Anti Cancer Drugs.pptx...............................................

chemotherapy of anti-cancer drugs

1. CANCER CHEMOTHERAPY Presented By Dr. A Chansoria Asst Professor

2. INTRODUCTION Cancer is a disease characterised by a loss in the normal control mechanisms that govern cell survival, proliferation and differentiation Second leading cause of mortality in 2008 It is not a single disease, group of 100 diseases Treatment of malignant diseases is a recent development, started in 1940.

3. Disease burden Worldwide – incidence: 10 million 6 million deaths every year commonest cancer – lung cancer in females – breast cancer In India- incidence – 7 lac commonest cancer – orodigestive tract in females – cervical cancer .

4. classification BENIGN TUMOURS – “ -oma” MALIGNANT TUMOURS – solid tumours - carcinoma(epithelium), adenocarcinoma (glandular epithelium), sarcoma(connective tissue) haematological – lymphoma, leukemia, hairy cell leukemia, myelodysplastic syndrome

5. 50.2 Rang Etiolopathology

6. Characteristics of Cancer Cells The problem: Cancer cells divide rapidly (cell cycle is accelerated) They are “immortal” Uncontrolled proliferation Dedifferentiation Invasiveness Ability to metastasise

7. Symptoms of cancer. Genaralisedweakness,weight loss, frequent infections

8. Established Rx Modalities 1. Surgery 2. Radiotherapy 3. Chemotherapy 4. Immunotherapy

9. The Goal of Cancer Treatments Curative Total eradication of cancer cells Curable cancers include testicular tumors, Wilms tumor Palliative Alleviation of symptoms Avoidance of life-threatening toxicity Increased survival and improved quality of life Adjuvant therapy/ neoadjuvant therapy Attempt to eradicate microscopic cancer after surgery e.g. breast cancer & colorectal cancer .

10. Cancer Chemotherapy After completion of mitosis, the resulting daughter cells have two options: (1) they can either enter G1 & repeat the cycle or (2) they can go into G0 and not participate in the cell cycle. Growth fraction - at any particular time some cells are going through the cell cycle whereas other cells are resting. The ratio of proliferating cells to cells in G0, is called the growth fraction. A tissue with a large percentage of proliferating cells & few cells in G0 has a high growth fraction. Conversely, a tissue composed of mostly of cells in G0 has a low growth fraction.

11. Cell Cycle Specific (CCS) drugs are useful in tumors with large proportions of proliferating cells or cells in the growth fraction Most effective in hematologic and solid tumors with high growth fraction CCNS drugs bind to DNA and damage it. Are useful in low growth fraction solid tumors as well as high growth fraction tumors. CCS kill only cycling cells, whereas CCNS drugs kill cell that are cycling or in G0 (quiescent) Cycling cells are more sensitive

12. Cell Cycle Specific (CCS) & Cell Cycle Non-Specific Agents (CCNS)

13. Cancer Chemotherapy 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 3 Advantages of combination therapy: 1. Suppression of drug resistance - less chance of a cell developing resistance to 2 drugs than to 1 drug. 2. Increased cancer cell kill - administration of drugs with different mechanisms of action. 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.

14. Resistance to Cytotoxic Drugs Increased expression of MDR-1 gene for a cell surface P-glycoprotein MDR-1 gene is involved with drug efflux Drugs that reverse MDR : verapamil, quinidine, cyclosporine MDR increases resistance to natural drug products including the anthracyclines, vinca alkaloids, and epipodophyllotoxins

15. 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

16. CLASSIFICATION . 1. Alkylating agents : Nitrogen mustard Nitrosoureas Other alkylating agents Platinum compounds 2. Anti-metabolites : Folic acid analogs Purine analogs Pyrimidine analogs 3. Mitotic spindle inhibitors : Vinca alkaloids Taxanes Ixabipilone Estramustine.

17. 4. Topoisomerase inhibitors : Camptothecins Epipodophyllotoxins Anti-tumour anti-biotics. 5. Tyrosine kinase inhibitors 6.Monoclonal antibodies 7. Hormone & Related compounds : Glucocorticoids Estrogens Anti-estrogens Progestins Anti-androgens GnRH agonist GnRH ntagonist.

18. Alkylating agents . Nitrogen mustards : mechlorethamine(mustine), cyclophosphamide, ifosphamide, chlorambucil, melphalan Ethyleneimine : thio-tepa, altretamine Alkyl sufonate : busulfan Nitrosoureas : carmustine, lomustine, semustine, bendamustine Triazine : dacarbazine Temozolamide Streptozocin Estramustine 19

19. MOA Intramolecular cyclisation – ethyleneimonium ion/ carbonium ion Transfer of alkyl group to cellular components(sulfhydryl, amino, carboxyl..) Major site of alkylation – N7 guanine, N1 N3 adenine, O6 guanine Miscoding due to abnormal basepairs, strand breakage, cross linking 20

20. Mechanism of resistance *** The mechanisms mentioned below are common for all the alkylating agents Increased DNA repair Decreased drug permeability Production of “trapping” agents (thiols) Increased metabolism of the drug (increased activity of glutathione or glutathione associated proteins.) 21

21. Pharmacological actions Cytotoxic action: Immunosuppressant action radiomimetic 22

22. Mechlorethamine / Mustine First nitrogen mustard Local irritant, vesicant Haematologic, solid cancers, lymphoma MOPP regimen – 6mg/m 2 .Day 1,8 of 28 day cycle.For Hodgkin’s lymphoma Toxicity- nausea, vomiting, lacrimation, myelosuppression, leukopenia, thrombocytopenia Not used now-a-days, due to toxicity 23

23. Cyclophosphamide It is a prodrug and is activated by the P-450 enzymes to its active form phosphoramide mustard The active drug alkylates nucleophilic groups on DNA bases Particularly at the N-7 position of guanine This leads to cross linking of bases, abnormal base pairing and DNA strand breakage Immunosuppresive 24

24. Dose : 100mg/m 2 oral – 14 days 500 mg/m 2 IV – every 2-4 weeks Indications : Breast cancer Ovarian cancer Non Hodgkins lymphoma CLL Rheumatoid arthritis Nephrotic syndrome Wegeners granulomatosis 25

25. Toxicity : Haemorrhagic cystitis – due to ACROLEIN Adequate hydration MESNA – 2-mercaptoethane sulfonate sodium 20% along with the drug. Alopecia SIADH 26

26. Ifosphamide / Oxazaphosphorine Analogue of cyclophosphamide Germ cell tumours, testicular tumours Dose – 2-14g/m 2 Neurotoxic Greater platelet suppression 27

27. Melphalan Phenylalanine nitrogen mustard Less irritant Alopecia rare Multiple myeloma- 6-8mg for 4 days oral IV-15mg/m 2 28

28. Chlorambucil Short acting nitrogen mustard Active against lymphoid series malignancy, Spares Myelocytes Local irritant, less alopecia Myelosuppressive action is dose dependent and reversible Drug of choice for CLL 29

29. Thiotepa Similar to mechlorethamine Not a local irritant Not absorbed orally, given IV Used by bladder instillation for superficial bladder tumours 30

30. Busulfan Ester of alkyl sulfonic acid Methylation of DNA More active against cells of myeloid series Selective depression of granulocyte and platelet production Along with chlorambucil-radiomimetic action CLL Dose-6mg/day In children- rapid clearance. 31

31. Nitrosoureas Carmustine, Lomustine, Semustine Highly lipophilic, crosses BBB Alkylating, carbamoylating Malignant glioma – 150-200mg/m 2 , IV infusion.Repeat after 6 wks Streptozocin –naturally occuring, sugar containing nitrosourea, used for insulin secreting islet cell tumour, carcinoid tumour Dose – 500mg/m 2 OD-5 days, every 8 wks Renal damage . 32

32. Non classic alkylating agents Procarbazine Methylhydrazine derivative Diazomethane- free radical mediated DNA damage Oxidation – azoprocarbazine,hydrogen peroxide MAO inhibitor Lymphoma, brain tumours Secondary cancers 33

33. Dacarbazine Synthetic compound N-demethylation – methylcarbonium ion Given parenterally Malignant melanoma, Hodgkin’s, soft tissue sarcoma Local vesicant myelosuppression 34

34. Bendamustine : Bifunctional alkylating agent Purine benzimidazole ring and nitrogen mustard Alkylates DNA, inhibits mitotic check points CLL,non-Hodgkins. 35

35. PLATINUM COMPOUNDS They are in-organic metal complexes that was initially discovered through a serendipitous observations that neutral platinum complexes inhibited division filamentous growth of E.coli. These are non-alkylating agents in true sense but are discussed here because of same mechanism of action. Only difference is they use platinum instead of alkyl group to form dimers of DNA.

36. Cisplatin-MOA

37. Cisplatin resistance Decreased intracellular accumulation Inactivation of drug by glutathione Loss of function of mismatch repair protein Pharmacokinetics given by I.V route Highly protein bound High concentration in kidney, liver, intestine, testis dose: 20 mg/m 2 for 5 days.

38. Cisplatin Uses Used in testicular carcinoma along with bleomycin, etoposide,ifosfomide Also used for Ca of bladder, lung and ovary, prostate and head and neck cancer,rectal cancer Toxicity Nephrotoxicity- can be prevented by adequate hydration with normal saline and by Amifostine Amifostine- dephosphorylated by alkaline phosphatase to thiol metabolite

39. Ototoxicity – tinnitus, high frequency hearing loss Peripheral neuropathy- sensory and motor Severe nausea and vomiting Myelosuppression- leucopenia, thrombocytopenia Hypocalcemia, hypokalemia, hypomagnesemia, hypophosphatemia Bronchoconstriction

40. Carboplatin Similar to cisplatin,but main toxicity is only myelosuppression, other toxicities are less than cisplatin Oxaliplatin MOA same as cisplatin Useful in colorectal cancer in combination with 5 FU and lecovorin[FOLFOX regimen], also gastroesophageal and pancreatic cancer Toxicity- mainly neural manifesting as laryngopharyngeal dysesthesias, paraesthesias, diarrhoea, myelosuppression

41. 43 Antimetabolites Folic Acid Analogs Purine Analogs Pyrimidine Analogs Methotrexate Mercaptoguanine Fluorouracil Legend Drug Class Sub-class Prototype Drug Trimetrexate Pemetrexed Thioguanine Fludarabine Phosphate Cladribine Cytarabine Gemcitabine Capecitabine

42. ANTI-METABOLITES. FOLIC ACID ANALOGS : Methoterxate Pemetrexate Pralatrexate

43. Methotrexate (MTX) MTX is a folic acid analog that binds with high affinity to the active catalytic site of dihydrofolate reductase (DHFR) Thus it interferes with the synthesis of tetrahydrofolate (THF) THF serves as the key one-carbon carrier for enzymatic processes involved in de novo synthesis of thymidylate, purine nucleotides, and the amino acids serine and methionine. Inhibition of these various metabolic processes thereby interferes with the formation of DNA, RNA, and key cellular proteins. 45

44. Contd.. Most commonly used anticancer drug. Cell cycle specific (CCS) drug and acts during S phase of the cell cycle. Well absorbed orally; can also be given IM, IV or intrathecally**. It is bound to plasma proteins, does not cross the BBB and most of the drug is excreted unchanged through kidney via glomerular filtration & tubular secretion. It is a weak acid and so is excreted better at high urine pH. Appropriate hydration and alkalinizing the urine is important to prevent renal toxicity with MTX 46

45. Pharmacological actions Cytotoxic action Immunosuppressive action Anti inflammatory action 47

46. Therapeutic uses ALL Choriocarcinoma Soft tissue sarcoma Breast cancer AML Rheumatoid arthritis Psoriasis As immunosuppressant MTP 48

47. ADR Megaloblastic anemia Bone marrow suppression (BMS) Mucositis Alopecia Folic acid deficiency The toxic effects of MTX on normal cells is reduced by administering folinic acid (leucovorin) This is called leucovorin rescue **** 49

48. Leucovorin Citrovorum factor / rescue factor N5 formyl tetrahydrofolinic acid Originally found in liver Growth promoting effect on Leuconostoc citrovorum Exists as enantiomer.Levo form is active Leucovorin is given 120mg for 1 day in divided doses, started 8-24hrs after initiation of methotrexate therapy, followed by 15mg oral/IM 6hrly for the next 48hrs 50

49. Methotrexate analogues TRIMEXETRATE – lipid soluble PEMETREXED PRALATREXATE RALTITREXED LOMETREXED 51

50. Premetexed same MOA as MTX . At present it is approved for treatment of mesothelioma , non-small cell lung cancer in combination with cisplatin. ADR : Hand Foot Syndrome (painful erythema & awelling of hands & feet). Treatment with dexamethasone is effective in this condition. Pralatrexate same as MTX. It is approved for relapsed or refractory peripheral T-cell lymphoma.

51. Purine antagonists : 6-MP 6-TG Fludarabine Cladarabine

52. 6-Mercaptopurine (6-MP) & Thioguanine Both 6-MP and Thioguanine are activated by HGPRT to toxic nucleotides that inhibit several enzymes involved in purine metabolism ***Resistance is due to cancer cells having ⇓d activity of HGPRT Cancer cells also ⇑es alkaline phosphatase that inactivate toxic nucleotides 54

53. 6-MP & Allopurinol 6-MP is metabolized in the liver by xanthine oxidase and the inactive metabolites are excreted in the urine ***Allopurinol is used frequently in acute leukemias to treat/prevent hyperuricemia due to tumour lysis. If Allopurinol is used with 6-MP then the dose of 6-MP is reduced by more than 75% Why?? 55

54. Fludarabine Diphosphate 🡪 inhibits formation of ribonucleotides Triphosphates 🡪 inhibits DNA polymerase α and β induces apoptosis. CLL Potent immunosuppressant. Opportunistic infections – PCP prophyloxis with Cotrimoxazole

55. Cladribine “High specificity for lymphoid cells”. Triphosphate 🡪 inhibits DNA polymerase α and β. Hairy cell leukemia CLL, non – Hodgkins lymphoma Single continuous 7 days infusion. Both Fludarabine & Cladarabine are has inhibitory effects on CD4 & CD8 cells.

56. PYRIMIDINE ANTAGONISTS : 5-FU Capecetabine Cytarabine Gemcitabine Decitabine 5-azacytidine

57. 5-FU 5-Fluorouracil (5-FU a flurorine-substituted analogue of uracil must be metabolically activated to a nucleotide, in this case FdUMP. Then its metabolite inhibits the synthetase of deoxythymidine monophosphate, blocking DNA synthesis & leading to “thymidine less” death. A phase-specific drug.

58. Also 5-FU 5- floro- uridine -tri phosphate (FUTP) incorporated into RNA & interferes with RNA processing & mRNA translation. Also 5-FU 5-fluroro- deoxy- uridine tri phosphate(FdUTP) Incorporated into DNA & inhibit synthesis.

59. Contd.. Resistance is due to ⇓d activation of 5-FU and ⇓d thymidylate synthase activity Uses ; Metastatic carcinomas of the breast and the GI tract, hepatoma Carcinomas of the ovary, cervix, urinary bladder, prostate, pancreas, and oropharyngeal areas Combined with levamisole for Rx of colon cancer. 61

60. ADR: Nausea, mucositis, diarrhea, ***hand and foot syndrome, Alopecia, hyperpigmentation, neurologic deficits, bone marrow depression

61. Capecitabine : Prodrug Undergoes metabolism in liver to deoxyfluorocytidine & deoxyfluorouridine & finally to 5-FU into tumour directly by thymidine phosphorylase. Thymidine phosphorylase, highly expressed in solid tumours so, used in the treatment metastatic breast cancer & adjuvant therapy for colo-rectal cancer.

62. Cytarabine : Ara-CTP- cytotoxic metabolite. Inhibits DNA polymerase –α and DNA polymerase β. Gets incorporated into DNA & RNA. Highly schedule dependent, due to rapid degradation. Metabolism by de-amination to its inactive forms Exclusively haematologic malignancies. Absolutely no activity in solid tumours.

63. Gemcitabine : Fluorine substitued deoxycytidine analogue. Di and Triphosphates. Uses : Advanced pancreatic cancer, non-small cell lung cancer, bladder cancer, NHL. ADR : Haemolytic uremic syndrome & Thrombotic Thromocytopaenic purpura .

64. 3. MITOTIC SPINDLE INHIBITORS : Vinca Alkaloids Taxanes Ixabipilone Estramustine

65. Vinka alkaloids (Vinblastine, vincristine) 67

66. VINCA ALKALOIDS Vinblastine : Alkaloid derived from periwinkle plant ‘ Vinca rosea’. MOA- inhibition of tubulin polymerisation 🡪 mitotic arrest in metaphase. Metabolised by P450 enzymes excreted via hepatobiliary system Dose adjustment required in liver dysfunction. Potent vesicant. Solid tumours.

67. Vincristine : Structural analogue of vinblastine. Haematologic malignancies, paediatric tumours. Neurotoxic, autonomic dysfunction, SIADH. Vinorelbine : Semisynthetic derivative of vinblastine .

68. TAXANES PACLITAXEL : Alkaloid ester – Pacific yew (Taxus brevifolia) & European yew (Taxus baccata). MOA – Enhancement of tubulin polymerisation, in the absence of microtubule – associated protein & Guanosine 🡪 inhibition of mitosis. Solid tumours. Metabolised by P450 enzymes excreted via hepatobiliary system Hepatic dysfunction 🡪 dose adjustment.

69. Hypersensitivity reactions 🡪 pretreatment with dexamethasone, anti-histaminics. Novel Albumin – bound paclitaxel – lesser incidence of hypersensitivity, myelosuppression & reversible neurotoxicity. Paclitaxel nanoparticles. Paclitaxel drug eluting stents . Docetaxel : Semisythetic taxane from European yew. Solid tumours.

70. Ixabepilone : Novel microtubule inhibitor. Semisynthetic analog of epothilone B. MOA – Binds to β – tubulin subunits on microtubules Inhibition of normal microtubule dynamics. Also active in drug resistant tumours with P-gly Overexpression / tubulin mutations. Myelosuppression, Hypersensitivity, Neurotoxicity.

71. Estramustine . Stable combination of oestrogen and mustine (Mechorethamine) Designed to enhance delivery of alkylating agent into estrogen sensitive prostatic cancer cells. Binds to Beta-tubulin & microtubule associated proteins to cause microtubule dis-assembly & anti-mitotic. Local cytostatic effect and hormonal effect Prostate cancer.

72. 4 . Topoisomerase inhibitors : Camptothecins Epipodophyllotoxins Anti-tumour antibiotics

73. CAMPTOTHECINS : Natural products derived from camptotheca acuminata. MOA🡪 inhibition of Topoisomerase I. Topotecan – ovarian cancer Renal excretion. Irinotecan 🡪 SN- 38 active metabolite. Biliary excretion. colorectal cancer. Toxicity – Diarrhoea 🡪 early & late form. Early form – within 24 hrs – cholinergic event. treated with atropine. Late form – 2-10 days of treatment, severe.

74. Topoisomerase inhibitors 76

75. ANTITUMOUR ANTIBIOTICS Anthracyclines : Streptomyces peucetius var caesius. Most widely used drugs. MOA: Inhibition of topoisomerase II . DNA interaction 🡪 strand breakage, block of synthesis. Semiquinone free radicals & oxygen free radicals& Mediated damage through iron dependent, enzyme Mediated reductive process. Alteration of cell permeability.

76. Doxorubicin & Daunorubicin These drugs intercalate between base pairs, inhibit topoisomerase II and also generate free radicals They block RNA and DNA synthesis and cause strand scission *These are CCNS drugs Used as a component in ABVD regimen in Hodgkin’s lymphoma 78

77. IV route. Hydroxylated metabolite- active, aglycone – inactive. Biliary excretion. Daunorubicin : First agent in this class. AML. Idarubicin semisynthetic. Epirubici n: Mitoxantrone : Bluish discoloration of fingernails, sclera& urine. Toxicity : cardiotoxicity, free radical mediated.

78. Acute : first 2-3 days- arrythmias , conduction abnormality ECG changes, pericarditis, myocarditis. Chronic : Dose dependent, dilated cardiomyopathy, heart failure. Not seen in doses below 50- 500mg/m2. Incidence reduced by lower weekly doses/continuous infusions Protectant🡪 Dexrazoxane (cumulative dose 300mg/m2 Of doxombicin). Radiation recall reaction : erythema, desquamation at prior radiation sites.

79. Mitomycin : Streptomyces caespitosus. Metabolic activation is by enzyme mediated reduction to generate alkylating agent that cross links DNA. Hypoxic tumours cells. Squamous cell carcinoma. (+5-FU in anus SCC) Intravesical applicaton of superficial bladder cancer. Haemolytic uremic syndrome, Interstitial pneumonitis.

80. Bleomycin : Small peptide that contains DNA – binding region & iron binding domain at opposite ends of the molecule. Binding of DNA & iron to bleomycin 🡪 DNA-bleomycin- Fe complex 🡪 chromosomal aberration 🡪 free radical damage & inhibition of DNA biosynthesis 🡪 DNA strand breaks .Renal excretion. Pulmonary toxicity.

81. SUMMARY CCS Drugs . . Etopside (G1-S) Antimetabolites (S) Bleomycin (G2-M) Vinca alkaloids (M) Taxanes (M) Ixabepilone (M) Estramustine (M) CCNS Drugs Platinum compounds Alkylating agents Anthracyclines Dactinomycin Mitomycin Camptothecins

82. Thank u