Cancer Chemotherapy

Anti Cancer Chemotherapy

Cancer Uncontrolled multiplication and spread within the body of abnormal forms of body's own cells Neoplasm A mass of tissue formed as a result of Abnormal Excessive Uncoordinated Autonomous andpurposeless Proliferation of cells Cancer is a disease in which there is uncontrolled multiplication and spread within the body of abnormal forms of bodys own cells. It is one of the major causes of death in developed nations atleast 1 in 5 of the population of europe and north america can expect to die of cancer. Cancers are more common in aged people as life expectancy is increasing the incidence of cancers is also increasing, with the present methods of treatment one third of the patients are cured with local modalities of treatment (surgery or irradiation therapy) which are quite effective when the tumor has not metastatized. In metastasis systemic chemotherpy is required along with surgery or irradiation at present 50 % of the patients of cancer can be treated with chemotherapy contributing to cure in 10 -15% of the patients. The terms cancer,malignant neoplasm and malignant tumor are synonymous2Why term chemotherapy Like infective disease Some malignant cells can be cultured Some malignancies can be transmitted by innoculation Treatment of systemic infections /malignancy with specific drugs that have selective toxicity for infecting organisms /malignant cell with no or minimal effects on host cells 3Cancer chemotherapy not as successful as antimicrobial chemotherapy Metabolism in parasite differs qualitatively from host cells, while metabolism in cancer cells differ only quantitatively from normal host cells Hence target selectivity is more difficult in cancercancer there is no substantial immune responseDiagnostic complexity: delay in institution of treatment

Hence target selectivity is more difficult in cancer*(exception in lymphoma , there is substantial selectivity)

4Modalities of treatment in cancer Surgery Radiotherapy Chemotherapy: 50 % of the patients can be treated with chemotherapy contributing to cure in 15 -20 % of patients 1/3 of patients can be cured, effective when tumor has not metastasized Chemotherapy is essentially required with surgery or irradiation when metastasis has occurred 5Cancer chemotherapy can be curative in Acute LeukemiasWilms Tumour Ewings SarcomaChoriocarcinomaHodgkins Disease LymphosarcomaBurkitts lymphoma Testicular TeratomasSeminomas

In childrenChemotherapy can have only Palliative effect inBreast CancerOvarian CancerEndometrial CancerProstatic CancerChronic Lymphatic LeukemiaChronic Myeloid LeukemiaHead & Neck CancerLung (small cell) CancerShrinkage of tumor , alleviation of symptoms 7Chemotherapy is less sensitive in Colorectal CancerCarcinoma StomachCarcinoma of esophagusRenal carcinomaHepatomaBronchogenic (non small cell) carcinomaMalignant MelanomaSarcoma Pathogenesis of cancer Chemicals, viruses, irradiation, etcAcquired Mutations Protooncogenes oncogenes expression of tumor supressor genes (P53, Rb etc)Promoters, co-carcinogen, hormones Uncontrolled cell proliferation, dedifferentiation apoptosis, alterations in telomeraseInherited Mutations Development of primary tumorOther factors promoters cocarcinogen, hormones, -- likely hood of mutation 9Pathogenesis of cancer Development of primary tumorProduction of metalloproteinases Invasion of nearby tissue by tumor cells Angiogenesis Metastasis Development of secondary tumorsCancer cells differ from normal cells by Uncontrolled proliferation De-differentiation & loss of function Invasiveness Metastasis Guiding principles in cancer chemotherapy To achieve cure a TOTAL CELL KILL must be tried Early diagnosis and early institution of treatment Combination chemotherapy Intermittent regimens Adjuvant and neoadjuvant chemotherapy occasionally Total cell killAimed at destroying all the malignant cells, leaving noneThis approach ensures Early recovery Prevents relapse Prolongs survival Pharmacological sancturies Aimed at destroying all the malignant cells, leaving none (lack of participation of host defence/immune response)order kinetics i.e given dose of a drug destroys constant fraction of cells. Term log kill is used to describe this phenomenon e.g leukemia diagnosis made when load of cells is >109 consequently if t/t leads leads to kill 99.99% of the cells then 0.001% i.e 104 cells remain this is equivalent to 5 log kill i.e 100000 fold. At this point patient appears asymptomatic i.e patient is in remission. For most bacterial infections a 5 log fold reduction in no of micro-organisms leads to cure . Since immune system can eradicate remaining bacterial cells. However cancer cells are not so easily destroyed Pharmacological sancturies: leukemia or other tumor cells find sanctury in tissues like CNS in which some chemotherapeutic agents can not enter, because of its transport constraints so pt may require irradiation of cerebrospinal axis or intrathecal administration of drugs at that site Cells of solid tumors can be considered as belonging to 3 compartments Compartment A: Consists of dividing cells, possibly being continously in cell cycle Compartment B: consists of resting cell in Go phase , the cells though not dividing are potentially able to do so Compartment C: cells no longer able to divide but contribute to tumor volume Essentially only cells in compartment A which may form as little as 5 % of some solid tumors are currently susceptible to main available cytotoxic drugs. Log kill: destruction of cancer cells by chemotherapeutic agents follows first

13Effects of various T/t on cancer cell burden

Early diagnosis and early T/t why?Survival time inversely related to initial number of cells Aging cancer cells are less susceptible to chemotherapy, because there is cell cycle (division) time No of actively dividing cells with more resting cells cell death within tumor Overcrowding of cells Overcrowding of cells: poor blood supply and nutrition and defective access of drugs

15Combination chemotherapy? Heterogenicity of cells remaining in different phase of growth cycle , showing different level of sensitivity Nature of drug (with different biochemical site of action)Avoid emergence of drug resistance Monotherapy adequate in Burkitts lymphoma & choriocarcinoma Heterogenecity of cells 16Why intermittent regimen? Favours risk benefit ratioAllows time for damaged normal host cells to recover Pulse therapyType of intermittent chemotherapeutic regime employing highest tolerated dose within a short administration period Based on principle of drug conc. (C) x duration of exposure (T) = constant Adjuvant & Neoadjuvant chemotherapy Adjuvant chemotherapy:Chemotherapy given after surgery or irradiation to destroy micrometastasis & prevent development of secondary neoplasm.Neo-adjuvant chemotherapy:Chemotherapy given before surgery or radiotherapy in order to diminish the volume of large primary neoplasm Nausea & Vomiting Bone marrow depression Alopecia Gonads: Oligospermia, impotence, ovulation Foetus: Abortion, foetal death, teratogenicity Carcinogenicity Hyperuricemia Immunosupression: Fludarabine Hazards to staffGeneral toxicity of cytotoxic drugs Majority of cytotoxic drugs have more profound effects on rapidly multiplying cells 19Phases of cell cycle

CLASSIFICATION - I: CELL CYCLE NON SPECIFIC : Kills resting cells & dividing cellsCyclophosphamideChlorambucilCisplatinActinomycin-DL-asparaginaseCELL CYCLE SPECIFIC Kills actively dividing cells

G1 VinblastineS Methotrexate 6-Mercaptopurine 5-FluorouracilG2 Bleomycin Etoposide, Topotecan DaunorubicinM Vincristine Vinblastine Paclitaxel,DocetaxelCLASSIFICATION - II:Depending on mechanism at cell levelDirectly acting cytotoxic drugs:Alkylating agentsAntimetabolitesNatural products AntibioticsVinca alkaloidsTaxanesEpipodophyllotoxins Camptothecin analogs Enzymes Biological response modifiers Miscellaneous: Cisplatin, carboplatin Indirectly acting- by altering the hormonal mileau :CorticosteroidsEstrogens & ERMs5 alpha reductase inhibitorsGnrh agonistsProgestinsNitrogen Mustards Meclorethamine, Melphalan, Chlorambucil, cyclophosphamide, ifosfamide Ethyleneimine : Thiotepa Alkyl Sulfonate: Busulfan Nitrosureas Carmustine,lomustine, streptozocin Triazines Dacarbazine, temozolamide Alkylating agents Folate AntagonistsMethotrexate Purine Antagonists 6 Mercaptopurine, 6 Thioguanine, AzathioprinePyrimidine antagonists 5 Fluorouracil, cytarabine, gemcitabine Antimetabolites AntibioticsActinomycin D, Doxorubicin, Daunorubicin, Bleomycin, Mitomycin CVinca alkaloids Vincristine, Vinblastine, Vinorelbine Taxanes Paclitaxel, docetaxelEnzymes L-Asparginase

Natural Products Epipodophyllotoxinsetoposide, tenoposide Camptothecin analogsTopotecan, irinotecanBiological response modifiers Interferons, Interleukins Cisplatin Carboplatin HydroxureaProcarbazineMitotane Imatinib

Miscellaneous Agents Hormones & antagonists CorticosteroidsPrednisolone Estrogens Ethinyl Estradiol SERM Tamoxifene, Toremifene SERD Fulvestrant Aromatase Inhibitors Letrozole, Anastrazole, Exemestane

Progestins Hydroxyprogesterone Anti-androgens Flutamide, Bicalutamide 5- reductase Inhibitors finasteride, dutasteride GnRH analogs Naferelin, goserelin, leuoprolide

27MOA of some anticancer drugs Purine & Pyrimidine synthesis Ribonucleotides Deoxy ribonucleotides DNA RNA Proteins Purine/ Pyrimidine antagonists MethotrexateInhibition of purine ring & dTMP biosynthesis 5 FU inhibits dTMP synthesis Dactinomycin , Intercalate with DNA disrupt DNA function Alkylating agentsAlter structure & function of DNA by cross linking and/or fragmenting DNA Cytarabine inhibits DNA chain elongation Alkylating agents Nitrogen Mustards (MCI)Meclorethamine, Melphalan, Chlorambucil, Cyclophosphamide, Ifosfamide Ethyleneimine : Thiotepa Alkyl Sulfonate: Busulfan Nitrosureas Carmustine,lomustine, streptozocin Triazines Dacarbazine, temozolamide Sulfur mustard in 1917 was first used alkylating agent in WW-1, it was used as chemical warfare and caused severe skin vesication, vesication in mucous membrane , GI ulcerations and myelosupression. The pharmacological actions became evident only after world war 2. 29Mechanism 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 All alkylating agents have alkyl groups and they can transfer this alkyl group to suitable receptor site. Alkylating agents in neutral or alkaline solution form highly reactive carbonium ion which is quaternary ammonium derivative(The carbon atom has only six electrons in its outer space so highly reactive). This carbonium ion is highly reactive and can react with groups like NH2, SH, OH or PO4 in physiologically important molecules in cell and render them unavailable for normal metabolic reactions. One more property of this carbonium ion is its nucleophilicity it can react with nucleic acid bases and inhibit DNA synthesis . The nitogen at guanine position 7 is especially more susceptible. So this results in cross linking inhibits DNA replication . Abnormal base pairing (alkylated guanine pairs with thymine instead of cytosine) results in production of defective protein DNA strands breakage decreased cell proliferation Alkylation also damages RNA and proteins Non cycle specific 30

Alkylation of guanine bases in DNA MOA OF MECHLORETHAMINE31Cytotoxic action Hemopoetic system highly susceptible Chlorambucil more against lymphoid series Busulfan more against myeloid series Epithelial tissues, hair folliclesSpermatogenesis , fetopathic effectImmunosupressant action Miscellaneous Severe nausea & vomiting Known as radiomimetic drugs

Pharmacological actions Common to the alkylating agents Cytotoxic action in general damage nuclei of growing multiplying cells, hemopoetic system highly susceptible to this action leads to anemia, thrombocytopenia, leukopenia and in toxic doses bonemarrow supression., Net result similar mode of action may differ chlorambucil more effective against lymphoid series and busulfan more effective against myeloid series. These drugs also effect epithelial tissues like cornea, intestinal mucosa leading to desquamation and ulcers Hair follicles- alopeciasprematogenesis, foetopathy sand ammenorrhoeaImmunosupressant action : supress antibody production Miscellaneous: nausea, vomitingRadiomimetic drugs: actions resemble that of biological or ionizing radiations, all alkylating agents different radiomimetic action. 32Mechlorethamine Melphalan Chlorambucil Cyclophosphamide Ifosfamide Nitrogen Mustards Very irritant drugDose = 0.4 mg/kg single or divided Uses Hematological cancers , lymphomas , solid tumors Hodkins as part of MOPP, CML, CLL Adverse effects Anorexia, nausea, vomiting Bone marrow depression, aplasia Menstrual irregularities Estramustine

Mechlorethamine (Mustine) First nitrogen mustard to be used in cancer chemotherapy Very irritant drug: vesicant for skin, eyes, resp tract , should be given only IV , Special care sloughing can occur with extravasation Available as 10 mg HCL with 90 mg NACL should be reconstituted in 10 ml NS or distilled water and given immediately because it becomes active in few minutes Hodkins stage III and stage IV as a part of MOPP mechlor, oncovin (Vincristine), procarbazine, prednisoloneChronic myelogenous leukemia, chronic lymphoblastic leulemia Because of serious toxicity use replaced by less toxic drugs carmustineEstramustine: stable combination of estrogen & mustine designed to deliver mustine to estrogen receptor site of tumor like prostrate cancerAdvantage: both cytostatic and hormonal effect 34Melphalan Very effective in MULTIPLE MYELOMALess irritant locally , less alopecia Dose:0.25 mg/kg daily for 4 days every 4-6 weeks Adverse Effects : Bone marrow DepressionInfections , diarrhoea and pancreatitis

Also used in advanced ovarian tumor, otherwise toxic effects and properties similar to mechlorethamine 35Most commonly used alkylating agent a prodrug Cyclophosphamide

Pharmacological actions similar to mechlorethamine Prodrug converted in body to active 36Cyclophosphamide Cyclophosphamide Aldophosphamide Phosphoramide mustard Acrolein Cytotoxic effect Hemorrhagic cystitis Mesna Hemorrhagic cystitis is specific toxicity of cyclophosphamide it is associated with dysuria, hematuria due to irritation of bladder mucosa by acrolein it is dose limiting toxicity. Mesna is also excreted in urine where it binds to and inactivates acrolein Should be given simultaneously and also 4-8 hrs after Acetyl cysteine can also be given Adequate hydration IV mesna (2 mercapto ethane sulfonate )

37 Uses of cyclophosphamide Neoplastic conditionsHodgkins 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

Wegeners granulomatosis

38Adverse effects:Hemorrhagic cystitis, alopecia, nausea & vomiting, SIADH hepatic damage Dose: 2-3 mg/kg/day oral 10-15 mg/kg IV every 7-10 daysIt can be administered IV, IM, IP, intrapleurally, Intraarterialy, directly into tumor

Cyclophosphamide Less damaging to the platelets can also cause transverse ridging of nails, increased pigmentation Leucocyte count serves as guide to dosage adjustment in prolonged therapy neutrophil count = 500 to 1000cells /mm3 desired target 39Ifosfamide Congener of cyclophosphamide Longer half life than cyclophosphamide Less alopecia and less emetogenic than cyclophosphamide Can cause hemorrhagic cystitis and severe neurological toxicity Used for germ cell testicular tumors and adult sarcomas1g vial+3 mesna ampoules 200mg for IV Bronchogenic, Breast, Testicular, Bladder , Head & Neck Carcinomas, Osteogenic Sarcoma& some lymphomas

40Chlorambucil (Leukeran)Slowest acting and least toxic alkylating agentMain action on lymphoid series produces marked lympholytic action Drug of choice for long term maintenance therapy of CLLDose: 0.1-0.2 mg/kg daily for 3-6 weeks then 2 mg daily for maintenance Also used in hodkins and other solid tumors 41ThioTEPA Triethylene phosphoramide Does not require to form active intermediate Active intravesicular agent can also be used topicaly in superficial bladder cancer Not well absorbed orally given IV High toxicity Busulfan (Myleran) Depresses bone marrow with selective action on myeloid series Primarily used in Chronic myelogenous leukemia 2-6 mg/day Adverse effect: Interstitial pulmonary fibrosisVenoocclusive disease of liver Hyperuricaemia Sterility Unique in that in conventional doses of busulfan exert few pharmacological actions other than myelosupression Other use- polycythemia vera Pigmentation of skin 43Nitrosureas Highly lipid soluble, Cross BBBUses: Meningeal / Brain tumoursDose :150-200 mg/m2 BSA every 6 wks (Carmustine)Adverse Effects: Delayed bone marrow suppression Visceral fibrosis, renal damage

Streptozocin indicated for T/t of islet cell carcinoma of pancreas 500mg/m2 for 5 days or 1000 mg/m2 weekly 44Triazenes Dacarbazine Primary inhibitory action on RNA & protein synthesis Used in malignant melanomaTemozolamide New alkylating agent Approved for malignant glioma Rapidly absorbed after oral absorption & crosses BBB

Mechanisms of resistance of alkylating agents Influx of drug Production of nucleophilic substances like glutathione that compete with target DNA for alkylation Activity of DNA repair enzymes metabolic inactivation of drugs Acquired resistance to one alkylating agent often but not always imparts cross resistance to others Guanine o-alkyl transferase46Cisplatin Non cell cycle specific killing Administered IV Highly bound to plasma proteins Gets conc in kidney, intestine, testes Poorly penetrates BBBSlowly excreted in urine PtNH3ClClNH3Dose: 20 mg/m2 for 5 days a week75 100 mg/m2 once in 4 weeks to treat ovarian cancer Heavy metal complex has water soluble planar coordination complex containing central platinium atom surrounded by 2 cl and 2 nh3 47Mechanism of action of cisplatinCisplatin enters cells Forms highly reactive platinum complexes DNA damage Intra strand & interstrand cross links Inhibits cell proliferation Cl-Cisplatin uses and adverse effects Uses Testicular cancer (85% - 95 % curative )Ovarian cancer Other solid tumors: lung, esophagus, gastric Adverse effectsEmesis Nephrotoxicity Peripheral neuropathy Ototoxicity

Nephrotoxicity can be reduced by hydration of patients and diuresis by litres of normal saline and mannitol, Hyperuricaemia can occur Neuropathy : large sensory fibres numbness, tinglingfollowed by loss of joint position and disabling sensory ataxia Ototoxicity : tinnitus and hearing loss in high frequency range , more pronounce in children Rarely shock mutagenic, teratogenic , carcinogenic adverse events reversible on stoppage 49Carboplatin Better tolerated Nephrotoxicity , ototoxicity , neurotoxicity low Less emetogenic But thrombocytopenia and leukopenia may occur Less plasma protein bindingUse: primarily in ovarian cancer of epithelial origin Squamous cell carcinoma of head and neck Excreted by kidneys t1/2 4to 6 hrs Oxaliplatin : less myelosupression but more paresthesia 50Antimetabolites Folate AntagonistsMethotrexate Purine Antagonists 6 Mercaptopurine, 6 Thioguanine, AzathioprinePyrimidine antagonists 5 Fluorouracil, cytarabine, gemcitabine Chemical substance which takes part in cellular metabolic reactions is called metabolite Antimetabolite is a chemical substance which by virtue of its close structural resemblence to metabolite blocks its action it can achieve this by 2 methods By preventing the combination of metabolite with its specific enzyme By itself combining with specific enzyme and getting converted to either metabolically inactive or harmful to cell ( lethal synthesis) 51Methotrexate

Adenine, guanine, thymidine , methionine, serine Folic acid not useful in toxicity Folinic acid N5 formyl FH4 should be given which is converted to N5,N10-Methylene FH4 and bypasses the inhibited reductaseOne of most commonly used anticancer agents Cell cycle specific drug acts in S phase Methotrexate has antineoplastic, immunosuoressant and anti-inflammatory action It produced the first striking although temporary remission of leukemia and first cure for choriocarcinoma Mechanism of action of methotrexate:methotrexate structurally resembles folic acid , it competitively inhibits dihydrofolate reductase enzyme and blocks conversion of DHFA to THFA THFA is an essential coenzyme required for one carbon transfer reactions in denovo purine synthesis and synthesis of thymidilate , amino acid conversions which are required for DNA SYNTHESIS it also inhibits RNA and protein synthesis. More toxic to rapidly dividing cells likw bone marrow 52Pharmacological actions Cytotoxic actions Predominant on bone marrowUlceration of intestinal mucosa Crosses placenta interferes with embroyogenesis foetal malformations and death Immunosupressive actionPrevents clonal expansion of B & T lymphocytes Anti-Inflammatory action Interferes with release of inflammatory cytokines IL-2, IL-6,IL-8 & TNF- , Rheumatoid Factor production Inhibit erythropoeisis, myelopoesis, and finally aplasia --- marked granulocytopenia , reticulocytopenia 53Pharmacokinetics Absorbed orally, 50 % protein bound Disappears rapidly from blood , remains in tissue longer than folate thus causes prolonged inhibitory effectC/I in renal impairment

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 Calcium folinate or calcium levofolinate Thymidine also counteracts methotrexate toxicity 55Uses of methotrexate Antineoplastic Choriocarcinoma and tropoblast tumor 15 -30 mg/day orally for 5 days Remission of ALL in children 2.5 to 15 mg/day Ca breast, head & neck, bladder, ovarian cancerImmuno-supressive agent Rheumatoid arthritis, resistant asthmaCrohns disease, wegeners granulomatosis Prevention of graft versus host reaction Psoriasis Medical termination of pregnancy

Choriocarcinoma and tropoblast tumor in women xure RHEUMATOID ARTHRITIS :5-7.5MG PER WEEK ORALLY FOR 8 WEEKSPSORIASIS2.5-5MG AT 12HRLY INTERVALS WEEKLY

Also used in mycosis fungoides , Some role in AML and non hodgkins lymphoma MTP: 25 TO 50 MG ORAL THEN 3-7 DAYS LATER misoprostol 800 microgram vaginally in early part of forst trimester < 8 weeks of gestation 566 Mercaptopurine 6 Thioguanine Azathioprine Fludarabine

Purine antagonists 57

HGPRT6 Mercaptopurine Ribonucleotide (HGPRT):hypoxanthine-guanine phosphoribosyl transferase1. Nucleotide formation: To exert its antileukemic effect, 6-MP must penetrate target cells and be converted to the nucleotide analog, 6-thioinosinic acid TIMP. The addition of the ribose phosphate is catalyzed by enzyme, hypoxanthine-guanine phosphoribosyl transferase (HGPRT).2. Inhibition of purine synthesis: A number of metabolic processes involving purine biosynthesis and interconversions are affected by, TIMP. Like adenosine monophosphate (AMP), guanosine monophosphate (GMP), and inosine monophosphate (IMP), TIMP can inhibit the first step of de novo purine-ring biosynthesis (catalyzed by glutamine phosphoribosyl pyrophosphate amidotransferase) by feed back mechanism. TIMP also blocks the formation of AMP and xanthinuric acid from inosinic acid.3. Incorporation into nucleic acids: TIMP is converted to thioguanine monophosphate (TGMP), which after phosphorylation to di- and triphosphates can be incorporated into RNA. The deoxyribonucleotide analogs that are also formed are incorporated into DNA. This results in nonfunctional RNA and DNA.

586 Mercaptopurine

6 MP 6 Thiouric acid Xanthine oxidase Allopurinol

TPMTInactive metabolite Well absorbed orally, metabolized rapidly by xanthine oxidase, use of xanthine oxidase inhibitor allopurinol decreases the inactivation of 6 MP, xanthine oxidase also required in uric acid synthesis, so allopurinol may be used in cancer chemotherapy to reduce dose of 6 MP and also decrease the hyperuricaemia 6 MP ALSO METABOLISED BY METHYLATION IN PRESENCE OF ENZYME THIOPURINE METHYL TRANSFERASE, GENTIC DEFICIENCY OF THIS ENZYME MAKES INDIVIDUAL MORE SUSCEPTIBLE TO 6 MP toxicity , while over expression is important method of resistance. Azathiprine is also substrate for xanthine oxidase but 6 thiguanine is not.59Use: Acute leukemia (ALL)Choriocarcinoma Adverse Effects:Bone marrow & GIT mainly Hepatic necrosis rarely Hyperuricaemia 6 Mercaptopurine

Hyperuricaemia occurs due to massive destruction of cells of lymphoid series , urine should be maintained alkaline and its volume adequate. Other purine analogs like 6 thioguanine and azathiprine also posses cytotoxic actions how ever they do not have any advantage over 6 mercaptopurine as antileukemic agentsMercaptopurine with azathiprine decrease the dose by to Azathiprine: ImuranUsed as immunosupressive agent in organ transplantation and autoimmune conditons like hemolytic anemia, glomerulonephritis, and rhe umatoid arthritis

60Phosphorylates intracellularly to form triphosphate Inhibits DNA polymerase and gets incorporated to form dysfunctional DNA Effective in slow growing tumors: (apoptosis)Use: CLL and non hodgkins recurring after treatment Adverse events: chills, fever, opportunistic infection, myelosupression Fludarabine Promotes tumor apoptosis 61Like fludarabine converted to triphosphate Incorporated into DNA Inhibits DNA polymerase and thus inhibits DNA synthesis and repair Used in treatment of Hairy cell leukemia, CLL and low grade lymphomas

Cladirabine Pentostatin Inhibits adenosine deaminase Accumulation of adenosine & deoxyadenosine Inhibits ribonucleotide reductase Blocks DNA synthesis S adenosyl homocysteine accumulation Toxic to lymphocytes Used inHairy cell leukemia Extremely effective in complete remission of hairy cell leukemia iv 4 g/m2 alternate week , sufficient hydration 500 ml to 1 l of dextrose in 0.45 % saline 635 fluoruracil Cytosine arabinoside (Cytarabine) Gemcitabine Pyrimidine antagonists 5 fluorouracil 5 FU FdUMPdUMPThymidine Monophosphate Thymidilate synthetase DNA Synthesis (Selective failure)Uses : stomach , colon, breast ovaries , liver, skin cancers

FdUMP = fluorodeoxyuridine monophosphate 5 fluoro uracil is converted in body to corresponding nucleotide fluorodeoxyuridine monophosphate, Fluorinated analog of pyrimidine acts by inhibiting thymidilate synthesis Also gets incorporated into DNA in place of uracil Uses: topically intreatment of premalignant keratosis Even resting cells are more affected though rapidly multipling cells are more susceptible Toxic to bone marrow , alimentary epitheliumand CNS Administered by slow IV infusion to prevent first pass metabolism. 65Pyrimidine analog considered drug of choice in inducing remission in AML Phosphorylated in body to triphosphate Triphosphate of cytarabine inhibits DNA polymerase & Thus inhibit DNA synthesis and repairCytosine arabinoside Gemcitabine Drug of choice in adenocarcinoma of pancreas ESPECIALLY IN ADULTS Uses : AML, Hodgkins & Non hodgkins

Gemcitabine Forms triphosphate that inhibits DNA synthesis Blocks DNA strand elongation Drug of choice in adenocarcinoma of pancreas 1000 mg/m2 over 30 min 66Obtained from periwinkle plant ( Vinca Rosea) Vincristine, vinblastine, vindesine, vinorelbine Vinca alkaloids

Mechanism of action

VX and VBL are both cell-cycle specific and phase specific, because they block mitosis in metaphase (M phase). Their binding to the microtubular protein, tubulin, is GTP dependent and blocks the ability of tubulin to polymerize to form microtubules. Instead, paracrystalline aggregates consisting of tubulin dimers and the alkaloid drug are formed. The resulting dysfunctional spindle apparatus, frozen in metaphase, prevents chromosomal segregation and cell proliferationResistance: Resistant cells have been shown to have an enhanced efflux of VX, VBL, and VRB via P-glycoprotein in the cell membrane. Alterations in tubulin structure may also affect binding of the vinca alkaloids.

68Comparison betweenVincristine Marrow sparing effectAlopecia more common Peripheral & autonomic neuropathy & muscle weakness (CNS)Constipation Uses: (Childhood cancers)ALL , Hodgkins, lymphosarcoma, Wilms tumor, Ewings sarcoma Vinblastine Bone marrow supressionLess common Less common, temp. mental depresssion Nausea, vomiting, diarrhoea usesHodgkins disease & other lymphomas , breast cancer, testicular cancer AFE: Unpredictable oral absorption, extensively conc in platelets, vinca alkaloids are not well absorbed by oral routeHighly irritant drugs so given continously by iv infusion, vinca alkaloids are conc and metabolized by CYP450 in liuver excreted in bile in liver dysfunction decrease the dosePhenytoin, phenobarbitone, carbamezepine may induce the metabolism and griseofulvin inhibits metabolism Vinorelbine: semisynthetic derivative for ca breast, testicular cancer, epithelial ovarian cancers.69Taxanes Paclitaxel & docetaxel Plant product obtained from bark of Pacific Yew ( Taxus Brevifolia) & European Yew (Taxus Buccata)

Mechanism of action

Cell cycle arrested in G2 and M phaseTaxanes bind to beta tubulin subunits of microtubules at a site different from binding site of vinca alkaloids, colchicine, podophyllotoxin, unlike vinca alkaloids they promote polymerization of microtubules & inhibit depolymerization, leading to stabilization of polymerized microtubules and arrests cells in mitosis and eventually leads to activation of apoptosisThe stabilization of microtubules is damaging to cells because of disturbances in in the dynamics of various microtubule dependent structures that are required for functions like mitosis, maintainence of cellular morphology, locomotion and secretion. 71Paclitaxel Administered IV Use: advanced breast & ovarian cancer also lungs, esophagus, prostrate cancer Adverse effects: Anaphylactoid reaction because of solvent cremaphorMyalgia, myelosupression, peripheral neuropathy DocetaxelOral Used in refractory breast & ovarian cancer Major toxicity neutropenia may cause aarrhythmias , hypotension

Dexamethasone, h1 antagonists supress the reaction Abraxane: Albumin bound form of paclitaxel no anaphylactoid reaction 72Epipodophyllotoxins Etoposide & tenoposide Semisynthetic derivatives of podophyllotoxins podophyllum peltatum (plant glycoside)

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

Type I topoisomerasecuts one strand of a DNA double helix, relaxation occurs, and then the cut strand is reannealed.Type II topoisomerasecuts both strands of one DNA double helix, passes another unbroken DNA helix through it, and then reanneals the cut strand.Testicular tumors in combination with bleomycin or cisplatin Tenoposide used in ALL74Derived from camptotheca accuminataInhibit Topoisomerase I: No resealing of DNA after strand has untwisted Topotecan:Used in metastatic ovarian cancer Major toxicity is bone marrow depression Irinotecan Used in metastatic cancer of colon/rectum Toxicity: diarrhoea, neutropenia, thrombocytopenia, cholinergic side effects Camptothecin analogs Topoisomerase I modulates supercoiling of DNA by complexing with it and nicking one of its strands 75Cell cycle non specific drugs Derived from streptomyces species MOA:Intercalation in the DNA between adjoining nucleotide pairs blocks DNA & RNA synthesis Generation of oxygen radicals which mediate single strand scission of DNA Action on Topoisomerase II Anticancer antibiotics Intercalation in the DNA: The drugs insert nonspecifically between adjacent base pairs and bind to the sugar-phosphate backbone of DNA. This causes local uncoiling and, thus, blocks DNA and RNA synthesis. Intercalation can interfere with the topoisomerase IIcatalyzed breakage/reunion reaction of supercoiled DNA strands, causing irreparable breaks.Generation of oxygen radicals: Cytochrome P450 reductase (present in cell nuclear membranes) catalyzes reduction of the anthracyclines to semiquinone free radicals. These in turn reduce molecular O2, producing superoxide ions and hydrogen peroxide, which mediate single-strand scission of DNA (Figure 39.18). Tissues with ample superoxide dismutase or glutathione peroxidase activity are protected.10 Tumors and heart tissue are generally low in SOD. In addition, cardiac tissue lacks catalase and, thus, cannot effectively scavenge hydrogen peroxide. Lipid peroxidation therefore may explain the cardiotoxicity of anthracyclines.

76Uses: Wilms tumor, gestational choriocarcinomaAdverse effects bone marrow supression Irritant like meclorethamine sensitizes to radiation, and inflammation at sites of prior radiation therapy may occurGastrointestinal adverse effects

Dactinomycin

Mechanism of action: The drug intercalates into the minor groove of the double helix between guanine-cytosine base pairs of DNA,8 forming a stable dactinomycin-DNA complex. The complex interferes primarily with DNA-dependent RNA polymerase, although at high doses, dactinomycin also hinders DNA synthesis. The drug also causes single-strand breaks, possibly due to action on topoisomerase II or by generation of free radicals.Adverse effects: The major dose-limiting toxicity is bone marrow depression. The drug is immunosuppressive. Other adverse reactions include nausea, vomiting, diarrhea, stomatitis, and alopecia. Extravasation during injection produces serious problems. Dactinomycin sensitizes to radiation, and inflammation at sites of prior radiation therapy may occur.

77Doxorubicin & Daunorubucin

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

Acute: ecg changes, arrhythmia, hypotension, delayed CCF Tissues with ample superoxide dismutase or glutathione peroxidase activity are protected.10 Tumors and heart tissue are generally low in SOD. In addition, cardiac tissue lacks catalase and, thus, cannot effectively scavenge hydrogen peroxide. Lipid peroxidation therefore may explain the cardiotoxicity of anthracyclines.79Mitoxantrone Analog of doxorubicin Lower cardiotoxicity Uses: Acute leukemia, CML, Non hodgkins Mitomycin C Highly toxic used only in resistant cancers of stomach, colon, rectumTransformed to form which acts like alkylating agent Mithramycin Reduces blood calcium levels by inhibiting osteoclasts Used in T/t of hypercalcemia with bone metastasis Bleomycin Reacts with iron, copper & O2 in presence of CYP -450 reductase Also can intercalate between DNA strands

DNA bleomycin Fe2+DNA bleomycin Fe3+Mixture of closely related glycopeptide antibiotics 81Uses :Epidermoid cancers of skin, oral cavity, genitourinary tract, esophagus Testicular tumors Hodgkins lymphomaAdverse effects:Pneumonitis Fatal pulmonary fibrosis Hyper pigmentation spares bone marrow

Bleomycin L-asparaginase

L-asparaginase Isolated from E.coliUse: Acute Lymphocytic Leukemia (ALL) Dose : 6000 to 10000U/kg IV daily for 3-4 weeksA/E: Hepatic damage Hypersensitivity , hemorrhage Hyperglycemia, headache, hallucinations , confusion, coma CLINICAL RESPONSE TO L-ASPARGINASE IS DISAPPOINTING, THOUGH REMISSIONINDUCED IN ACUTE LEUKEMIA IS SHORT LASTING , IT IS NOW USED WHWN OTHER DRUGS HAVE FAILED , INEFFECTIVE IN SOLID TUMORS 84HydroxyureaUses: CML, Polycythemia, psoriasis Dose: 20-30 mg/kg /day orallyRibonucleotides Deoxyribonucleotides Ribonucleoside diphosphate reductaseHydroxyurea

Adverse effectsMyelosuppression (Minimal)Hypersensitivity Hyperglycemia Hypoalbuminemia Blocks enzyme Less GI toxicity 85ProcarbazineMOA: Depolymerizes DNA & causes chromosomal damageUSES: Hodgkins disease ( MOPP regimen)Non hodgkins lymphoma 100-200mg daily orallyA/e: MAO inhibitor action & antabuse actionMethyl hydrazine derivative, inactive as such but undergoes metabolic activation to highly reactive alkylating species which cause methylation of DNA 86Radio active isotopes I131 Emits beta radiation , half life-8.04 days use:Follicular Ca- ThyroidP32 - Emits beta radiation , half life- 14.3 days. use : Polycythemia vera198Au gives low energy beta & gamma radiation, half life- 2.69 days use :malignant pleural, peritoneal effusionEmit b and gamma radiations disrupt cellular metabolism and cause cellular destruction. 87Hormones & antagonists CorticosteroidsPrednisolone Estrogens Ethinyl Estradiol SERM Tamoxifene, Toremifene SERD Fulvestrant Aromatase Inhibitors Letrozole, Anastrazole, Exemestane

Progestins Hydroxyprogesterone Anti-androgens Flutamide, Bicalutamide 5- reductase Inhibitors finasteride, dutasteride GnRH analogs Naferelin, goserelin, leuoprolide

88Glucocorticoids Marked lympholytic effect so used in acute leukaemias & lymphomas, They alsoHave Anti-inflammatory effect Increase appetite, prevent anemia Produce sense of well being Increase body weight Supress hypersensitivity reaction Control hypercalcemia & bleeding Non specific antipyretic effect Increase antiemetic effect of ondansetron

Prevent anemia: prevent acceletated erythrocytic destruction, They effectively counter hemolytic and hemorrhagic complications accompanying chronic lymphocytic and malignant lymphomas, Prednisolone is generally started in doses of 60 100 mg daily in divided doses and then depending on response reduced to maintenance dose of 20 -40 mg /day

The use of this compound in the treatment of lymphomas arose when it was observed that patients with Cushing's syndrome, which is associated with hypersecretion of cortisol, have lymphocytopenia and decreased lymphoid mass. [Note: At high doses, cortisol is also lymphocytolytic and leads to hyperuricemia due to the breakdown of lymphocytes.] Prednisone is primarily employed to induce remission in patients with acute lymphocytic leukemia and in the treatment of both Hodgkin's and non-Hodgkin's lymphomas.Glucocorticoids have some secondary role in hormone responsive breast cancers, they are also valuable for treatment of complications like treatment of hypercalcemia, hemolytic anemias, thrombocytopenia, incresed intracranial tension, mediastinal edema occuring after radiotherapy, they afford symptomatic relief by mood elevating and antipyretic effects and also adjuvants of antiemetics. Useful in treating cerebral edemas due to intracranial cerebral metastasis 89Estrogens Physiological antagonists of androgens Thus used to antagonize the effects of androgens in androgen dependent prostatic cancer Fofesterol Prodrug , phosphate derivative of stilbesterol 600-1200mg IV initially later 120-240 mg orally

Fosfesterol is activated to slibesterol in prostatic tissue and acheives high conc in prostatic tissue thus it is used in prostrate cancerAdverse effects impotence and gynaecomastia 90Tamoxifen : Non steroidal antiestrogen Selective Estrogen Receptor Modulators (SERMs)

Agonistic: Uterus, bone, liver, pitutary Antagonistic: Breast and blood vessels SERMS are non steroidal synthetic agents whose agonist or antagonist action on estrogen receptors are tissue selective, produces beneficial estrogenic actions in some tissues (bone, brain, liver), and prevent certain deleterious effect in breast and endometrium by exhibiting antagonistic or no action on ER

Tamoxifen: Non steroidal antiestrogen related structuraly to slilbesterol, given orally it competes with the circulating estrogen for cytoplasmic estrogen receptor binding site, the metabolites of tamoxifen have much stronger affinity for receptors and are not easily displaced by circulating estradiol. At low concentration they have cytostatic effect on ER positive cells, higher conc cause cytotoxic effect . Because of antagonistic action in breast DOC in treatment of ca breast in ER+ AS WELL as some ER- breast cancer also male breast 91Tamoxifen DOSE:10-20mg bdStandard hormonal treatment in breast cancerAdverse effects:Hot flushes , vomiting, vaginal bleeding, menstrual irregularities, venous thromboembolism, dermatitis, rarely endometrial cancer

Well absorbed orally, biphasic half life 10 hrs and also 7 days, and long duration ofaction some metabolites of tamoxifen are more potent antiestrogens, the drug is excreted primarily in bile. Other SERMS- raloxifene no risk of endometrial carcinoma, used as first line drug in treatment of postmenopausal osteoporosis, toremifene new congener of tamoxifen with similar actions uses and adverse effects ORMELOXIFENE dub, acts as antagonist in breast and uterus92Pure estrogen antagonistUSES: Metastatic ER+ Breast Ca in postmenopausal womenMOA: Inhibits ER dimerization & prevents interaction of ER with DNAER is down regulated resulting in more complete supression of ER responsive gene function Selective Estrogen Receptor Down regulator (fulvestrant)USES: Metastatic ER+ Breast Ca in postmenopausal women which has stopped responding to tamoxifenHigher affinity for ER probably accounts for efficacy in tamoxifen resistant cases

93LetrozoleOrally active non steroidal compoundMOA : Inhibits aromatisation of testosterone & androstenedione to form estrogen.Uses : Breast Ca- & adj. to mastectomyDose :2.5mg bd orallyAnastrozole : more potent 1mg OD in ER+ Breast CaA/E : hot flushesAromatase InhibitorsAromatization of A ring of testesterone and androstenedione is final and key step in production of estrogens estradiol and estrone in body, in addition to circulating hormone the locally produced hormone may play an important role in breast cancer development, exemestane also aromatase inhibitor

94FLUTAMIDE & BICALUTAMIDE :Androgen Receptor antagonistsDose : 250 mg tds, 50mg od resp.Palliative effect in metastatic Prostatic Ca after orchidectomyAnti androgens5- reductase inhibitorsFinasterideOrally activeDHT levels Benign prostatic hyperplasia Dose: 5mg/day

Prostate volumeSymptom scorePeak urine flow rateDHT level in prostateSide effects: Loss of libido & impotence in 5 % pts.Also used for prevention of hair lossNAFERELIN : nasal spray / SC injFSH & LH release from pituitary- the release of estrogen & testosteroneUSE : Breast Ca, Prostatic CaPROGESTINS:Hydroxyprogesterone used in metastatic endometrial Ca.A/E: bleeding GnRH agonists

Newer anticancer drugs Inhibitors of growth factors receptors Imatinib: CML (BCR-ABL gene)Gefitinib: Non small cell cancer of lungs (EGFR)Nilotinib : CML (Tyrosine kinase inhibitor)Dasatinib : CML (Tyrosine kinase inhibitor)Lapatinib : metastatic breast cancer (HER2/neu)Sunitinib : renal cell carcinoma (VEGF)Sorafinib : renal cell carcinoma (VEGF)

100Monoclonal antibodies Trastuzumab : breast cancer (HER2/neu)Bevacizumab: metastatic colon cancer (VEGF) Rituximab : non hodgkins lymphoma (CD-20)Panitumumab : metastatic colon cancer (EGFR)Alemtuzumab : CLL (CD 52 antigen)Iodine tositumonab : Non hodgkins (CD-20)Newer anticancer drugs

102Important drug combinations REGIMEN CANCER DRUGS MOPPHodgkins Mechlorethamine, oncovin, prednisolone, procarbazineABVDHodgkins Doxorubicin, bleomycin, vinblastine, dacarbazine CMF BreastCyclophosphamide, methotrexate, 5-FUCAFBreast Cyclophosphamide, doxorubicin, 5FUALL Vincristine, prednisolone, aspargine, daunorubicin AML Cytarabine, methotrexateCML Hydroxyurea, interferonWilms Actinomycin, vincristine, doxorubicin