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  1. 1. Cancer Chemotherapy-1 Dr. R. Senthil Kumar
  2. 2. 50.2 Rang Etiolopathology
  3. 3. Apoptosis <ul><li>Programmed cell death </li></ul><ul><li>Cascade of proteases initiate process </li></ul>
  4. 4. Characteristics of Cancer Cells <ul><li>The problem: </li></ul><ul><ul><li>Cancer cells divide rapidly (cell cycle is accelerated) </li></ul></ul><ul><ul><li>They are “immortal” </li></ul></ul><ul><ul><li>Cell-cell communication is altered </li></ul></ul><ul><ul><li>uncontrolled proliferation </li></ul></ul><ul><ul><li>invasiveness </li></ul></ul><ul><ul><li>Ability to metastasise </li></ul></ul>
  5. 5. The Goal of Cancer Treatments <ul><li>Curative </li></ul><ul><ul><li>Total irradication of cancer cells </li></ul></ul><ul><ul><li>Curable cancers include testicular tumors, Wills tumor </li></ul></ul><ul><li>Palliative </li></ul><ul><ul><li>Alleviation of symptoms </li></ul></ul><ul><ul><li>Avoidance of life-threatening toxicity </li></ul></ul><ul><ul><li>Increased survival and improved quality of life </li></ul></ul><ul><li>Adjuvant therapy </li></ul><ul><ul><li>Attempt to eradicate microscopic cancer after surgery </li></ul></ul><ul><ul><li>e.g. breast cancer & colorectal cancer </li></ul></ul>
  6. 6. Six Established Rx Modalities <ul><li>Surgery </li></ul><ul><li>Radiotherapy </li></ul><ul><li>Chemotherapy </li></ul><ul><li>Endocrine therapy </li></ul><ul><li>Immunotherapy </li></ul><ul><li>Biological therapy </li></ul>
  7. 7. Major approaches to therapy of cancers
  8. 8. Cell Cycle = Growth, Division
  9. 10. Cancer Chemotherapy <ul><li>After completion of mitosis, the resulting daughter cells have two options: </li></ul><ul><li>(1) they can either enter G1 & repeat the cycle or </li></ul><ul><li>(2) they can go into G0 and not participate in the cell cycle. </li></ul><ul><li>Growth fraction - at any particular time some cells are going through the cell cycle whereas other cells are resting. </li></ul><ul><li>The ratio of proliferating cells to cells in G0, is called the growth fraction. </li></ul><ul><li>A tissue with a large percentage of proliferating cells & few cells in G0 has a high growth fraction. </li></ul><ul><li>Conversely, a tissue composed of mostly of cells in G0 has a low growth fraction. </li></ul>
  10. 12. Cell Cycle Specific (CCS) & Cell Cycle Non-Specific Agents (CCNS)
  11. 13. Log kill hypothesis <ul><li>According to the log-kill hypothesis , chemotherapeutic agents kill a constant fraction of cells (first order kinetics), rather than a specific number of cells , after each dose </li></ul><ul><li>1. Solid cancer tumors - generally have a low growth fraction thus respond poorly to chemotherapy & in most cases need to be removed by surgery </li></ul><ul><li>2. Disseminated cancers- generally have a high growth fraction & generally respond well to chemotherapy </li></ul>
  12. 14. <ul><li>Log kill hypothesis: </li></ul>
  13. 15. LOG kill hypothesis <ul><li>The example shows the effects of tumor burden, scheduling, initiation/duration of treatment on patient survival. </li></ul><ul><li>The tumor burden in an untreated patient would progress along the path described by the RED LINE – </li></ul><ul><li>The tumor is detected (using conventional techniques) when the tumor burden reaches 10 9 cells </li></ul><ul><li>The patient is symptomatic at 10 10 -10 11 cells </li></ul><ul><li>Dies at 10 12 cells. </li></ul>
  14. 16. Cancer Chemotherapy <ul><li>Combinations of agents with differing toxicities & mechanisms of action are often employed to overcome the limited cell kill of individual anti cancer agents. Each drug selected should be effective alone </li></ul><ul><li>3 advantages of combination therapy: </li></ul><ul><li>1. Suppression of drug resistance - less chance of a cell developing resistance to 2 drugs than to 1 drug. </li></ul><ul><li>2. Increased cancer cell kill - administration of drugs with different mechanisms of action. </li></ul><ul><li>3. Reduced injury to normal cells - by using a combination of drugs that do not have overlapping toxicities, we can achieve a greater anticancer effect than we could by using any one agent alone. </li></ul>
  15. 17. Resistance to Cytotoxic Drugs <ul><li>Increased expression of </li></ul><ul><li>MDR-1 gene for a cell </li></ul><ul><li>surface P-glycoprotein </li></ul><ul><li>MDR-1 gene is involved </li></ul><ul><li>with drug efflux </li></ul><ul><li>Drugs that reverse MDR : </li></ul><ul><li>verapamil, quinidine, </li></ul><ul><li>cyclosporine </li></ul><ul><li>MDR increases resistance </li></ul><ul><li>to natural drug products </li></ul><ul><li>including the anthracyclines, vinca alkaloids, and epipodophyllotoxins </li></ul>
  16. 18. Modes of Resistance to Anticancer Drugs Mechanism Drugs or Drug Groups Change in sensitivity (or ↑ level) or ↓ binding affinity of target enzymes or receptors Etoposide, methotrexate, vinca alkaloids , estrogen & androgen receptors Decreased drug accumulation via ↑ expression of glycoprotein transporters, or ↓ permeability Methotrexate, alkylating agents, dactinomycin Formation of drug-inactivating enzymes Purine & pyrimidine antimetabolites Production of reactive chemicals that “trap” the anticancer drug Alkylators, bleomycin, cisplatin. doxorubicin Increased nucleic acid repair mechanisms Alkylating agents, cisplatin Reduced activation of pro-drugs Purine & pyrimidine antimetabolites
  17. 19. General problems with anticancer drugs <ul><li>Most of them are antiproliferative, i.e. they damage DNA and so initiate apoptosis. </li></ul><ul><li>They also affect rapidly dividing normal cells. </li></ul><ul><li>This leads to toxicity which are usually severe. </li></ul><ul><li>To greater or lesser extent the following toxicities are exhibits by all anticancer drugs. </li></ul>
  18. 20. ADR of Antineoplastic Drugs in Humans
  19. 21. Distinctive Toxicities of Some Anticancer Drugs Toxicity Drug(s) Renal Cisplatin,* methotrexate Hepatic 6-MP, busulfan, cyclophosphamide Pulmonary Bleomycin,* busulfan, procarbazine Cardiac Doxorubicin, daunorubicin Neurologic Vincristine,* cisplatin, paclitaxel Immunosuppressive Cyclophosphamide, cytarabine, dactinomycin, methotrexate Other Cyclophosphamide (hemorrhagic cystitis); procarbazine (leukemia); asparaginase* (pancreatitis) *Less Bone marrow suppression – “marrow sparing”
  20. 22. <ul><li>Proliferating cells are especially sensitive to chemotherapy because cytotoxic drugs usually act by disrupting DNA synthesis or mitosis , cellular activities that only proliferating cells carry out. </li></ul><ul><li>Unfortunately, toxicity to the anticancer agents is to any rapidly dividing cells. (e.g. bone marrow, hair follicles, sperm forming cells). </li></ul>Chemotherapeutic agents are much more toxic to tissues that have a high growth fraction than to tissues that have a low growth fraction.
  21. 23. Prevention or Management of Drug Induced toxicities <ul><li>The toxicities of some anticancer drugs can be well anticipated and hence be prevented by giving proper medications </li></ul><ul><li>E.g. mesna is given to prevent hemorrhagic cystitis by cyclophosphamide </li></ul><ul><li>Dexrazoxane, is used to reduce the risk of anthracycline-induced cardiomyopathy </li></ul>
  22. 24. Anti-cancer drugs