1、Anticancer Drugs,Dr.Qamar Barakzai Department of Pharmacology Ziauddin Medical University Karachi.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 met
2、astasize.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 agentsAre cytotoxic not tumoricidal Only kill cells during mitosis, andNot all cancer cells are dividing at
3、 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 SuppressorGenes -ve (p53)Growth FactorsOncogenes +ve,SDNA Synthesis,G2PremitoticInterval,M,PROPHASE METAPHASE ANAPHASE TELOPHASE,MITOSIS,G0,G1,S P
4、HASESPECIFICCytosineArbinosideHydroxyureaS PHASESPECIFICSELF LIMITING 6-Mercaptpurine Methotrexate.,M PHASE SPECIFIC vincristine vinblastine paclitaxel,PHASE NONSPECIFIC alkylating agents, cis-platinum nitrosoureas, dacarbazine antibiotics procarbazine,G0,Differentiation,CELL GROWTH CYCLE5 DISTINCT
5、PHASES OF 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 days,PENTOSTATIN,Inhibits adenosineDeaminase,PALA,Inhibits
6、PyrimidineBiosynthesis,Purine synthesis,Pyrimidinesynthesis,Ribonucleotides,Deoxyribonucleotides,DNA,HYDROXYUREA,Inhibit RibonucleotideReductase,6-MERCAPTOPURINE6-THIOGAUNINE,Inhibit Puring ringbiosynthesis,Inhibit Neocleotideinterconversions,5-FLOUROURACIL,Inhibit TMP Synthesis,METHOTREXATE,Inhibit
7、 dihydrofolate reduction, blocks TMP and Purine synthesis,DNA,RNA,(Transfer, messenger, ribosomal),CYTARABINEFLUDARABINE 2-CHLORODEOXYADENOSINE,Inhibit DNASynthesis,ALKYLATING AGENTS MITOMYCETIN CISPLATIN PROCARBAZINE DACARBAZINE,Form adducts w/ DNA,BLEOMYCIN ETOPOSIDE TENIPOSIDE,Damage DNA and Prev
8、ent repair,DACTINOMYCINE DAUNORUBICIN DOXORUBICIN MITOXANTRONE,Intercalate with DNA Inhibit RNA synthesis,PROTEINS,Enzymes,Microtubules,A-ASPARAGINASE,Deaminate asparagine,Inhibits protein synthesis,PACLITAXEL VINCA ALKALOIDS COLCHICINE,Inhibit function of Microtubules,ANTINEOPLASTIC AGENTS DEFINITI
9、ONS: ALKYLATION - chemical reaction that cleaves DNA and 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
10、 to cause N & V,ANTINEOPLASTIC AGENTSADVERSE EFFECTS: Kills all fast growing cells Hair folliclesGI tract mucosaBone 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 limb,Antineoplasti
11、c AgentsADVERSE EFFECTS: (Contd)All have a BMS and emetic index All have wide interaction with other 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 leu
12、covorin to reverse methotrexate-induced toxicity MITOTIC INDEX number of cells per unit undergoing mitosis during a given time NADIR lowest point (as in blood count) after being depressed by chemotherapy PARANEOPLASTIC SYNDROME (PNS) S/S of cancer located distant from tumor or its metastatic sites,A
13、NTINEOPLASTIC AGENTS2 MAIN GROUPS OF AGENTS: CELL CYCLE - NONSPECIFIC (CCNS) ALKYLATING AGENTScytotoxic 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 AN
14、TIBIOTICS (some are CCNS) effective against rapidly growing tumors,ALKYLATING AGENTS NITROGEN 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 wi
15、dely used agent, often in combination with other agents.,ALKYLATING 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
16、used to tread brain lesions OTHER AGENTS: Chlorambucil, Streptozotocin,Hepatic cytochrome P450 0xidase4-Hydroxycyclophosphamide AldophosphamideEnzymatic Non enzymaticHepatic aldehyde oxidase 4-Ketocyclophosphamide(Inactive). Acrolein Cytotoxic Phosphamide Mustard Cytotoxic.Carboxyphosphamide (Inacti
17、ve).Responsible for unwanted effects,Cyclophosphamide (Inactive),Cyclophosphamide (Inactive),Hepatic cytochrome P450 0xidase,4-Hydroxycyclophosphamide,Aldophosphamide,Enzymatic,Non enzymatic,Hepatic aldehyde oxidase,4-Ketocyclophosphamide(Inactive).,Acrolein Cytotoxic Phosphamide Mustard Cytotoxic,C
18、arboxyphosphamide (Inactive).,Responsible for unwanted effects,ANTIMETABOLITESACTIONS: 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 ag
19、ents also immunosuppressive, Useful in treating immune-mediated diseases,ANTIMETABOLITESSELECTED 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 fo
20、r therapeutic abortion Causes profound anemia (folate depletion) Therefore leucovorin “rescue” often used to counteract,ANTIMETABOLITESSELECTED AGENTS: PURINE ANALOG - MERCAPTOPURINE (6-MP, Purinethol) - Purine antagonist - PO only, adult and pediatric use PYRIMIDINE ANALOG - CYTARABINE (Ara-C, Cyto
21、sar-U) -Pyrimidine antagonist -IV and intrathecal (within spinal 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, testi
22、cular, etc.),MITOTIC INHIBITORSSELECTED AGENTS: ETOPOSIDE (VP-16, 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 leukemia,CYTOTOXIC ANTIBIOTI
23、CSACTIONS: 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 too toxic to use for infections IV extravasation constant danger ! USES: wide variety of solid tumors, always used in com
24、bination with other agents,CYTOTOXIC ANTIBIOTICSSELECTED AGENTS: DOXORUBICIN (ADR, Rubex, Doxil) IV only, adult use only BLEOMYCIN (BLM, Blenoxane) IM, IV, SQ, adult use only very toxic agents !,MISCELLANEOUS ANTINEOPLASTICS Various actions, Both CCNS and CCS Used in combinations with other agents S
25、ELECTED AGENTS: Cisplatin (Platinol) IV, adult and pediatric use ALTRETAMINE (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 only,MISCELLANEOUS ANTINEOPLASTICSHORMONES AND ANTAGON
26、ISTS. 1. Adrenocortical Suppressant:Mitotane, Aminoglutethimide. (Adrenal 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),
