抗腫瘤藥英文版

1、Anticancer Drugs,Dr.Qamar BarakzaiDepartment of PharmacologyZiauddin Medical UniversityKarachi.Pakistan,“CANCER” Refers to a Malignant neoplasm (New growth)Cancer cells can manifest: Uncontrolled Proliferatio

2、n. Loss of function due to lack of ability to differentiate. Invasiveness. The ability to metastasize.Cancer arises as a result of a series of genetic changes in the cell, the main genetic lesions being: Inact

3、ivation 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 at the same ti

4、me. 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 O

5、ncogenes +ve,,,,,,,,,,,,,S DNA Synthesis,G2 Premitotic Interval,M,PROPHASEMETAPHASEANAPHASETELOPHASE,MITOSIS,G0,G1,,S PHASE SPECIFIC Cytosine Arbinoside Hydroxyurea S PHASE SPECIFIC SELF LIMI

6、TING6-MercaptpurineMethotrexate.,,M PHASESPECIFICvincristinevinblastinepaclitaxel,,PHASE NONSPECIFICalkylating agents, cis-platinumnitrosoureas, dacarbazineantibioticsprocarbazine,,G0,,,Differentiation,CELL GRO

7、WTH CYCLE 5 DISTINCT PHASES OF MITOSIS 1. G0 - Resting - no mitosis 2. G1 - Postmitotic - first growth 3. S - DNA synthesis phase 4. G2 - Premitotic - second growth 5.

8、 M - Mitosis phase GENERATION TIME - one complete cycle different in all tumors, from hours to days,,,,,,,,PENTOSTATIN,Inhibits adenosine Deaminase,PALA,Inhibits Pyrimidine Biosynthesis,Purinesynthes

9、is,Pyrimidine synthesis,,,Ribonucleotides,,Deoxyribonucleotides,,,,DNA,HYDROXYUREA,InhibitRibonucleotide Reductase,6-MERCAPTOPURINE 6-THIOGAUNINE,Inhibit Puring ring biosynthesis,Inhibit Neocleotide interc

10、onversions,5-FLOUROURACIL,Inhibit TMPSynthesis,METHOTREXATE,Inhibit dihydrofolatereduction, blocksTMP and Purinesynthesis,,,,,,,,,,,,,,,,,,,,,,,,DNA,RNA,(Transfer, messenger, ribosomal),CYTARABINE FLUDARABINE2-CHL

11、ORODEOXY ADENOSINE,Inhibit DNA Synthesis,ALKYLATING AGENTSMITOMYCETINCISPLATINPROCARBAZINEDACARBAZINE,Form adducts w/ DNA,,BLEOMYCINETOPOSIDETENIPOSIDE,Damage DNA andPrevent repair,,DACTINOMYCINEDAUNORUBICI

12、NDOXORUBICINMITOXANTRONE,Intercalate with DNAInhibit RNA synthesis,,,,,PROTEINS,Enzymes,Microtubules,A-ASPARAGINASE,Deaminate asparagine,Inhibits proteinsynthesis,PACLITAXELVINCA ALKALOIDSCOLCHICINE,Inhibit functi

13、on ofMicrotubules,,,,,,,,,ANTINEOPLASTIC AGENTS DEFINITIONS: ? ALKYLATION - chemical reaction that cleaves DNA and interferes with mitosis ? BIFUNCTIONAL ALKYLATING AGENTS - have 2 alkyl groups

14、 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 & V,ANT

15、INEOPLASTIC AGENTSADVERSE EFFECTS: Kills all fast growing cells Hair follicles GI tract mucosa Bone marrow suppression (BMS) causing anemiaand leukopenia All are pregnancy category D ! Most

16、are nephro- hepato- and ototoxic Extravasation of IV can result in loss of limb,Antineoplastic AgentsADVERSE EFFECTS: (Contd) All have a BMS and emetic index All have wide interaction with othe

17、r drugs. Special training required for nursing Most agents can be harmful to nurse administering them,DEFINITIONS: GROWTH FRACTION % of cells in mitosis at any given time LEUCOVORIN RESCUE - use of leucov

18、orin to reverse methotrexate-induced toxicity MITOTIC INDEXnumber of cells per unit undergoing mitosis during a given time NADIRlowest point (as in blood count) after being depressed by chemotherapy PARANEOPLA

19、STIC SYNDROME (PNS)S/S of cancer located distant from tumor or its metastatic sites,ANTINEOPLASTIC AGENTS 2 MAIN GROUPS OF AGENTS: CELL CYCLE - NONSPECIFIC (CCNS) ALKYLATING AGENTS cytotoxic in any ph

20、ase 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 ANTIBIO

21、TICS (some are CCNS) effective against rapidly growing tumors,ALKYLATING AGENTSNITROGEN MUSTARDS first developed in 1940s CCNS killing ability mechlorethamine is the prototypical agent USES: Hodgkin

22、’s disease & lymphomas. leukemias, CANCERS OF lung, breast, ovary, testes, brain,

23、 bladder,Most widely used agent, often in combination with other agents.,ALKYLATING AGENTSSELECTED AGENTS: Mechlorethamine (Mustine, Mustargen) IV only (adult use only) Cyclop

24、hosphamide (Cytoxan, Neosar) IV and PO, adults and pediatric use Carmustine (BiCNU) IV, adult only, can cross blood-brain barrier, therefore used to tread brain lesionsOT

25、HER AGENTS: Chlorambucil, Streptozotocin,Hepatic cytochrome P450 0xidase 4-Hydroxycyclophosphamide Aldophosphamide

26、 Enzymatic Non enzymatic Hepatic aldehyde oxidase 4-Ketocyclophosp

27、hamide (Inactive).

28、 Acrolein Cytotoxic Phosphamide Mustard Cytotoxic. Carboxyphosphamide (Inactive).

29、 Responsible for unwanted effects,,,,,,,,,,Cyclophosphamide (Inactive),,,,,,,,,,,Cyclophosphamide (Inactive),Hepatic cytochrome P450 0xidase,4-Hydr

30、oxycyclophosphamide,Aldophosphamide,Enzymatic,Non enzymatic,Hepatic aldehyde oxidase,4-Ketocyclophosphamide (Inactive).,Acrolein Cytotoxic Phosphamide Mustard

31、 Cytotoxic,Carboxyphosphamide (Inactive).,Responsible for unwanted effects,ANTIMETABOLITESACTIONS: Antagonism of folate, purines, and pyrimidines needed for synthesis of nucleic acids -stops cell replication

32、 USES: Solid tumors (breast, lung, liver, brain, colon. Stomach, pancreas) Lymphomas, leukemias. Some agents also immunosuppressive, Useful in treating immune-mediated diseases,ANTIMETABOLITESSELECTED AGENTS: (FO

33、LIC 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 misoprosto

34、l for therapeutic abortion Causes profound anemia (folate depletion) Therefore leucovorin “rescue” often used to counteract,ANTIMETABOLITES SELECTED AGENTS: PURINE ANALOG - MERCAPTOPURINE (6-

35、MP, Purinethol) - Purine antagonist - PO only, adult and pediatric use PYRIMIDINE ANALOG -CYTARABINE (Ara-C, Cytosar-U) -Pyrimidine antagonist -IV and intrathecal (wi

36、thin spinal canal),MITOTIC INHIBITORSACTIONS: Plant alkaloids (periwinkle, yew tree, mandrake plant, etc.) Bind to and disrupt mitotic spindles USES: Lymphomas (Hodgkin’s and non-Hodgkin’s),Neuroblastoma Kaposi

37、’s sarcoma,Solid tumors (breast, testicular, etc.),MITOTIC INHIBITORS SELECTED AGENTS: ETOPOSIDE (VP-16, VePesid) IV and PO, adult use only PACLITAZEL (Taxol) IV only, adult

38、 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 leukemia,CYTOTOXIC ANTIBIOTICS ACTION

39、S: Source: Streptomyces mold - work by intercalation (insertion of drug molecule between the 2 DNA strands causing it to (“unwind”) Kill some bacteria and viruses but are

40、 too toxic to use for infections IV extravasation constant danger ! USES: wide variety of solid tumors, always used in combination with other agents,CYTOTOXIC ANTIBIOTICS SELECTED AGENTS: DOXORUBI

41、CIN (ADR, Rubex, Doxil) IV only, adult use only BLEOMYCIN (BLM, Blenoxane) IM, IV, SQ, adult use only very toxic agents !!!,MISCELLANEOUS ANTINEOPLASTICSVarious actions,Both

42、 CCNS and CCS Used in combinations with other agents SELECTED AGENTS: Cisplatin (Platinol) IV, adult and pediatric useALTRETAMINE (Hexalen) PO only, adult use only, primarily used to trea

43、t ovarian cancer ASPARAGINASE (Elspar) IV only, adult and pediatric use HYDROXYUREA (Hydrea) PO only, adult use only,MISCELLANEOUS ANTINEOPLASTICSHORMONES AND ANTAGONISTS.1. Adrenocortical Supp

44、ressant: Mitotane, Aminoglutethimide. (Adrenal Cortex)2.Adrenocortical Steroids. Prednisone. (Lukemias, Lymphomas, Breast)3.Progestins. Hydroxyprogestrone.(Endometrium

45、, (Breast) Medroprogestrone, Megesterol acetate.4.Estrogens. DES, Ethinylesterdiol.(Breast, Prostate)5.Antiestrogens. Tamoxifen .(Breast)6.Androgens.