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Introduction 03 Ch 21. Anticancer agents Angiogenesis As a tumour grows, its cancerous cells require a steady supply of amino acids, nucleic acid bases, carbohydrates, oxygen, and growth factors bloody supply hypoxia :depletion of oxygen, in the center of the tumour. Hypoxia-inducible factors, HIF-1 upregulate gene release growth factors; vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF-2). leading to the branching and extension of existing capillaries. Angiogenesis. Normally, angiogenesis helps in the repair of the injured tissues and controlled by angiogenesis inhibitors, angiostatin, thrombospondin. Angiogenesis Metastasis increased availability of blood vessels. Interleukin-6; released from newly developing endothelial cells. Blood vessel arising from angiogenesis -- abnormal Disorganized, dilated, and leaky structure. Integrin, on the surface: absent from mature vessels, protect the new cells from apoptosis. Matrix metalloproteinases (MMPs) : Before angiogenesis can begin, the basement membrane round the blood vessels has to be broken down by MMPs. Angiogenesis Metastasis increased availability of blood vessels. Interleukin-6; released from newly developing endothelial cells. Blood vessel arising from angiogenesis -- abnormal Disorganized, dilated, and leaky structure. Integrin, on the surface: absent from mature vessels, protect the new cells from apoptosis. Matrix metalloproteinases (MMPs) : Before angiogenesis can begin, the basement membrane round the blood vessels has to be broken down by MMPs. Angiogenesis inhibitors: generally safer and less toxic than traditional chemotherapeutic agents. Normalization of abnormal blood vessels help anticancer agents reach tumour more effectively tumour becomes starved. - Angiogenesis Cells in the center of the tumour are starved of oxygen and nutrients stop growing and become dormant. anticancer drugs do not work. (most anticancer drugs act best on actively dividing cells) After stop of anticancer therapy, dormant cells start multiplying. Hypoxic of condition in tumour center glycolysis acidic byproducts exporting acidic protons into the extracellular space tumour is more acidic than normal tissue. Tissue invasion and metastasis Benign tumours grow and remain in localized site without fatal result. Malignant cancers are life threatening; break away from the primary tumour, invade a blood vessel or a lymphatic vessel, travel through the circulation, set up tumours elsewhere in the body. Cell adhesion molecules (e.g., E-cadherin) : a molecular signature on their surface which identifies whether they are in the correct part of the body or not. Integrin : a transmembrane receptor that is the bridge for cell-cell and cell-extracellular matrix (ECM) interactions. anchoring process. If a normal cell becomes detached, it stops growing and apoptosis is triggered. This prevents cells from one part of the body straying to other parts of the body. Tissue invasion and metastasis Cell adhesion molecules are missing in metastasized in cancer cells, allowing them to break away from the primary tumour. It is thought that oncogene in metastasized tumour cells send false messages back to the nucleus implying that the cell is still attached. It is noticeable that most cancers derived from epithelial cells. Epithelial cells grow on a basement membrane, barriers to the movement of the cells. Moving cells : cancer cells and whit blood cells; contain matrix metalloproteinase; hydrolyses the proteins composing the barrier. Tissue invasion and metastasis Once a cancer cell breaks through the basement barrier, it has break down a similar barrier surrounding the blood vessel in order to enter the blood supply. spread round the body. finally adhere to the blood vessels. break out by the opposite process in order to reach new tissue. fewer than 1 in 10000 cells succeed in setting up a secondary tumour. metastasis. From starting in most tissues, finally lung. From starting in intestines, finally liver. Treatment of cancer There are three traditional approaches to the treatment of cancer; Surgery, Radiotherapy, Chemotherapy. Chemotherapy; normally used alongside surgery and radiotherapy. Combination therapy; the simultaneous use of various anticancer drugs with different mechanisms of action. ; increase efficiency of action, decreased toxicity, and evasion of drug resistance. Treatment of cancer Identifying unique targets of cancer cells is not easy. Cancer cells are normally growing faster than normal cells. They accumulate nutrients, synthetic building blocks, and drugs more quickly. Traditional anticancer drug: severe side effect; weakening of the immune response and a decreased resistance to infection secondary infection. impaired wound healing, loss of hair, damage to the epithelium of the gastrointestinal tract, depression of growth in children, sterility, teratogenicity, nausea, and kidney damage. Treatment of cancer Most traditional anticancer drugs: disrupting the function of DNA. Molecular targeted therapeutics : highly selective agents which target specific molecular targets that are abnormal or overexpressed in the cancer cells. Imatinib (Glivec) ; kinase inhibitor. Antibodies, gene therapy. Knowledge of the cell cycle; some drugs are more effective during one part of the cell cycle than another. Micortubule : M-phase, DNA: S-phase. Cisplatin : alkylating agents. Treatment of cancer A better understanding of the molecular mechanisms behind specific cancers is yielding better and more specific treatments. Early detection of cancer is very important. Personalized medicine; the genetic analysis of tumours in individual patients allows the early detection and identification of cancer, as well as identifying the best treatment. Genetic finger printing. Reducing cancer : smoking, drinking, vs high-fibre food, fruit, vegetables. Dithiolthiones, Genistein, Epigallocatechin gallate. Resistance Intrinsic resistance : the tumours shows little responseto an anticancer agent from the very start ; slow growth rate, poor uptake of the drug, the biochemical /genetic properties of the cell. The cells in the center of the tumour may be in the resting state and be intrinsically resistant as a result. Tumour stem cells : ingerently resistant to current anticancer agents re-emergence of certain tumours after successful initial treatment. Resistance Acquired resistance : When a tumour is initially susceptible to a drug, but becomes resistant. The presence of a mixture of drug-sensitive and drug-resistant cells within the tumour. The drug wipes out the drug-sensitive cells but this only serves to select out and enrich the drug-resistant cells. The survival of even one such cell can lead to failure of the treatment. Genetically, cancer cells are unstable, and to induce mutations. Resistance Acquired resistance. Decreased uptake of drugs. Inhibitions of drug activation. Efflux : expelled from the cells. ABC transporters : ATP-binding cassette transporters : It normally - - expels toxins from normal cells. Mutation can result in increased expression of this kind of proteins. P-glycoprotein. Multidrug resistance (MDR) : cells acquiring resistance to the vinca alkaloid are also resistant to dactinomycin (actinomycin D) and anthracyclines. Verapamil, ciclosporin A, quinine : Inhibitors for P-glycoprotein.