. This phenomenon is due to the fact that malignant cells have an increased capacity to initiate the coagulation cascade. Clotting arises from a complex interaction of various mechanisms, including the activation of the coagulation and fibrinolytic systems, disruption of the vascular endothelium, and the generalized activation of the cellular mechanisms resulting in clotting on the surface of monocytes and platelets in circulation (Kee et al., 2008).
The association between hypercoagulability and malignancy has been recognized, for the first time, in 1865, by professor Trousseau, who drew attention to the high incidence of deep vein thrombosis of the extremities in patients with gastric carcinoma. Subsequently, several clinical and pathologic observations confirmed the underlying the presence of an interaction between tumoral cells and coagulation and/or fibrinolytic systems. Mucin producing carcinoma of gastrointestinal tract, ovarian, pancreatic, prostate, lung cancer, acute promyelocytic leukemia36 and all myeloproliferative disorders are among the malignancies more frequently associated with thromboembolic episodes (Loreto et al., 2000). Due to the recognized link between cancer and hypercoagulation, medications able to treat cancer and having antithrombotic/anticoagulant activity would be idea (Lorenzo et al., 2006)
Tumors might directly activate the coagulation pathway by two mechanisms predominate. The first, and best understood, is the production of tissue factor (TF, thromboplastin) by tumor cells. TF, on association with circulating factor VII, constitutes an extremely potent procoagulant factor which, through the 'extrinsic' coagulation pathway, directly activates factor X. TF is a normal component of many cell types, including endothelial cells and monocyte/macrophages, however its biological activity is rarely expressed. Secondly, several human and rodent tumours have been shown to express a specific enzyme, known as cancer procoagulant (CP), which directly activates factor X and is not factor VII-dependent. This activity is, for the most part, absent from normal tissues (Murray, 1991).
ddFig.5 Pathways of activation of coagulation in cancer
Tumor cells activate the coagulation cascade indirectly by the secretion of tumor necrosis factor-a (TNF) and interleukin-1 (IL-1). These cytokines up regulate TF on blood vessel endothelial cells and on monocytes. Increased TF activity is found on circulating monocytes in patients with different types of cancer. The TF procoagulant activity on monocytes and on tissue macrophages plays a crucial role in the clotting activation in cancer. Besides the procoagulant activity of monocytes and endothelial cells, tumour cells or circulating tumour membrane vesicles induce platelet adhesion and aggregation. This mechanism is induced by the generation of small amounts of thrombin on tumour cell membranes. The net result of TF and CP on tumour cells, TF on monocytes and endothelial cells and enhanced platelet aggregation is the formation of thrombin and fibrin deposition in and around malignant tissue, ultimately leading to Venous Thromboembolism (VTE) in cancer patients (Agnes et al., 2003).
1.10. ANTICOAGULANTS AS ANTICANCER THERAPY
A final question is whether anticoagulation offer any advantage in delicacy the underlying malignant disease. In vitro studies show that warfarin, and even antiplatelet agents slow down tumor growth and metastasis. Fibrin and thrombin have been establish to add to the adhesion and scion of tumor cells, so antifibrin or antithrombin agents might exert their effects by inhibiting this implantation. Each of which may contribute to angiogenesis. It has also been assumed that fibrin deposits around tumors can offer protection aligned with immune examination; so that anticoagulants might aid in immune clearance of small deposits of cancer cells (Letai and kuter, 1999).
1.11. ROLE OF MEDICINAL PLANTS IN CANCER RESEARCH
In developing countries, plants are the main source of medicine. According to WHO as many as 80% of the world's populations rely for their primary health care on traditional medicines, most of types of which use remedies from plants. Two largest users of medicinal plants are India and China. Traditional Chinese Medicine (TCM) uses over 5000 plant species and India uses about 7000. Plant products too play an important role in the health care systems of the remaining 20% of the population who mainly reside in developed countries. The United States National Cancer Institute (NCI) has monitored well over 1,00,000 plant extracts for anticancer activity. Over 25% of our common medicines contain at least some compound obtained from plants (Cragg and Newman, 2005).
(Desai et al., 2008).
The investigate for anti-cancer drugs from plant sources in progress in earnest in the 1950s with the detection and growth of the vinca alkaloids, and the separation of the cytotoxic podophyllotoxines.. A frequent liability of natural products, at least in the area of cancer chemotherapy, is that, although many are generally very potent, they have limited solubility in aqueous solvents and exhibit narrow therapeutic indices. These factors have reported in the demise of a number of pure natural products, such as the plant-derived agents, bruceantin and maytansine, as promising leads. An another approach to utilizing such agents is to investigate their potential as 'warheads" attached to monoclonal antibodies specifically targeted to epitopes on tumors of interest (Samy et al., 2008).
Chemotherapy is one of the promising methods for cancer control. Studies and interests in cancer chemoprevention by the biological activity and pharmaceutical value of naturally occurring substances, which were derived from food and medicinal plants, have increased in recent decades. In particular, the discovery of natural products with specific action on tumor cells would be helpful in cancer chemoprevention or chemotherapy (Kametani et al., 2007).