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1、Anticancer DrugsDr.Qamar BarakzaiDepartment of PharmacologyZiauddin Medical UniversityKarachi.Pakistan“CANCER Refers to a Malignant neoplasm (New growth)Cancer cells can manifest: Uncontrolled Proliferation. Loss of function due to lack of ability to differentiate. Invasiveness. The ability to metas
2、tasize.Cancer arises as a result of a series of genetic changes in the cell, the main genetic lesions being: Inactivation of tumor suppressor genes. The activation of oncogenes.Antineoplastic agents Are cytotoxic not tumoricidal Only kill cells during mitosis, and Not all cancer cells are dividing a
3、t the same time. SUCCESS DEPENDS ON: Stage of cancer at time of diagnosis Type of cancer Development of drug resistance Overall health of patient. R Tumor Suppressor Genes -ve (p53) Growth Factors Oncogenes +ve S DNA Synthesis G2 Premitotic IntervalMPROPHASEMETAPHASEANAPHASETELOPHASEMITOSISG0G1 S PH
4、ASE SPECIFIC Cytosine Arbinoside Hydroxyurea S PHASE SPECIFIC SELF LIMITING6-MercaptpurineMethotrexate.M PHASESPECIFICvincristinevinblastinepaclitaxelPHASE NONSPECIFICalkylating agents, cis-platinumnitrosoureas, dacarbazineantibioticsprocarbazineG0DifferentiationCELL GROWTH CYCLE 5 DISTINCT PHASES O
5、F MITOSIS 1. G0 - Resting - no mitosis 2. G1 - Postmitotic - first growth 3. S - DNA synthesis phase 4. G2 - Premitotic - second growth 5. M - Mitosis phase GENERATION TIME - one complete cycle different in all tumors, from hours to daysPENTOSTATINInhibits adenosine DeaminasePALAInhibits Pyrimidine
6、Biosynthesis Purinesynthesis Pyrimidine synthesisRibonucleotidesDeoxyribonucleotidesDNAHYDROXYUREAInhibitRibonucleotide Reductase6-MERCAPTOPURINE 6-THIOGAUNINEInhibit Puring ring biosynthesisInhibit Neocleotide interconversions5-FLOUROURACILInhibit TMPSynthesisMETHOTREXATEInhibit dihydrofolatereduct
7、ion, blocksTMP and PurinesynthesisDNARNA(Transfer, messenger, ribosomal) CYTARABINE FLUDARABINE2-CHLORODEOXY ADENOSINEInhibit DNA SynthesisALKYLATING AGENTSMITOMYCETINCISPLATINPROCARBAZINEDACARBAZINEForm adducts w/ DNABLEOMYCINETOPOSIDETENIPOSIDEDamage DNA andPrevent repairDACTINOMYCINEDAUNORUBICIND
8、OXORUBICINMITOXANTRONEIntercalate with DNAInhibit RNA synthesisPROTEINSEnzymesMicrotubulesA-ASPARAGINASEDeaminate asparagineInhibits proteinsynthesisPACLITAXELVINCA ALKALOIDSCOLCHICINEInhibit function ofMicrotubules ANTINEOPLASTIC AGENTS DEFINITIONS: ALKYLATION - chemical reaction that cleaves DNA a
9、nd interferes with mitosis BIFUNCTIONAL ALKYLATING AGENTS - have 2 alkyl groups and alkalate 2 DNA strands DOSE-LIMITED SIDE EFFECTS - adverse effects that prevent an agent from being given in higher doses EMETIC POTENTIAL - potential of an agent to cause N & VANTINEOPLASTIC AGENTSADVERSE EFFECTS: K
10、ills all fast growing cells Hair follicles GI tract mucosa Bone marrow suppression (BMS) causing anemiaand leukopenia All are pregnancy category D ! Most are nephro- hepato- and ototoxic Extravasation of IV can result in loss of limbAntineoplastic AgentsADVERSE EFFECTS: (Contd) All have a BMS and em
11、etic index All have wide interaction with other drugs. Special training required for nursing Most agents can be harmful to nurse administering themDEFINITIONS: GROWTH FRACTION % of cells in mitosis at any given time LEUCOVORIN RESCUE - use of leucovorin to reverse methotrexate-induced toxicity MITOT
12、IC INDEXnumber of cells per unit undergoing mitosis during a given time NADIRlowest point (as in blood count) after being depressed by chemotherapy PARANEOPLASTIC SYNDROME (PNS)S/S of cancer located distant from tumor or its metastatic sitesANTINEOPLASTIC AGENTS 2 MAIN GROUPS OF AGENTS: CELL CYCLE -
13、 NONSPECIFIC (CCNS) ALKYLATING AGENTS cytotoxic in any phase of cell cycle effective against slowly growing tumors CELL CYCLE - SPECIFIC (CCS) 3 TYPES ANTIMETABOLITES - cytotoxic is S phase MITOTIC INHIBITORS - cytotoxic in M phase CYTOTOXIC ANTIBIOTICS (some are CCNS) effective against rapidly grow
14、ing tumorsALKYLATING AGENTSNITROGEN MUSTARDS first developed in 1940s CCNS killing ability mechlorethamine is the prototypical agent USES: Hodgkins disease & lymphomas. leukemias, CANCERS OF lung, breast, ovary, testes, brain, bladder,Most widely used agent, often in combination with other agents.AL
15、KYLATING AGENTSSELECTED AGENTS: Mechlorethamine (Mustine, Mustargen) IV only (adult use only) Cyclophosphamide (Cytoxan, Neosar) IV and PO, adults and pediatric use Carmustine (BiCNU) IV, adult only, can cross blood-brain barrier, therefore used to tread brain lesionsOTHER AGENTS: Chlorambucil, Stre
16、ptozotocin Hepatic cytochrome P450 0xidase 4-Hydroxycyclophosphamide Aldophosphamide Enzymatic Non enzymatic Hepatic aldehyde oxidase 4-Ketocyclophosphamide (Inactive). Acrolein Cytotoxic Phosphamide Mustard Cytotoxic. Carboxyphosphamide (Inactive). Responsible for unwanted effects Cyclophosphamide
17、(Inactive) Cyclophosphamide (Inactive)Hepatic cytochrome P450 0xidase4-HydroxycyclophosphamideAldophosphamide Enzymatic Non enzymaticHepatic aldehyde oxidase 4-Ketocyclophosphamide (Inactive). Acrolein Cytotoxic Phosphamide Mustard CytotoxicCarboxyphosphamide (Inactive). Responsible for unwanted eff
18、ectsANTIMETABOLITESACTIONS: Antagonism of folate, purines, and pyrimidines needed for synthesis of nucleic acids -stops cell replication USES: Solid tumors (breast, lung, liver, brain, colon. Stomach, pancreas) Lymphomas, leukemias. Some agents also immunosuppressive, Useful in treating immune-media
19、ted diseasesANTIMETABOLITESSELECTED AGENTS: (FOLIC ACID ANALOG) METHOTREXATE (Folex, Rheumatrex, MTx) Folic acid antagonist PO & IM, adult and pediatric use Also used to treat immune-mediated diseases, Used incombination with misoprostol for therapeutic abortion Causes profound anemia (folate deplet
20、ion) Therefore leucovorin “rescue often used to counteractANTIMETABOLITES SELECTED AGENTS: PURINE ANALOG - MERCAPTOPURINE (6-MP, Purinethol) - Purine antagonist - PO only, adult and pediatric use PYRIMIDINE ANALOG -CYTARABINE (Ara-C, Cytosar-U) -Pyrimidine antagonist -IV and intrathecal (within spin
21、al canal)MITOTIC INHIBITORSACTIONS: Plant alkaloids (periwinkle, yew tree, mandrake plant, etc.) Bind to and disrupt mitotic spindles USES: Lymphomas (Hodgkins and non-Hodgkins),Neuroblastoma Kaposis sarcoma,Solid tumors (breast, testicular, etc.)MITOTIC INHIBITORS SELECTED AGENTS: ETOPOSIDE (VP-16,
22、 VePesid) IV and PO, adult use only PACLITAZEL (Taxol) IV only, adult use only drug of choice for ovary and breast ca VINCRISTINE (LCR, VCR,Oncovin) IV only, adult and pediatric use drug of choice for acute leukemiaCYTOTOXIC ANTIBIOTICS ACTIONS: Source: Streptomyces mold - work by intercalation (ins
23、ertion of drug molecule between the 2 DNA strands causing it to (“unwind) Kill some bacteria and viruses but are too toxic to use for infections IV extravasation constant danger ! USES: wide variety of solid tumors, always used in combination with other agentsCYTOTOXIC ANTIBIOTICS SELECTED AGENTS: D
24、OXORUBICIN (ADR, Rubex, Doxil) IV only, adult use only BLEOMYCIN (BLM, Blenoxane) IM, IV, SQ, adult use only very toxic agents !MISCELLANEOUS ANTINEOPLASTICSVarious actions,Both CCNS and CCS Used in combinations with other agents SELECTED AGENTS: Cisplatin (Platinol) IV, adult and pediatric useALTRE
25、TAMINE (Hexalen) PO only, adult use only, primarily used to treat ovarian cancer ASPARAGINASE (Elspar) IV only, adult and pediatric use HYDROXYUREA (Hydrea) PO only, adult use onlyMISCELLANEOUS ANTINEOPLASTICSHORMONES AND ANTAGONISTS.1. Adrenocortical Suppressant: Mitotane, Aminoglutethimide. (Adren
26、al Cortex)2.Adrenocortical Steroids. Prednisone. (Lukemias, Lymphomas, Breast)3.Progestins. Hydroxyprogestrone.(Endometrium, (Breast) Medroprogestrone, Megesterol acetate.4.Estrogens. DES, Ethinylesterdiol.(Breast, Prostate)5.Antiestrogens. Tamoxifen .(Breast)6.Androgens. Testosterone (Breast)7.Antiandrogens. Flutamide (Prostate).8.Gonadotropin Releasing Hormone Analog. Leuprolide. (Prostate)
