Cancer chemotherapy

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Cancer chemotherapy

  1. 1. CANCER CHEMOTHERAPY
  2. 2. • CANCER: is disease characterized by loss in normal control mechanism’s that govern cell survival, poliferation and differentiation. • METASTASIS: is ability of tumor stem cells to migrate to distant sites in body to colonize various organs. • ONCOGENE: mutant form of normal gene found in naturally occuring tumors w/c when expressed in non-cancerous cells cause them to behave like cancer cells.
  3. 3. CLASS OF DRUG Cyclophosphamide Melphalan Mechlorethamine Busulfan NITROSOUREAS Carmustine Streptazocin TRIAZINES Dacarbazine PLATINUM COORDINATION COMPOUNDS ANTI-METABOLITES NITROGEN MUSTARDS ALKYL SULFONES ALKYLATING AGENT DRUGS Cisplatin Carboplatin Oxaliplatin FOLIC ACID ANTAGONIST Methotrexate PYRIMIDINE ANTAGONIST 5-fluorouracil Cytarabine Gemcitabine PURINE ANTAGONIST 6-mercaptopurine thioguanine
  4. 4. NATURAL PRODUCTS Vinblastine Vincristine TAXANES Paclitaxel Docetaxel EPIPODOPHYLLOTOXINS Paclitaxel Docitaxel ANTIBIOTICS Dactinomycin Daunorubin Doxorubicin Bleomycin ENZYMES MISCELLANEOUS AGENTS VINCA ALKALOIDS L-asparginase SUBSTITUTED UREA DERIVATIVES Hydroxy urea PROTEIN TYROSINE KINASE INHIBITOR imatinib INTERFERON’S AND CYTOKINE Interferon α, IL 2
  5. 5. HORMONES ADRENOCORTICOSTEROID S Prednisolone ANTIESTROGENS Tamoxifen AROMATASE INHIBITORS Anastrozole Letrozole ANTI ANDROGENS Flutamide GONADOTROPHIN RELEASING HORMONE leuprolide
  6. 6. PRINCIPLES OF CANCER CHEMOTHERAPY • Cause a lethal cytotoxic event or apoptosis in cancer cell that can arrest tumor’s progression. • Attack is generally directed towards DNA or against metabolic sites essential to cell replication. ( E.G DNA and RNA synthesis w/c have purines and pyrimidines presence).
  7. 7. TREATMENT STRATEGIES: • GOAL OF TREATMENT: • 1. ERADICATION OF EVERY NEOPLASTIC CELL. If cure not possible so next step is control of disease ( stop from spreading). Initially the neoplastic cell is reduced ( either by surgery / radiation) followed by chemotherapy, immunotherapy or combination of treatments. PALLIATION: alleviation of symptoms + avoidance of life threatening toxicity is goal of advanced stage cancer.
  8. 8. INDICATIONS FOR TREATMENT: • 1. chemotherapy is indicated when neoplasm are disseminated and not feasable for surgery. • 2. also used as supplemental treatment to attack micrometastases following surgery and radiation treatment “ ADJUVANT CHEMOTHERAPY”. • 3. neo adjuvant chemotherapy is given prior to surgery to shrink cancer. • 4. maintenance chemotherapy is given in low doses to assist in prolonging remission.
  9. 9. CELL CYCLE • PODOPHYLLOTOXIN • BLEOMYCIN • Mitotic phase ( cell divides) • VINCA ALKALOIDS G2 S • DNA is replicated • ANTIMETABOLITES • PODOPHYLLOTOXIN M G1 • Synthesis of enzymes needed for DNA synthesis
  10. 10. • Rapidly dividing cells are generally more sensitive to anticancer drugs whereas slowly proliferating cells are less sensitive. • G0 phase cell survive most agents.
  11. 11. • CELL CYCLE SPECIFICITY OF DRUGS: • NORMAL CELL and cancer cell both go through growth cycle difference is in number • Chemotherapeutic agents effective only against replicating cells are called “ CELL CYCLE SPECIFIC” • Antimetabolites • Bleomycin • Antibiotics • Vinca alkaloids • etoposide
  12. 12. • Effective for high growth fraction malignancies as hematologic cancers. • NON CELL CYCLE SPECIFIC DRUGS: • More toxicity in cycling cells but are useful against tumors that have low % of replicating cells e.g • Alkylating agents • Cisplatin • Nitrosoureas • Solid tumors + low + high growth fraction malignancies.
  13. 13. TUMOR GROWTH RATE: • Initially rapid but growth rate decreases as tumor size ↑. • This occurs b/c of unavailability of nutrients and oxygen caused by ↓ blood circulation.
  14. 14. TREATMENT REGIMENS AND SCHEDULING: • LOG KILL: • Destruction of cancer cells by chemotherapeutic agents follow first order kinetics i.e given dose of drug destroys a constant fraction of cells not constant number of cells. • Diagnosis of leukemia made when 109 total leukemic cells . • Five log kill means pt becomes asymptomatic ie is in remission.
  15. 15. PHARMACOLOGIC SANCTUARIES: • Leukemic or other tumor cells sometimes find sanctuaries in tissues such as CNS where chemotherapeutic agents cannnot penetrate require IT drugs to eliminate leukemic cells or irradiation of craniospinal axis
  16. 16. TREATMENT PROTOCOLS: • Combination drug chemotherapy is more successful than single drug treatment • COMBINATION OF DRUGS: • Cytotoxic agents with different toxicities, different molecular sites and MOA are combined. • Better effects due to potentiated effects. • If similar toxicity drugs combined dose should be reduced.
  17. 17. ADVANTAGES OF COMBINATION THERAPY: • 1. provide maximal cell killing within range of tolerated toxicity. • 2. are effective against broader range of cell lines in heterogenous tumor population. • 3. may delay or prevent development of resistant cell lines.
  18. 18. TOXICITY • • • • • • • • • COMMON ADR: Narrow therapeutic index Nausea Vomitting ( anti-emetic) Stomatitis. Bone marrow suppression. Allopecia. Cardiotoxicity( doxorubicin) Pulmonary fibrosis( bleomycin)
  19. 19. MINIMIZING ADR: • Megaloblastic anemia caused by methotrexate can be overcome by FOLINIC ACID ( LEUCOVORIN) • Neutropenia ( human granulocyte colony stimulating factor) FILGRASTIM can be given.
  20. 20. ALKYLATING AGENTS: • Highly reactive , transfer their alkyl groups to imp cellular constituents DNA or RNA at an electron rich site making them non-functional. • Alkylation takes place by chemical formation of (+) charged carbonium ion that reacts with functional constituents of DNA.
  21. 21. NITROGEN MUSTARDS • MECHLORETHAMINE: • Hodgkins disease ( 3 and 4 stage) • MOPP regimen ( mechlorethamine, oncovin, procarbazine and prednisolone). • Chronic myelogenous leukemia. • Chronic lymphoblastic leukemia. • 10mg vial reconstituted with 10ml 0.9% NACl given IV. • ADR: vesicant action.
  22. 22. CYCLOPHOSPHAMIDE: • Converted to 4-hydroxycyclophosph CyP2B enzyme → in tumor cell cleav phosphoramide and acrolein • Phosphoramide mustard is responsib activity. • ADR : • Acrolein causes hemorrhagic cystitis • Ample fluid should be taken • MESNA ( mercaptoethane sulfonate) cystitis traps acrolein. • allopecia
  23. 23. • • • • • • • USES: 1. malignant lymphomas. 2. Hodgkins disease. 3. neuroblastoma. 4. breast and ovarian cancer. IV dose 50mg/kg divided dose over 2-5 days. Orally 1-5 mg/kg for initial and maintenace treatment
  24. 24. NITROSOUREAS: • • • • • • CARMUSTINE: Lipid soluble Useful for brain tumor Metastatic brain tumor Hodgkins and non hodgkins lymphoma DOSE: 150-200mg/m2 given IV for 6 weeks as single dose
  25. 25. PLATINUM COORDINATION COMPLEXES: • • • • Cisplatin Carboplatin Oxaliplatin. MOA: they kill tumor cells in all stages of cell cycle by binding to DNA and preventing its replication by forming intrastrand as well as interstrand crosslinks.
  26. 26. • • • • • • USE: 1. non-small cell and small cell lung cancer. 2. esophageal and gastric cancer. 3. head and neck cancer. 4. genitourinary cancer ( testicular + bladder) Oxaliplatin in advanced colon cancer.
  27. 27. • • • • ADR: Neurotoxic ( peripheral neuropathy) Nephrotoxic( reduced by hydration and mannitol) Carboplatin less nephrotoxic but causes tinnitus and hearing loss but greater myelosuppression. • DOSE: 20mg/m2 for 5 days. • 75-100mg/m2 once over 4 weeks for ovarian cancer.
  28. 28. PROCARBAZINE: • Is reactive agent that forms hydrogen peroxide w/c generates free radicals that cause DNA strand scission. • KINETICS: orally active penetrates tissues including CSF • USE: component regimen for Hodgkins lymphoma • ADR: myelosuppressant • GI irritation
  29. 29. ANTIMETABOLITES • CCS drugs acting primarily in S phase of cell cycle. • METHOTREXATE: • MOA: competitively inhibits enzyme dihydrofolate reductase w/c catalyzes reduction of dihydrofolate to tetrahydrofolate→ blocks synthesis of purines and pyrimidines→ results in interfering of formation of DNA, RNA and protein • Polyglutamate derivatives of methotrexate imp for cytotoxic reactions.
  30. 30. • RESISTANCE: • 1. drug accumulation decreased. • 2. changes in drug sensitivity or activity of dihydrofolate reductase. • 3. decrease formation of polyglutamate. • KINETICS: • IV and oral good distribution except CNS. • Not metabolized clearance depends on renal function. • Adequate hydration needed to prevent crystallization in renal tubules.
  31. 31. • • • • • • • USE: 1.choriocarcinoma. 2.acute leukemia. 3.nonHodgkins 4 cutaneous T cell lymphoma. 5 breast cancer DOSE: 15-30mg/day orally or IV 5 days.
  32. 32. • • • • • • • Meningiocarcinoma given IT. ADR: 1.mucositis. 2.bone marrow suppression. 3.bloody diarrhea. 4.wt loss. Leucovorin rescue( tetra hydrofolate is accumulated more readily by normal cells) • It bypasses dihydrofolate reductase step in folic acid synthesis dose 15mg (10mg/m2 every 6 hrly)
  33. 33. PYRIMIDINE ANALOGUE: • 5-FLUOROURACIL: • Prodrug gets converted to → 5-fluoro-2deoxyuridine (5dump) w/c binds to enzyme thymidylate synthase and folate cofactors→ covalently preventing formation of thymidylate and inhibits DNA synthesis. • 5FU forms Futp ( 5 fluorodine 5 tri phosphate) w/c is incorporated into RNA where it interferes with RNA processing and mRNA translation.
  34. 34. • USES: • Treatment of bladder, breast, colon, head and neck, liver and ovarian cancers. • DOSE: • 12mg/kg IV for 4 days. • 6 mg/kg on alternate days for 4 doses. • ADR: • Myelosuppression. • ALLOPECIA • jaundice
  35. 35. PURINE ANTAGONIST: • • • • 6-MERCAPTOPURINE: Thiopurine. Prodrug Mercaptopurine in presence of hypoxanthine guanine phosphoribosyl transferase → thioinosine mono phosphate (TIMP) → inhibits purine synthesis. • TIMP → thiguanine mono phosphate and thioguanine triphosphate . • Cytotoxic effect of mercaptopurine is result of incorporation of these nucleotides into DNA.
  36. 36. • • • • • • • • USE: 1. acute lymphoid leukemia 2. acute myeloid leukemia. DOSE: 2.5-5 mg/kg once aday. ADR: Myelosuppression ( dose limiting) Hepatic dysfunction ( jaundice)
  37. 37. NATURAL PRODUCTS: • PLANT ALKALOIDS: • VINCA ROSEA: vincristine, vinblastine and vinorelbine. • Cell cycle specific agents blocks in metaphase of mitosis. • MOA: • Binds to tubulin monomers inhibiting formation of microtubules → without microtubules newly replicated chromosomes cannot be seperated→ cell division blocked.
  38. 38. VINCRISTINE (ONCOVIN) • USE: • Acute lymphocytic lymphoma 1.4-2mg/m2 IV at weekly interval. • Choriocarcinoma. • ADR: • Myelosuppression • GI mucosal damage • Allopecia. • Neurotoxic effects( peripheral neuritis)
  39. 39. ETOPOSIDE: • • • • Semi-synthetic derivatives of podophyllotoxin Given IV MOA: Inhibit topoisomerase 2 w/c results in breakage or inhibition of DNA strands and facilitating accumulation of DNA breaks. • USE: • Testicular and prostrate carcinomas • DOSE: 50-100mg/m2 for 5 days.
  40. 40. PACLITAXEL: • Taxanes. • MOA: binds to β tubulin subunit of microtubule ( diff from vinca)→ promote microtubule polymerization, inhibit depolymerization→ arrested in G2 and M phases. • USE: ovarian and breast cancer • IV 75mg/m2 over 3 hrs infusion • ADR: neutropenia • Thrombocytopenia • Peripheral neuropathy • Hypersensitivity ( give dexa and H1 antagonist)
  41. 41. ANTIBIOTICS • ADRIAMYCIN( DOXORUBICIN , DAUNORUBICIN) • Anthracycline antibiotics • MOA: cause DNA damage by intercalation into DNA → intercalation interferes with action of topoisomerase 2 resulting in blockade of synthesis of DNA and RNA. • Intracellular formation of free radicals also cause DNA damage.
  42. 42. • Given IV • Doxorubicin dose 75mg/m2 repeated after 21 days. • USE • Hodgkins lymphoma • Myeloma • Sarcoma • Breast, endometrial, ovarian • Lung • Thyroid cancers
  43. 43. • • • • • ADR: Myelosuppression. Cardiotoxicity ( arrthymia , abnormal ECG) Brief not cause serious problem. Dextrazoxane given for it b/c inhibitor of iron mediated free radical formation. • Liposomal formulation less cardiotoxic.
  44. 44. BLEOMYCIN: • Glycopeptide mixture • MOA: binds to DNA cause single strand and double strand DNA breaks following free radical formation and inhibition of DNA synthesis. • Cell cycle specific • Active in G2 phase
  45. 45. • • • • • • • DOSE IV or IM or SC weekly 10-30units/m2 USE: Hodgkins lymphoma Head + neck cancer Squamous cell cancer of cervix Testicular cancer.
  46. 46. • • • • ADR: Pulmonary dysfunction ( fibrosis , pneumonia) Dose limiting Mucocutaneous reaction ( alopecia, hyperkeratosis) • Hypersensitivity reactions common.
  47. 47. OTHER ANTI-CANCER AGENTS: • L-ASPARGINASE: • Is an enzyme used to treat acute lymphocytic leukemia of childhood. • MOA: • Hydrolyzes asparagine w/c is required for growth of tumor cell. • Inhibits asparagine → drug shuts off protein + nucleic acid synthesis. • DOSE: 6000-10,000 IV every 3rd day for 3-4 weeks. • ADR: hypersensitivity, pancreatitis.
  48. 48. PROTEIN TYROSINE KINASE INHIBITOR • IMATINIB: • MOA: is specific anticancer drug acts on specific oncogene. • Inhibits tyrosine kinase activity of protein product of B cr-Abl oncogene that is expressed in chronic myelogenous leukemia→ as result proliferation of oncogene inhibited→ apoptosis results.
  49. 49. • • • • • • • • USE: (1) CML (2) GI stromal tumors ( C-kit tyrosine kinase) ADR: Diarrhea. Fluid retention DOSE: 400mg chronic dose QD orally.
  50. 50. GROWTH RECEPTOR INHIBITOR: • • • • BEVACIZUMAB: Is recombinant humanized monoclonal antibody. MOA: Inhibits natural protein vascular endothelial growth factor (VEGF) that stimulates new blood vessel formation. • When VEGF is targeted and bound to bevacizumab, no growth of blood vessels , tumor do not get oxygen and nutrient for growth.
  51. 51. • USE: • Metastatic colorectal cancer IV or infusion 5mg/kg once every 14 days. • ADR: • Myelosuppression • Hypertension • Stroke • Angina • CHF
  52. 52. INTERFERONS • Effective in hairy cell leukemia
  53. 53. GONADAL HORMONE ANTAGONIST: • TAMOXIFEN: • MOA: acts by binding to estrogen receptors and blocking estrogen dependent transcription in cells in G phase. • USE: breast cancer • ADR: b/c it has agonist action in endometrium can cause endometrial hyperplasia • Nausea • Vomitting • Venous thrombosis • Hot flushes.
  54. 54. • FLUTAMIDE: • Anti-androgen • MOA: bind to androgen receptor inhibit androgen effects. • USE: prostatic carcinoma. • ADR: hot flushes • Hepatic dysfunction • Gynecomastia.
  55. 55. AROMATASE INHIBITOR: • ANASTRAZOLE: • Inhibit aromatase w/c catalyses conversion of androstenedione (androgenic precursor) to estrone ( estrogenic hormone) • USE: advanced breast cancer • ADR: hot flushes, bone and back pain • Dyspnea • DOSE: 1mg orally daily
  56. 56. MONOCLONAL ANTIBODIES: • RITUXIMAB: • Monoclonal antibody binds to surface protein in non-hodgkin’s cell induces complement mediated lysis , direct cytotoxicity and induction of apoptosis • USE: low grade lymphoma. • ADR: • Myelo suppression • Hypersensitivity.
  57. 57. REGIMEN • • • • • MOPP → HODGKIN’S Mechlorethamine Vincristine Procarbazine Prednisolone.
  58. 58. • • • • • ABVD HODGKIN’S Doxorubicin Bleomycin Vinblastine Dacarbazine.
  59. 59. • • • • CMF BREAST Cyclophosphamide Methotrexate 5FU
  60. 60. • • • • • • CHOP non hodgkin’s Carcinoma stomach Cyclophosphamide Doxorubicin Vincristine Prednisolone.

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