Chemotherapeutic agents

chemotherapy agents

1. Chemotherapeutic agents from perspective of Radiation oncologist Dr Prachi Upadhyay Moderator- Dr. Pavan Kumar / Dr. Ayush Garg

2. CONTENTS History Classification of anticancer drug Mechanism of action Chemotherapy

3. HISTORY Chemotherapy began during the world war II after the observation of autopsy of soldiers who died due to the use of nitrogen mustard Aplasia of bone marrow Dissolution of lymphoid tissue Ulceration of the GIT Led to the use of these agents to treat Hodgkins and non- Hodgkins lymphomas at Yale in 1943 Luis Goodman and Alfred Gillmen demonstrated it for the first time.

4. Paul Ehrlich 1854 - 1915 Father of Chemotherapy Salvarsan for Treatment of Syphilis Nobel Prize 1908 “Magic Bullet Concept

5. MODES OF CHEMOTHERAPY PRIMARY CHEMOTHERAPY - chemotherapy is used as the sole anti-cancer treatment in a highly sensitive tumor types Example – CHOP for Non- Hodgkins lymphoma ADJUVANT CHEMOTHERAPY – treatment is given after surgery to “mop up” microscopic residual disease Example – Adriamycin, cyclophosphamide for breast cancer NEOADJUVANT CHEMOTHERAPY – treatment is given before surgery to shrink tumor and increase chance of successful resection Example – Adriamycin, ifosfamide for osteosarcoma CONCURRENT CHEMOTHERAPY – treatment is given simultaneous to radiation to increase sensitivity of cancer cells to radiation Example – Cisplatin, 5-fluourouracil, mitomycin C

6. Classification

7. Cell Cycle and Clinical Importance All cells—normal or neoplastic—must traverse before and during cell division Malignant cells spend time in each phase - longest time at G1, but may vary Many of the effective anticancer drugs exert their action on cells traversing the cell cycle - cell cycle-specific (CCS) drugs Cell cycle-nonspecific (CCNS) drugs - sterilize tumor cells whether they are cycling or resting in the G0 compartment CCNS drugs can kill both G0 and cycling cells - CCS are more effective on cycling cells

8. Information on cell and population kinetics of cancer cells explains, in part, the limited effectiveness of most available anticancer drugs Information is valuable in knowing - mode of action, indications, and scheduling of cell cycle-specific (CCS) and cell cycle-nonspecific (CCNS) drugs CCS – effective against hematologic malignancies and in solid tumors with large growth fraction CCNS drugs – solid tumors with low growth fraction solid tumors CCS drugs are given after a course of CCNS

9. Drugs Based on Cell Cycle

10. CLASSIFICATION 1. ALKYLATING AGENTS 2. ANTIMETABOLITES 3. ANTITUMOR ANTIBODIES 4. MITOTIC SPINDLE AGENTS 5. TOPOISOMERASE INHIBITORS 6. TYROSINE KINASE INHIBITORS 7. MONOCLONAL ANTIBODIES 8. MISCELLANEOUS AGENTS 9. HORMONAL AGENTS 10. CYTOPROTECTIVE AGENTS

11. ALKYLATING AGENTS Are cell cycle non specific, i.e act on dividing as well as resting cells. Alkylate nucleophilic groups on DNA bases Position 7 of guanine residues in DNA/RNA is specially susceptible, but other molecular sites are also involved. Leads to cross linking of bases, abnormal base pairing and DNA strand breakage

12. Classified Nitrogen mustards- Cyclophosphamide, Chlorambucil, Ifosfamide Alkyl Sulfonate- Busulfan Nitrosoureas- Carmustine , Lomustine Triazine- Dacarbazine, Temozolomide Ethylenime - Thio - TEPA

13. Mechanism of action Alkylating Agents Form highly reactive carbonium ion Transfer alkyl groups to nucleophilic sites on DNA bases Results in Cross linkage Abnormal base pairing DNA strand breakage ↓ cell proliferation Alkylation also damages RNA and proteins

14. Cyclophosphamide Most commonly used alkylating agent a prodrug Cyclophosphamide Aldophosphamide Ph o spho r amide mustard Acrolein Cytotoxic effect Hemorrhagic cystitis Mesna

15. Uses of cyclophosphamide Neoplastic conditions Hodgkins and non hodgkins lymphoma ALL, CLL, Multiple myeloma Burkits lymphoma Neuroblastoma , retinoblastoma Ca breast , adenocarcinoma of ovaries Non neoplastic conditions Control of graft versus host reaction Rheumatoid arthritis Nephrotic syndrome

16. COMMON TOXICITIES Hematopoietic toxicity Gastrointestinal toxicity Gonadal toxicity Pulmonary toxicity Alopecia Teratogenicity Carcinogenesis Myleosuppression

17. Atypical alkylating ( PLATINUM COMPOUNDS ) Cell cycle non specific. Platinum compounds act by covalently binding to DNA with preferentially binding to N7 position in guanine and adenine . Form strong covalent bonds – DNA cross linking

18. COMMONLY USED PLATINUM COMPOUNDS CISPLATIN CARBOPLATIN OXALIPLATIN

19. CISPLATIN CDDP – Cis Di amine Dichloro platinum Alkylating agent Used in – in concurrent settings and ca bladder, ca ovary ,ca oesophagus, ca testis , head and neck, ca lung , ca gall bladder ,ca cervix, sarcomas , melanoma , mesothelioma Administration – iv infusion, substituted with 2.5 lits of iv fluids , inj mannitol , inj mgso4 , inj kcl Highly emetogenic – should be given good anti emetic cover

20. Mechanism of action – it damages DNA , RNA and inhibits cell division Side effects – nausea / vomiting , low blood counts , renal toxicity , ototoxicity , low ca, Mg, k , peripheral neuropathy, loss of appetite , metallic taste sensation, hair loss, diarrhoea, fatigue, oral ulcers , malena , anaphylactic reactions

21. ANTIMETABOLITES These drugs act in the S phase of cell cycle Thus only dividing cells are responsive Folate antagonists - Methotrexate Purine antagonists - 6-Mercaptopurine - 6-Azathioprine - 6-Thioguanine Pyrimidine antagonists - 5-Flurouracil - Cytarabine

22. Methotrexate Folic acid Tetra hydro folic acid Purine synthesis - DRUG CLASS: Antemetabolite Folate antagonist Dihydro folic acid Dihydro folate reductase DNA synthesis Cell cycle specific: S phase AICAR TS

23. INTERMITTENT IV ADMINISTRATION IT CAN ALSO BE GIVEN : IM ORALLY REGIONAL INTRA-ARTERIAL INFUSION (INTO THE SUPERFICIAL TEMPORAL OR SUPERIOR THYROID ARTERY)

24. Adverse effects Megaloblastic anemia Thrombocytopenia, leukopenia, aplasia Oral, intestinal ulcer , diarrhoea Alopecia , liver damage, nephrpathy Folinic acid (citrovorum factor, N5 Formyl THF) IM/IV 8 to 24 hrs after initiation of methotrexate 120 mg in divided doses in first 24 hrs , then 25 mg oral/IM 6 hrly for next 48 hrs Treatment of methotrexate toxicity

25. Uses of methotrexate Antineoplastic Choriocarcinoma and tropoblast tumor15 -30 mg/day orally for 5 days Remission of ALL in children 2.5 to 15 mg/day Ca breast, head & neck, bladder, ovarian cancer Immuno- supressive agent Rheumatoid arthritis , resistant asthma Crohns disease, wegeners granulomatosis Prevention of graft versus host reaction Psoriasis Medical termination of pregnancy

26. Mercaptopurine: purine antagonist Mechanism of action: Inhibits the formation of nucleotides from adenine & guanine ( purine) Highly effective antineoplastic drugs. Common side effects: Bone marrow depression Nausea and vomiting Hyperurecemia DOSE Active Phase: 2.5 mg/Kg/day I.V. Maintenance Phase: ½ Dose

27. 5-FLUOROURACIL : PYRIMIDINE ANTAGONIST Mechanism of action: Disrupts pyrimidine synthesis Capecitabine is an oral pro-drug Route of administration: Intravenously Orally continuous iv infusion

28. Even resting cells are affected (though rapidly multiplying cells are more susceptible) – particularly useful for many solid tumors . Side-effects: Myelosuppression Hand and foot syndrome Mucosal ulceration/mucositis Nausea and vomiting Alopecia.

29. MITOTIC SPINDLE AGENTS M phase of cell cycle Bind to micro tubular proteins – inhibit micro tubular assembly --- dissolution mitotic spindle structures . Vinka alkaloids. Taxanes

30. VINCA ALKALOIDS ( Vincristine , Vineblastine ) Inhibits microtubule formation (mitotic inhibitor) Inhibits RNA synthesis by affecting DNA dependent RNA polymerases. Cell cycle specific ( M phase )

31. Comparison between Vin c ristine Marrow sparing effect Alopecia more common Peripheral & autonomic neuropathy & muscle weakness ( C NS) C onstipation Uses: ( C hildhood cancers) ALL , Hodgkins , lymphosarcoma , Wilms tumor, Ewings sarcoma Vin b lastine B one marrow supression Less common Less common, temp. mental depresssion Nausea, vomiting, diarrhoea uses Hodgkins disease & other lymphomas , b reast cancer, testicular cancer

32. TAXANES ( PACLITAXEL,DOCETXEL ) Isolated from bark of yew tree ( taxus brevifolia ) Microtubule-stabilizing agent Blocking of cell cycle at the G2 or M phase by promoting microtubule polymerization.- Non functional microtubules Commonly used agents – paclitaxel ,docetaxel

33. Mechanism of action Cell cycle arrested in G2 and M phase

34. TAXANES USED PACLITAXEL DOCETAXEL CABAZITAXEL ERIBULINE ESTRAMUSTINE IXABEPILONE

35. COMON TOXICITIES OF TAXANES NEUTROPENIA. HYPERSENSITIVITY. PERIPHERIAL NEUROPATHY. ALOPECIA. CARDIOTOXIC. MYLEOSUPRESSION.

36. ANTITUMOR ANTIBIOTICS (ACTINOMYCIN, BLEOMYCIN) Mechanism of action: Intercalate between DNA strands and interfere with its template function. Cell cycle non specific Side effects: Vomiting, stomatitis, diarrhea Desquamation of skin, alopecia Bone marrow depression Pulmonary fibrosis( esp bleomycin)

37. COMMON ANTI TUMOR ANTIBIOTICS ACTINOMYCIN D BLEOMYCIN MITOMYCIN C DAUNORUBICIN DOXORUBICIN EPIRUBICIN IDARUBICIN MITOXANTRONE

38. Doxorubicin & Daunorubucin

39. Doxorubicin: Used in acute leukemias, malignant lymphoma and many solid tumors, direct instillation in bladder cancer Daunorubicin: Use limited to ALL and granulocytic leukemias Toxicity: Both cause cardiotoxicity (cardiomyopathy) Marrow Depression, Alopecia

40. Mechanism of Anthracycline Cardiac Toxicity As well as intercalating into DNA, daunorubicin avidly binds mitochondrial inner membrane of cardiac muscle Daunorubicin chelates iron, which catalyzes formation of the free radical semiquinone Redox cycling transfers high energy electron to oxygen, generating oxygen free radicals Produce lipid peroxidation damage to mitochondrial membranes

41. Epipodophyllotoxins Etoposide & tenoposide Semisynthetic derivatives of podophyllotoxins podophyllum peltatum (plant glycoside)

42. TOPOISOMERASE I INHIBITOR Topoisomerase I inhibitor prevents the ligation of DNA Irinotecan and topotecan are commonly used drugs Topotecan is approved in ovarian cancer Irinotecan is approved in colorectal cancer

43. TOPOISOMERASE INHIBITOR II INHIBITOR Etoposide ( VP 16 ) – semisynthetic derivative of podophyllotoxin Induces strand breaks in DNA Indicated in small and non small cell lung cancer ,germ cell tumor. Myelosuppression is commonly seen drug toxicity.

44. Etoposide Act in S & G2 phase Inhibit topoisomerase II which results in breakage of DNA strands & cell death Uses: Testicular tumors , squamous cell cancer of lungs

45. L- asparaginase

46. L-asparaginase Isolated from E.coli Use: Acute Lymphocytic Leukemia (ALL) Dose : 6000 to 10000U/kg IV daily for 3-4 weeks A/E: Hepatic damage Hypersensitivity , hemorrhage Hyperglycemia , headache, hallucinations , confusion, coma

47. Hydroxyurea Uses: CML, Polycythemia , psoriasis Dose: 20-30 mg/kg /day orally Ribonucleotides Deoxyribonucleotides Ribonucleoside diphosphate reductase Hydroxyurea Adverse effects Myelosuppression (Minimal) Hypersensitivity Hyperglycemia Hypoalbuminemia

48. TARGETED THERAPIES Monoclonal antibodies : proteins that trigger the body’s pathways involved in cancer growth to fight cancer more effectively. EGFR : family of receptors found on surface of normal and cancer cells that bind with an epidermal growth factor (EGF) causing cells to divide. Tyrosine Kinase Inhibitors : Part of the cell that signals it to divide and multiply; enhances cell growth. Still investigational

49. TYROSINE KINASE INHIBITORS A tyrosine kinase receptor is a molecular structure or site on the surface of a cell that binds with substances such as hormones, antigens, drugs, or neurotransmitters

50. Mechanism of action When it binds with one of the triggering substances, the receptor performs a chemical reaction, which in turn triggers a series of reactions inside the cell.

51. Monoclonal antibiodies Mechanism Of Action

52.   Monoclonal antibodies such as Rituximab and Trastuzumab are also use in the cancer chemotherapy.   This antibodies activate the host immune mechanism and kills the cancer cells.   Rituximab is used for B cell lymphoma and Trastuzumab is used for breast cancer treatment. MONOCLONAL ANTIBODIES

53. Common Side effects of mAb Fever Chills Weakness Headache Nausea Vomiting Diarrhoea Low blood pressure Rashes

54. Endocrine therapies Selective Estrogen Receptor Modulators: Tamoxifen Raloxifen Torimefene Androgens Fluoxymesterone Progestin Megestrol acetate Medroxyprogesterone acetate High dose Estrogens Aromatase inhibitors: Letrozole Anastrazole Exemestane Steroidal Antiestrogens: Fulvestrant LHRH agonists Leuprolide Goserelin Gland ablation Ovary Pituitary Adrenals

55. Ovary Pituitary gland LHRH (hypothalamus) Pre-/post- menopausal Premenopausal Gonadotrophins (FSH + LH) ACTH Adrenal glands Oestrogens Progesterone Progesterone Androgens Oestrogens Peripheral conversion ACTH, adrenocorticotrophic hormone; FSH, follicle stimulating hormone; LH, luteinising hormone; LHRH, LH releasing hormone LHRHa Ar omatase Inhibitors Hormonal mechanism Ovary

56. Oxygen effect and chemotherapeutic agents

57. Adjunct use of chemotherapeutic agents with radiation The initial rationale for the combination of radiation and chemotherapeutic agents was what is usually known as “spatial cooperation”. C hemotherapy is the primary treatment modality, and radiation is used only to treat “sanctuary” sites not reached by the drug.

58. Although spatial cooperation was the original rationale, it is no longer the only one. Cells in the G2 and M cell cycle phases were approximately three times more sensitive to Radiation than cells in the S phase. The drugs that can block transition of cells through mitosis, with the result that cells accumulate in the radiosensitive G2 and M phases of the cell cycle e.g - Taxanes Elimination of the radioresistant S-phase cells by the chemotherapeutic agents. e.g - Nucleoside analogs, such as fludarabine or gemcitabine

59. to graded doses of γ -rays alone and after a 24-hour treatment with a 10-nM concentration of paclitaxel. This drug concentration killed 95% of the cells and, as indicated by the inset , synchronized the survivors in the radiosensitive phase of the cell cycle.

60. In general, a therapeutic gain requires differential effects between tumor and normal tissue. One or more of the following tumor characteristics may be exploited to achieve this difference: 1. Genetic instability of tumor cells 2. Rapid proliferation of some tumor cells 3. Cell age distribution of tumor cell populations 4. Hypoxia (characteristic of larger tumors) 5. pH (often low in tumors) 6. Elevation of specific pathways in tumors (e.g., EGFR)

61. Second malignancy

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