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Principles of cancer chemotherapy

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Principles of cancer chemotherapy

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Principles of cancer chemotherapy

  1. 1. Sufyan Akram MBBS PhD Principles of Cancer Chemotherapy National Cancer Institute’s website (an excellent resource): http://www.cancer.gov/
  2. 2. What is Cancer?  Cancer is a diverse class of diseases which differ widely in their causes and biology  Any organism, even plants, can acquire cancer  Nearly all known cancers arise gradually, as errors build up in the cancer cell and its progeny
  3. 3. What is Cancer?  Cancer is a complex disease characterized by deregulation of cell proliferation and apoptotic mechanisms, stromal and microenvironmental changes, angiogenesis and cell metastasis
  4. 4. Incidence According to the American Cancer Society, 7.6 million people died from cancer in the world during 2007
  5. 5. Cell Cycle  Starting from a single-celled zygote… An adult human being has approximately 100,000 billion cells  Cell division does not stop with formation of mature organism, but continues throughout its life  Tens of millions of cells undergo division at any given moment in an adult human. This amount of division is needed to replace cells that have aged or died
  6. 6. The Eukaryotic Cell Cycle  Most eukaryotic cells will pass through an ordered series of events in which the cell duplicates its contents and then divides into two cells  This process of cell division in multicellular organisms must be highly ordered and tightly regulated
  7. 7. G0 G2 Checkpoint G1 Checkpoint Metaphase Checkpoint Is cell big enough? Is environment favourable? Is all DNA replicated? Is cell big enough? Is environment favourable? Are all chromosomes aligned on spindle?
  8. 8. How Cancer Develops?  Cancer arises from a loss of normal growth control. In normal tissues, the rates of new cell growth and old cell death are kept in balance. In cancer, this balance is disrupted  This disruption can result from uncontrolled cell growth or loss of a cell’s ability to undergo cell suicide by a process called “apoptosis”  Apoptosis, or “cell suicide,” is the mechanism by which old or damaged cells normally self-destruct
  9. 9. How Cancer Develops? • Cancer cells do not respond normally to body’s control mechanisms: • Ignore density dependent inhibition, cells continue to multiply until nutrients are exhausted • Divide excessively and invade other tissues
  10. 10. Loss of normal growth control Cancer cell division Fourth or later mutation Third mutation Second mutation First mutation Uncontrolled growth Cell Suicide or Apoptosis Cell damage that couldn’t be repaired Normal cell division
  11. 11. Example of normal growth Cell migration Dermis Dividing cells in basal layer Dead cells shed from outer surface Epidermis
  12. 12. Cancerous growth Underlying tissue
  13. 13. Benign vs Malignant neoplasms Malignant (cancer) cells invade neighboring tissues, enter blood vessels, and metastasize to different sites Time Benign (not cancer) tumor cells grow only locally and cannot spread by invasion or metastasis
  14. 14. Properties of Cancer Cell  Unchecked growth  Loss of capacity for apoptosis (growth despite genetic errors and external anti-growth signals)  Loss of capacity for senescence (immortality)  Sustained angiogenesis  Invasion of neighbouring tissues  Acquisition of ability to build metastases at distant sites, the classical property of malignant tumours
  15. 15. What causes Cancer?
  16. 16. Genes and Cancer Chromosomes are DNA molecules Heredity RadiationChemicals Viruses
  17. 17. Tumour Suppressor Genes Normal genes prevent cancer Remove or inactivate tumor suppressor genes Mutated/inactivated tumor suppressor genes Damage to both genes leads to cancer Cancer cell Normal cell
  18. 18. Oncogenes Mutated/damaged oncogene Oncogenes accelerate cell growth and division Cancer cell Normal cell Normal genes regulate cell growth
  19. 19. Cancer tend to involve multiple mutations Malignant cells invade neighboring tissues, enter blood vessels, and metastasize to different sites More mutations, more genetic instability, metastatic disease Proto-oncogenes mutate to oncogenes Mutations inactivate DNA repair genes Cells proliferate Mutation inactivates suppressor gene Benign tumor cells grow only locally and cannot spread by invasion or metastasis Time
  20. 20. Causative/ Contributing Factors Some viruses or bacteria Heredity Diet Hormones RadiationSome chemicals
  21. 21. Examples of Human Cancer Viruses
  22. 22. Occupational Carcinogens Some Carcinogens in the Workplace
  23. 23. Types of Cancer Lung Breast (women) Colon Bladder Prostate (men) Some common sarcomas: Fat Bone Muscle Lymphomas: Lymph nodes Leukemias: Bloodstream Some common carcinomas:
  24. 24. Types of Cancer  Carcinomas, the most common types of cancer, arise from the cells that cover external and internal body surfaces. Lung, breast, and colon are the most frequent cancers of this type  Sarcomas are cancers arising from cells found in the supporting tissues of the body such as bone, cartilage, fat, connective tissue, and muscle  Lymphomas are cancers that arise in the lymph nodes and tissues of the body’s immune system  Leukemias are cancers of the immature blood cells that grow in the bone marrow and tend to accumulate in large numbers in the bloodstream
  25. 25. Why cancer is dangerous? Melanoma cells travel through bloodstream Melanoma (initial tumor) Brain Liver
  26. 26. Early cancer is usually symptom-less  Major problem in detecting and treating cancer is its late presentation  Various screening programs has been proposed and implemented but without much success  Major emphasis on prevention !!!
  27. 27. Symptoms & Complications
  28. 28. Local  Unusual lumps or swelling (tumour)  Haemorrhage (bleeding)  Pain and/or ulceration  Compression of surrounding tissues may cause pressure symptoms  Erosion  Angiogenesis
  29. 29. Symptoms of metastasis  Enlarged lymph nodes  Cough and haemoptysis  Hepatomegaly (enlarged liver)  Bone pain, fracture of affected bones  Neurological symptoms  Although advanced cancer may cause pain, it is often not the first symptom
  30. 30. Systemic  Weight loss  Poor appetite  Fatigue and cachexia (wasting)  Excessive sweating (night sweats)  Anaemia  Specific paraneoplastic phenomena, i.e. specific conditions that are due to an active cancer, such as ectopic production of hormones by cancer cells
  31. 31. Cancer Treatment
  32. 32. 3 Major Modalities of Rx
  33. 33. Multidisciplinary Approach  Cancer treatment requires the cooperation of a multidisciplinary team to coordinate the delivery of the appropriate treatment (surgery, chemotherapy, radiotherapy and biological/endocrine therapy), supportive and symptomatic care, and psychosocial support
  34. 34. Chemotherapy  Conventional chemotherapy kills all rapidly dividing cells  High (and sometimes toxic) doses of these drugs are usually given with the hope that all cancer cells will be killed  An unavoidable consequence of this approach is killing of normal actively dividing cells  e.g., Hair follicles, Bone Marrow, GI Mucosa
  35. 35. Major Side Effects  This results in the most common side effects of chemotherapy:  myelosuppression (decreased production of blood cells, hence also immunosuppression),  mucositis (inflammation of the lining of the digestive tract), and  alopecia (hair loss)  Other serious side effects are:  Severe Nausea and Vomitting  Infertility  Secondary Tumors
  36. 36. Classes of Drugs 1. Alkylating Agents 2. Antimetabolites 3. Anthracyclins 4. Plant Alkaloids 5. Topoisomerase Inhibitors 6. Cytotoxic Antibiotics
  37. 37. 1. Alkylating Agents  Alkylating agents act by covalently binding alkyl groups, and their major effect is to cross-link DNA strands, interfering with DNA synthesis and causing strand breaks  Despite being among the earliest cytotoxic drugs developed, they maintain a central position in the treatment of cancer  They work by chemically modifying a cell's DNA
  38. 38. 2. Antimetabolites  Anti-metabolites masquerade as purines or pyrimidines  They prevent these substances from becoming incorporated into DNA during the "S" phase (of the cell cycle), stopping normal development and division  They also affect RNA synthesis  Due to their efficiency, these drugs are the most widely used cytostatics
  39. 39. Antimetabolites (cont’d)  Folic acid antagonist  methotrexate  Pyrimidine antagonists  5-Fluorouracil (5-FU)  Arabinosides inhibit DNA synthesis by inhibiting DNA polymerase  Cytosine arabinoside (cytarabine)  Purine antagonists  6-mercaptopurine and 6-tioguanine
  40. 40. 3. Anthracyclins  Anthracyclines (or anthracycline antibiotics) are a class of drugs derived from Streptomyces bacteria  The anthracyclines are some of the most effective anticancer treatments ever developed and are effective against more types of cancer than any other class of chemotherapy agents  Their main adverse effects are heart damage (cardiotoxicity), which considerably limits their usefulness
  41. 41. Anthracyclins (cont’d)  Mechanisms of Action:  1.Inhibit DNA and RNA synthesis by intercalating between base pairs of the DNA/RNA strand, thus preventing the replication of rapidly-growing cancer cells  2.Inhibit topoiosomerase II enzyme, preventing the relaxing of supercoiled DNA and thus blocking DNA transcription and replication  3.Creates iron-mediated free oxygen radicals that damage the DNA and cell membranes
  42. 42. 4. Plant Alkaloids  These alkaloids are derived from plants and block cell division by preventing microtubule function  The main examples are vinca alkaloids and taxanes  Vinca alkaloids bind to specific sites on tubulin, inhibiting the assembly of tubulin into microtubules (M phase of the cell cycle)  Taxanes enhance stability of microtubules, preventing the separation of chromosomes during anaphase
  43. 43. 5. Topoisomerase Inhibitors  Inhibition of type I or type II topoisomerases interferes with both transcription and replication of DNA by upsetting proper DNA supercoiling
  44. 44. 6. Cytotoxic Antibiotics  These include doxorubicin, epirubicin, bleomycin and others  Have different mechanisms of action:  Doxorubicin works by intercalating DNA  Bleomycin works by causing breaks in DNA
  45. 45. Chemotherapy Regimen  Most tumours rapidly develop resistance to single agents given on their own. For this reason the principle of intermittent combination chemotherapy was developed  Several drugs are combined together  These drugs are given over a period of a few days followed by a rest of a few weeks, during which time the normal tissues have the opportunity for re-growth
  46. 46. Response to Chemotherapy  As chemotherapy affects cell division, tumors with high growth fractions (such as acute leukemia and the aggressive lymphomas, including Hodgkin's disease) are more sensitive to chemotherapy, as a larger proportion of the targeted cells are undergoing cell division at any time  Malignancies with slower growth rates do not tend to respond to chemotherapy
  47. 47. Targeted Therapy  Newer anticancer drugs act directly against abnormal proteins in cancer cells; this is termed targeted therapy  Any Examples??
  48. 48. Targeted Therapy  The first molecular target for targeted cancer therapy was the cellular receptor for the female sex hormone estrogen, which many breast cancers require for growth  When estrogen binds to the estrogen receptor (ER) inside cells, the resulting hormone-receptor complex activates the expression of specific genes, including genes involved in cell growth and proliferation  Tamoxifen was the first drug developed as a targeted therapy
  49. 49. Signal Transduction Inhibitors  Imatinib mesylate (Gleevec®) is approved to treat gastrointestinal stromal tumor (a rare cancer of the gastrointestinal tract) and certain kinds of leukemia  It targets several members of tyrosine kinase enzymes that participate in signal transduction
  50. 50. In Summary…  Cancer is a heterogeneous group of diseases, with wide range of causative factors  Cancer treatment requires the cooperation of a multidisciplinary team (surgery, chemotherapy, radiotherapy and biological/ endocrine therapy)  The improved understanding of molecular biology and cellular biology due to cancer research has led to a number of new and effective treatments
  51. 51. References National Cancer Institute’s website http://www.cancer.gov/ Lippincott Illustrated Reviews: Pharmacology 5th ed (2011)

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