CHEMOTHERAPY.pptx

chemotherapy

1. CYTOTOXIC DRUGS

2. WWI Exposure led to the observation that alkylating agents caused destruction of bone marrow and lymphatic tissues, which was further studied in WW II. This led to observation to the direct application of such agents to the patients with Hodgkin’s disease and lymphocytic lymphomas at Yale Cancer Centre in 1943. Louis Goodman and Alfred Gillman studied it for the first time. ORIGIN OF CHEMOTHERAPY

3. 1948, Sydney Farber successfully used Antifolates to induce remission in children with Leukemias 1955, National Chemotherapy Program begins for drug screening 1958, Roy Hertz and Min Chiu Li demonstrate Methotrexate as a single best agent for Choriocarcinoma 1959, FDA approve Alkylating agent Cyclophosphamide 1965, began the era of Combination Chemotherapy

4. To achieve cure a TOTAL CELL KILL must be tried Complete remission is the goal thus, early and intensive treatment Early diagnosis and early initiation of treatment Combination chemotherapy Intermittent regimens Adjuvant and neoadjuvant chemotherapy occasionally Guiding principles in cancer chemotherapy

5. Cytotoxic chemotherapy refers to agents which kills the rapidly dividing cells . Cytotoxic chemotherapy mechanisms of action may be by either inhibiting mitosis or DNA damage To fully understand chemotherapy it is important to have an understanding of the cell cycle.

6. CELL CYCLE The cell cycle comprises of four stages. The cell must progress through these in order to duplicate its chromosomes and divide . G0 (Resting Phase) – Normal functions G1 phase (Gap 1) During this phase, the cell is growing and preparing to double its DNA. S phase (DNA synthesis) This is the phase in which the amount of DNA is doubled. G2 phase (Gap 2) The cell prepares for mitosis M phase (mitosis) Division of the nucleus.

7. All cells, normal or neoplastic, must traverse through cell division Malignant cells spend time in each phase - longest time at G1 , but the time 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 Cell Cycle and Clinical Importance

8. CLASSIFICATION Alkylating agents Mechlorethamine Melphalan Busulfan Cyclophosphamide  Ifosfamide Chlorambucil Procarbazine Dacarbazine Nitrosureas : Carmustine / Lomustine / Semustine Antimetabolites Folic acid antagonist MTX Pemetrexed Ralitrexed Purine antagonist 6MP 6TG Pyrimidine antagonist SFU Cytrabine Capecitabine Anti tumour Abx Hormonal Plant alkaloids Mitotic inhibitors Vinca Taxanes Eribuliny Epothilones Topoisomerase inhibitors Topotecan Irinotecan Miscellaneous

9. Alkylating agents

10. Mechlorethamine Melphalan Busulfan Cyclophosphamide  Ifosfamide Chlorambucil Procarbazine Dacarbazine Nitrosureas : Carmustine / Lomustine / Semustine ALKYLATING AGENTS

11. Mechlorethamine Melphalan Chlorambucil Cyclophosphamide  Ifosfamide NITROGEN MUSTARDS

12. Very irritant drug ( potent vesicant ) MOA : Analog of mustard gas . Classic alkylating agent that forms interstrand and intrastrand cross-links with DNA resulting in inhibition of DNA synthesis and function. Cell cycle-nonspecific , with activity in all phases of the cell cycle.  Uses : Haematological cancers, lymphomas- Hodgkin’s (as part of MOPP), CML, CLL Dose : Hodgkin's lymphoma: 6 mg/m2 IV on days 1 and 8 every 28 days, as part of the MOPP regimen. MECHLORETHAMINE (MUSTINE)

13. Adverse effects Anorexia, nausea, vomiting Bone marrow depression, aplasia Menstrual irregularities Latent viral infection (herpes zoster) - supressed immunity Extravasation- (infiltrate with isotonic sodium Thiosulfite to inactivate) Estramustine is a combination of estradiol with nitrogen mustard . MECHLORETHAMINE (MUSTINE)

14. Regimen for Hodgkin's dis ABVD МОРР Methchlorethamine   Oncoven (vincristine) P rednisolone Procarbazine Adriamycin (doxorubicin) Bleomycin. VinBlastin DacarBazine .

15.  Phenylalanine derivative of nitrogen mustard  It is an orally active drug ; plasma concentration varies with individual due to variation in intestinal absorption and metabolism Very effective in MULTIPLE MYELOMA MELPHALAN

16. Dose: 9 mg/m2 daily for 4 days every 4-6 weeks along with prednisone Dose should be adjusted by monitoring platelets and WBCs count Adverse Effects : Less irritant locally, causes less alopecia Bone marrow Depression : Infections (low WBC), low platelets count  bleeding pancreatitis N/V, oral ulceration MELPHALAN

17. Most commonly used alkylating agent as a prodrug Cytotoxic effect generate after formation of their alkylating species  Broad spectrum : used single/ as part of a regimen B oth cyclophosphamide and ifosfamide orally active Can be given parenterally also CYCLOPHOSPHAMIDE

18. Good bioavailability of 90% after per oral administration After administration, parent drug activated after phosphorylation with cytochrome p450. T ½ : 4-6 hours Excreted into feces by biliary transporter Parent drug excreted via kidneys exclusively CYCLOPHOSPHAMIDE

19. Neoplastic conditions Hodgkin's and non-Hodgkin's lymphoma ALL, CLL, Multiple myeloma Burkitt's lymphoma Neuroblastoma , retinoblastoma Ca breast , adenocarcinoma of ovaries Non neoplastic conditions Control of graft versus host reaction Rheumatoid arthritis Nephrotic syndrome USES OF CYCLOPHOSPHAMIDE

20. Haemorrhagic cystitis, SIADH Effects on the germ cells: amenorrhea, testicular atrophy, aspermia, sterility hepatic damage: Veno -occlusive diseases Dose: Breast cancer- When given orally , the usual dose is 100 mg/m2 PO on days 1-14 given every 28 days. When administered IV , the usual dose is 600 mg/m2 given every 21 days as part of the AC or CMF regimens. ADVERSE EFFECTS

21. Congener of cyclophosphamide Longer half life than cyclophosphamide T ½ : 3-10 hours Only IV form available as Orally it is highly neurotoxic Less alopecia and less emetogenic than cyclophosphamide Used for germ cell testicular tumors and adult sarcomas; Ewing’s Sarcoma; bladder cancers Dose: Testicular cancer: 1,200 mg/m2 IV on days 1-5 every 21 days , as part of the VelP salvage regimen. Soft tissue sarcoma: 2,000 mg/m2 IV continuous infusion on days 1-3 every 21 days, as part of the MAID regimen. IFOSFAMIDE

22. Aromatic analogue of Nitrogen Mustard Bifunctional alkylating agent Slowest acting and least toxic alkylating agent Oral bioavailability is 75% when taken along with food. Main action on lymphoid series produces marked lympholytic action  DOC for long term maintenance therapy of CLL Dose: 0.1-0.2 mg/kg daily for 3-6 weeks then 2 mg daily for maintenance Adverse Effects: moderate GI upset and haematologic toxicity CHLORAMBUCIL (LEUKERAN)

23. Triethylene phosphoramide (TEPA) Both thiotepa and its desulfurated primary metabolite, TEPA  rapidly converted by hepatic cytochrome P450 to form DNA cross-links  aziridine rings open after pronation of the ring-nitrogen  reactive species which gives cytotoxic effects THIOTEPA

24.  U ses Active intra-vesicular agent Used in superficial bladder cancer Not well absorbed orally so given IV Dose : for bladder instillation 60mg in 60ml sterile water for upto 4 weeks Adverse Reactions : Myelosuppression; Nausea and Vomiting are dose limiting. Highly neurotoxic can lead to seizure and coma THIOTEPA

25. Bifunctional alkylating agent Cell cycle non specific Depresses bone marrow with selective action on myeloid series Primarily used in Chronic Myelogenous Leukemia(CML) Good oral Bioavailability , T 1/2 : 2-3 hours Dose : Dose for remission is 4-6 mg/ per day/ PO, and dose for maintenance is 1-3 mg/ per day/ PO  Adverse effect : Interstitial pulmonary fibrosis Impotence and Sterility CNS toxicities: seizures - anti convulsant drug - always useful in high dose regimen of busulfan (0.8mg/kg, every 6hours for 4 days) BUSULFAN (MYLERAN)

26. NITROSOUREAS

27. Highly lipid soluble Cross BBB Cell Cycle non specific No cross resistance with other alkylating agents Require biotransformation (by nonenzymatic decompositions) Metabolites: bifunctional activities More effective against plateau phase than exponentially growing phase Metabolites : peak plasma level appear within1-4 hrs CNS concentration reach 30-40 % Initial t1/2: 6hrs; second t1/2 : 1-2 days NITROSOUREAS

28. Uses : Meningeal/Brain tumours Dose :150-200 mg/m2 every 6 weeks (Carmustine) Administered slowly over 4-6 hours to avoid injection site pains Adverse Effects: Delayed bone marrow suppression Skin discolouration on contact with injection. Streptozocin : sugar containing nitrosourea with Minimal BM toxicity Used intreatment of insulin-secreting islet cell carcinoma of the pancreas NITROSOUREAS

29. Triazenes

30. O ral drugs MOA : uncertain , still these are mechanism works: inhibits the synthesis of DNA, RNA, and protein; prolongs interphase; and produces chromosome breaks. Oxidative metabolism by microsomal enzymes  azo-procarbazine and H202  DNA strand scissoring. Used in Combination regimens to treat Hodgkin's & non Hodgkin's lymphoma, brain tumor  Leukemogenic , Teratogenic, Mutagenic Variety of this drug's metabolites have cytotoxic activity one metabolite, is act as MAO inhibitor Higher risk to cause secondary cancer as a form of acute L eukemia Procarbazine (methylhydrazine)

31.  I nitially developed as a purine metabolite Metabolic activation by liver microsomal enzymes  oxidative N-demethylation to the monomethyl derivative  Spontaneous decomposes to 5-aminoimidazole-4-carboxamide (Excreted) and diazomethan Later metabolite forms methyl carbonium ion which is believed to be cytotoxic. Para-enterally active, there is slow and variable oral absorption N on-schedule dependent CC NS drug Dacarbazine

32. Uses : malignant melanoma ; Hodgkin’s diseases; soft tissue sarcoma Metabolized by P450 and excreted unchanged via urine T ½ : 5-6 hours ADR: Nausea and vomiting (highly emetogenic) flu-like symptoms, neuropathy (paraesthesia; ataxia; increased photosensitivity) myelosuppression Dacarbazine

33. New alkylating agent Imidazole ring analogue structurally and functionally similar to Dacarbazine Approved for use against treatment-resistant gliomas and anaplastic astrocytomas Rapidly absorbed after oral absorption & crosses BBB Unlike dacarbazine, temozolamide: does not not require cytochrome P450 system for metabolic transformation Undergoes chemical transformation under normal physiological pH It has the property of inhibiting the repair enzyme, O6-guanine-DNA-alkyltransferase Temozolamide

34. T aken orally and has excellent oral bioavailability Food reduces the rate and extent of drug absorption Able to cross BBB due to lipophilicity T 1/2: 2 hours Dose : Anaplastic astrocytoma: 150 mg/m2 PO daily for 5 days every 28 days. Newly diagnosed GBM: 75 mg/m2 PO daily for 42 days along with radiotherapy (60 Gy in 30 fractions). Temozolamide

35. PLATINUM BASED COMPOUNDS

36. Inorganic metal complex Serendipitous drugs Broad activities Synergistic action with other anticancer agents  U sed to treat ovarian, head neck, bladder, esophagus , lung and colon cancers PLATINUM COORDINATION COMPLEXES

37. CDDP : cis-diamine di- chloro platinum Non cell cycle specific killing Administered IV Highly bound to plasma proteins Less than 10% remains in plasma after infusion T ½ : 20-30 minutes Gets concentrated in kidney, intestine, testes  Poorly penetrates BBB  Slowly excreted in urine Cisplatin

38. Uses : Testicular cancer (85% - 95 % curative rates) Head and Neck Cancers Nonseminomatous testicular cancer (combination regimens) Ovarian cancer, bladder cancer Other solid tumors: lung (small & non small), esophagus , gastric Adverse effects: Highly Emetogenic Nephrotoxicity (reduced by hydration with iv saline infusion /saline & mannitol/ other diuretics) Peripheral neuropathy Ototoxicity CISPLATIN

39. Second generation platinum analogues with Better tolerability Crosses the BBB and enters the CSF Less plasma protein binding Vigorous I /v hydration not required Excreted exclusively via kidneys with 60-70% drug excreted within 24 hours T ½: 2-6 hours Nephrotoxicity , ototoxicity , neurotoxicity however low Less emetogenic, but thrombocytopenia and leukopenia may occur (dose liming toxicities) CARBOPLATIN

40. Can be Used in place of Cisplatin Uses : Solid tumours Primarily in ovarian cancer of epithelial origin Germ cell tumours; Bladder Cancer; Relapsed Acute Leukemia CALVERT formula is used to calculate the dose T otal dose = Target AUC x (GFR + 25) Target AUC is usually between 5-7 mg/ml/min in previously untreated cases; and 4-6 mg/ml/min CARBOPLATIN

41. 3rd generation diaminocyclohexane platinum analogues  No cross-resistance to cancer cells that are resistant to cisplatin or carboplatin on the basis of mismatch repair defects 50 times higher volume of distribution than Cisplatin About 40 % of the drug gets sequestered in RBCs within 2-5 hours of administration Approved for second-line therapy in metastatic colorectal cancer following treatment with 5-fluorouracil-leucovorin and irinotecan First line drug for this disease Also used in metastatic pancreatic and Gastro- esophageal cancers OXALIPLATIN

42. Adverse Effects:  Neurotoxicity : dose-limiting, is seen in acute and chronic forms; peripheral sensory neuropathy( worsened upon cold exposure ) Dysesthesias in the upper extremities and laryngopharyngeal region with episodes of difficulty breathing or swallowing can be observed and usually within hours or 1-3 days after therapy. Myelosuppression is relatively mild with anemia and thrombocytopenia more common that neutropenia OXALIPLATIN

43. ANTIMETABOLITES

44. SITES OF DRUG ACTION

45. Analogues related to the normal components of DNA or of coenzymes involved in nucleic acid synthesis Competitively inhibit utilization of the normal substrate or get themselves incorporated forming dysfunctional macromolecules Folic acid analogue - Methotrexate, Pemetrexed Purine analogue - 6-MP, 6-TG, Fludarabine, Cytarabine, P entostatin  Pyrimidine analogue - 5-Fluorouracil, Cytarabine (cytosine arabinoside), Capecitabine, Gemcitabine Anti-Metabolites

46. Folate antagonist Most commonly used and oldest anticancer drug Cell Cycle Specific drug Acts during S phase of the cell cycle Has Antineoplastic, immunosuppressant and anti-inflammatory effects Methotrexate

47. Methotrexate structurally resembles folic acid - competitively inhibits dihydrofolate reductase enzyme and prevents the conversion of DHFA to THFA - depletes intracellular THFA THFA is necessary for synthesis of purines and thymidylate which is necessary for DNA and RNA synthesis Utilizing the folate carrier - enters the cells - transforms into more active polyglutamate form by enzyme foly -polyglutamate synthase (FPGS) Methotrexate

48. Methotrexate well absorbed after oral administration, can be given i.m , i.v or intrathecally 50% bound to plasma proteins Poorly crosses BBB and most of the drug excreted unchanged in urine  DOC - choriocarcinoma ; 15-30 mg/m2/day for 5 days orally or 20-40 mg/m2 i.m or i.v twice weekly Also used in Acute Leukemia, Burkitt's Lymphoma and Breast Ca. Low dose Methotrexate ( 7.5-30 mg once weekly) – Rheumatoid Arthritis (DMARDS) Other Uses - Psoriasis, IBD and in Organ transplantation Methotrexate

49.  Toxic effects of Methotrexate on normal cells can be minimized by giving folinic acid Availability of folinic acid has helped the use of very high doses of Methotrexate for better antineoplastic effect A nearly 100 times higher dose ( 250-1000 mg/m2) of Methotrexate infused i.v over 6 hrs, followed by 3-15 mg i.v calcium leucovorin within 3 hrs , repeated as required Can be repeated weekly Folinic acid (Active CoA) - bypasses the block produced by Methotrexate and rapidly reverses the toxicity Folinic acid rescue/ Leucovorin rescue

50. Newer congener of Methotrexate Primarily targets the enzyme Thymidylate synthase Though not a DHFRase inhibitor, the pool of THFA is not markedly reduced Like Methotrexate, it utilizes the folate carrier to enter cells and requires transformation into polyglutamate form by FPGS for activity enhancement  Adverse effects - Mucositis, Diarrhoea, Myelosuppression (same as Methotrexate) P ainful, itching erythematous rash , mostly involving the hands and feet 'hands foot syndrome’ is common Pemetrexed

51. Only administered IV, peak plasma levels reach at about 30 mins Dose - 500 mg/m2 i.v every 3 weeks All patients should receive vitamin supplementation with 350 mc g/day of folic acid PO and 1,000 mcg of vitamin B12 IM every 3 cycles to reduce the risk and incidence of toxicity while on drug therapy. Folic acid supplementation should begin 7 days prior to initiation of pemetrexed treatment, and the first vitamin B12 injection should be administered at least 1 week prior to the start of pemetrexed. Prophylactic use of steroids may ameliorate and/or completely eliminate the development of skin rash. Dexamethasone can be given at a dose of 4 mg PO bid for 3 days beginning the day before therapy. Pemetrexed

52. Purine Analogues

53. Highly effective anti-neoplastic drugs synthesised in the body Mono-ribonucleotides : inhibit the conversion of Inosine monophosphate to adenine and guanine nucleotides which are the building blocks for DNA and RNA Also cause Feedback inhibition of de novo purine synthesis, get incorporated into RNA and DNA rendering them dysfunctional Indicated in ALL only Especially useful in childhood acute leukemias , choriocarcinoma and few solid tumors 6-MERCAPTOPURINE and 6-THIOGUANINE

54. CCS with activity in S phase Absorbed orally , poor penetration BBB Plasma half life after oral administration is 1.5 hours only Does not cross BBB Metabolized in Liver exclusively vis oxidation by xanthine oxidase. Allopurinol inhibits xanthine oxidase and the catabolic breakdown of 6-MP, resulting in enhanced toxicity . Dose of mercaptopurine must be reduced by 50%-75% when given concurrently with allopurinol. 6-MERCAPTOPURINE and 6-THIOGUANINE

55. Newer purine anti-metabolite P hosphorylated intracellularly  active triphosphate form which inhibits DNA polymerase and ribonucleotide polymerase  interferes with DNA repair as well as gets incorporated to form dysfunctional DNA Indicated in Chronic Lymphatic Leukemia and Non-Hodgkin's lymphoma that have recured after treatment Adverse effects - chills, fever, myalgia, arthralgia and vomiting after injection, myelosuppression and oppurtunistic infections Dose - 25 mg/m2 daily for 5 days every 28 days by i.v infusion Fludarabine

56. Pyrimidine analogues

57. Mechanism of the cytotoxic action of 5-FU 5-FU is converted to 5-FdUMP, which competes with deoxyuridine monophosphate ( dUMP ) for the enzyme thymidylate synthetase. Causes Thymidine-less death of the cells Resistance is due to decreased activation of 5-FU and decreased thymidylate synthase activity 5-FU

58. Uses : Mainly used in treatment of slowly growing tumours C olorectal, Upper GIT, Breast and Ovarian carcinomas Oral absorption of 5-FU is unreliable, primarily used by i.v infusion 5-FU rapidly metabolized by dihydro-pyrimidine dehydrogenase (DPD) which is already present in plasma Thus; T1/2 : 15-20 mins after i.v infusion Genetic deficiency of DPD - severe 5-FU toxicity 5-FU

59. Adverse Reactions – Myelosuppression Peripheral Neuropathy (Hand-foot Syndrome) Nausea, Vomiting, Diarrhea Alopecia, Severe Ulceration Of The Oral And GI Mucosa, Bone Marrow Depression (With Bolus Injection), Allopurinol Mouthwash: Used To Reduce Oral Toxicity 5-FU

60. palmar-plantar erythrodysesthesia It is a  side effect   of some  chemotherapy  drugs that can cause redness, swelling and blistering on the palms of the hands and soles of the feet. Hand-foot syndrome

61. Newer, Oral Fluoro -pyrimidine Carbamate Unlike 5-FU, orally well absorded After being absorbed it undergoes a series of enzymatic reactions, the last of which is hydrolysis to 5-FU Thus, Oral Prodrug of 5-FU Metabolised into fluoro -b-alanine and CO2 Excreted in urine Peak plasma levels are reached in 1.5 hours but rate and amount of absorption decreases with food. CAPECITABINE

62. FDA approved drug for metastatic breast cancer that is resistant to first-line drugs Currently used in colorectal cancer Treatment DOSAGE RANGE Recommended dose is 1,250 mg/m2 PO BD (morning and evening) for 2 weeks with 1 week rest. May decrease dose of capecitabine to 850-1,000 mg/m2 BD to reduce risk of toxicity without compromising efficacy CAPECITABINE

63. Adverse Reactions: Peripheral Neuropathy (Hand-foot Syndrome) Myelosuppression Nausea and Vomiting, Diarrhoea Caution with renal & kidney function impaired patients CAPECITABINE

64. Cytidine analogue O riginally isolated from the sponge Cryptotethya crypta Single most effective agent for induction of remission in AML Drug is activated and phosphorylated by deoxy-cytidine kinases to Ara C - inhibitor of DNA polymerases Of all antimetabolites - Cytarabine is the most specific for the S phase of the cell cycle CYTARABINE

65. Crosses BBB T ½ : 2-6 hours but in CSF, T ½ is prolonged 2-11 hours Can be administered iv , as oral bioavailability <20% Highly schedule dependent and should be given by continuous infusion or every 8-12 hours for 5-7 days Adverse Reactions Thrombocytopenia and leukopenia Mild to moderate emetogenic High dose - Neurotoxicity (Cerebellar Ataxia and peripheral neuropathy) CYTARABINE

66. Ara-C syndrome Seen in paediatric patients and represents an allergic reaction to cytarabine. Characterized by fever, myalgia, malaise, bone pain, maculopapular skin rash, conjunctivitis, and occasional chest pain. Usually occurs within 12 hours of drug infusion. Steroids appear to be effective in treating and/or preventing the onset of this syndrome. CYTARABINE

67. Deoxy-Cytidine analogue C onverted to active diphosphate and triphopshate nucleotide form Gemcitabine diphosphate - inhibits ribonucleotide reductase - diminish pool of deoxyribonucleoside triphosphates required for DNA synthesis Can be incorporated into DNA and leads to chain termination Administered only via IV route as extensively deamination takes place in GI tract E limination mainly by metabolism U ses: initially Pancreatic Ca, nowadays widely Non-Small Cell Lung Ca, Bladder Ca, and Non- H odgkin's lymphoma GEMCITABINE

68. NATURAL PRODUCTS ANTICANCER DRUGS

69. Most important of these plant derived, CCS drugs are Vinca Alkaloids ( Vinblastine, Vincristine, Vinorelbine), P odophyllotoxins ( Etoposide, Teniposide), The Camptothecins (Topotecan, Irinotecan), The Taxanes (Paclitaxel, Docetaxel) Mitotic Spindle Inhibitors

70. Vinblastine and Vincristine are derived from the periwinkle plant CCS agent, act during M phase of the cycle Block the formation of Mitotic Spindle by preventing the assembly of tubulin dimers into microtubules These drugs block the formation of mitotic spindle by preventing t he assembly of tubulin dimers into microtubules VINKA ALKALOIDS

71. DISTRIBUTION Widely and rapidly distributed into body tissues within 30 minutes of administration. Poor penetration across the blood-brain barrier and into the CSF. G iven parenterally METABOLISM Metabolized in the liver by the cytochrome P450 microsomal system. The majority of vinka alkaloids are excreted in bile and feces . Only 15%-20% of the drug is recovered in urine. T 1/2 is long, on the order of 85 hours (VINCRISTINE) T ½ for VinBlastine is 25 hours Vinca alkaloids

72. Special caution to be taken during administration as they cause EXTRAVASCATION Clinical use: Vincristine - Acute leukemias , lymphomas, Wilm's Tumor and Neuroblastoma Vinblastine - Lymphomas, Neuroblastomas, Testicular cancers and Kaposi's sarcoma Vinorelbine - non-small cell lung carcinoma and breast Ca Vinca alkaloids

73. Vinca alkaloids Vin B lastine Vin C ristine (oncovin ) M O PP(Hodgkin's disease) C hildhood leukemias C hildhood tumors- Wilm's tumor, Neuroblastoma Toxicity: Peripheral neuritis with Paresthesia , Muscle weakness, Foot Drop *Vincristine has marrow sparing effect Hodgkin's disease(A B VD) Lymphomas Carcinoma B reast Testicular tumors Toxicity: B one marrow suppression, nausea and vomiting, Diarrhea , Alopecia Use with Bleomycin increases risk for Reynaud’s Syndrome

74. The inappropriate or accidental infiltration of chemotherapy into the subcutaneous tissue or subdermal tissues surrounding the administration site. VESICANTS : Drugs which have corrosive properties and have the potential to cause tissue destruction if extravasated. Varying degrees of pain, oedema, erythema, blistering and necrosis may occur. EXTRAVASCATION

75. Vesicants (Paclitaxel; Vinblastine; Vincristine; Vinorelbine ) First step is always to STOP the infusion and try to aspirate the leaked solution through the catheter. Firmly apply a heat pack to the extravasated area for 20 minutes every 6 hours for the first 24 hours. For extravasations of <5ml, infiltrate the site with 1500 units of hyaluronidase in 1ml water for injection . Inject subcutaneously at several areas around site. Gently massage area to facilitate dispersion. For Paclitaxel extravasations, follow this with application of 1% hydrocortisone cream every 6 hours for 7 days . EXTRAVASCATION

76. PODOPHYLLOTOXINS

77. Plant derivative of Podophyllum peltatum (Mayapples) Etoposide is a semisynthetic derivative of podophyllotoxin I nduces DNA breakage through its inhibition of topoisomerase lI Teniposide is an analogue with similar properties Most active in late S and early G phase of the cell cycle ETOPOSIDE and TENIPOSIDE

78. O ral bioavailability is 50% which means it requires twice the oral dose as the of IV dose W ell absorbed and distributes to most body tissues Elimination is mainly via kidneys T ½ : 3- 10 hours Clinical use : Germ cell tumours Testicular cancer Lung cancer Non- hodgkin's lymphoma and AIDS related Kaposi's Sarcoma ETOPOSIDE

79. Adverse Drug Reactions: Myelosuppression Alopecia with podophyllotoxins is well documented and seen in approximately 2/3 rd of the patients. Increases risk of secondary malignancies (associated with translocation 11:23 ) ETOPOSIDE

80. C amptothecins

81. Obtained from Camptotheca acuminata tree C amptothecins, Topotecan and Irinotecan, produce DNA damage by inhibiting Topoisomerase I Irinotecan is a prodrug - converted to active metabolite (SN 38) in Liver Topotecan is a semisynthetic derivative of Camptotheca acuminata tree. Only IV route of administration TOPOTECAN and IRINOTECAN

82. Irinotecan and its metabolite are eliminated via bile and feces Topotecan is eliminated renally Clinical use: Topotecan - 2nd line agent - Advanced Ovarian Ca and Recurrent/ relapsed/ stage IV B Cervical Cancer and for small cell lung Ca. Irinotecan - Metastatic Colorectal Ca and Lung carcinoma TOPOTECAN and IRINOTECAN

83. Toxicity : Myelosuppression Moderately emetogenic “Early Diarrhoea” which is a cholinergic response and happens within 24 hours of drug administration and is managed with Atropine Late diarrhoea typically 3-10 days after treatment. TOPOTECAN and IRINOTECAN