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1、Anti-Cancer DrugsLeading causes of deathEpidemiologyHeart DiseasesCancerCerebrovascular DiseasesChronic Obstructive Lung DiseasesAccidentsPneumonia&InfluenzaDiabetes MellitusSuicideHomicideHIV InfectionPercentage of Total Deaths,US8.8 million8.8 millionpeople worldwide died from cancer in 2015.1 in
2、6 of all global deaths.US$1.16 trillionUS$1.16 trillionannual economic cost of cancer in 2010.http:/www.who.int/cancer/en/http:/www.who.int/cancer/country-profiles/en/ClassificationCarcinoma derived from epithelial cells.breast,prostate,lung,colorectal and pancreas.Sarcoma arise from connective tiss
3、ue bone,cartilage,fat,nerveLymphoma and leukemia arise from hematopoietic mature in lymph nodes and bloodHallmarks of cancerTreatment options of cancer Surgery:before 1955Radiotherapy:19551965Chemotherapy:after 1965Immunotherapy and Gene therapyCancer ChemotherapyDisease Name5 Years Survival Rate Ch
4、ildhood Acute Lymphoblastic Leukemia5080%Adult Acute Lymphoblastic Leukemia2060%Childhood Acute Myeloblastic Leukemia2060%Adult Acute Myeloblastic Leukemia1020%Breast Cancer(Premenopausal)1020%Breast Cancer(Postmenopausal)015%Hodgkin s lymphoma*4080%Small Cell Lung Cancer(Limited Stage)1020%(Extensi
5、ve Stage)05%The Classification of chemotherapeutic drugsAccording to chemical structure and resource of the drug:Alkylating Agents,Antimetabolite,Antibiotics,Plant Extracts，Hormones，OthersThe Classification of chemotherapeutic drugsAccording to biochemistry mechanisms of anticancer action:Block nucl
6、eic acid biosynthesisDirect influence the structure and function of DNA Interfere transcription and block RNA synthesisInterfere protein synthesis and functionInfluence hormone homeostasisOthers11PENTOSTATINInhibits adenosineDeaminasePALAInhibits PyrimidineBiosynthesisPurinesynthesisPyrimidinesynthe
7、sisRibonucleotidesDeoxyribonucleotidesDNAHYDROXYUREAInhibitRibonucleotideReductase6-MERCAPTOPURINE6-THIOGAUNINEInhibit Puring ringbiosynthesisInhibit Neocleotideinterconversions5-FLOUROURACILInhibit TMPSynthesisMETHOTREXATEInhibit dihydrofolatereduction,blocksTMP and Purinesynthesis12DNARNA(Transfer
8、,messenger,ribosomal)CYTARABINEFLUDARABINE2-CHLORODEOXYADENOSINEInhibit DNASynthesisALKYLATING AGENTSMITOMYCETINCISPLATINPROCARBAZINEDACARBAZINEForm adducts DNABLEOMYCINETOPOSIDETENIPOSIDEDamage DNA andPrevent repairDACTINOMYCINEDAUNORUBICINDOXORUBICINMITOXANTRONEIntercalate with DNAInhibit RNA synt
9、hesisPROTEINSEnzymesMicrotubulesA-PARAGINASEDeaminate asparagineInhibits proteinsynthesisPACLITAXELVINCA ALKALOIDSCOLCHICINEInhibit function ofMicrotubulesThe Classification of chemotherapeutic drugsAccording to the cycle or phase specificity of the drug:cell cycle nonspecific agents(CCNSA)cell cycl
10、e specific agents(CCSA)The Basic Concept of Cell Generation Cycle The cycle of cell replication includes:M（Mitosis）phaseG1（Gap1,period before S）phaseS（DNA synthesis）phaseG2（Gap2,period after S）phaseCell Cycle Nonspecific Agents(CCNSA)drugs that are active throughout the cell cycleAlkylating AgentsPl
11、atinum CompoundsAntibioticsCell cycle specific agents and Cell cycle Non-specific agentsCell cycle specific agents and Cell cycle Non-specific agentsCell Cycle Specific Agents(CCSA)drugs that act during a specific phase ofthe cell cycleS Phase Specific Drug:Antimetabolites,Topoisomerase InhibitorsM
12、Phase Specific Drug:Vinca Alkaloids,TaxanesG2 Phase Specific Drug:BbleomycinInfluence Hormone HomeostasisThese drugs bind to hormone receptors to block the actions of the sex hormones which results in inhibition of tumor growth.Estrogens and estrogen antagonistic drug Androgens and androgen antagoni
13、stic drug Progestogen drug Glucocorticoid drug gonadotropin-releasing hormone inhibitor:leuprolide,goserelin aromatase inhibitor:aminoglutethimide,anastrazoleAnticancer DrugsAlkylating AgentAntimetaboliteAntibioticsAlkaloidHormonesOthers(cis-platinum，carboplatin，lobaplatin)Alkylating Agents One of t
14、he frightening developments of World War I was the introduction of chemical warfare.These compounds were known as the nitrogen mustard gases.The nitrogen mustards were observed to inhibit cell growth,especially of bone marrow.Shortly after the war,these compounds were investigated and shown to inhib
15、it the growth of cancer cells.Alkylating AgentsMechanism of Action Nitrogen mustards inhibit cell reproduction by binding irreversibly with the nucleic acids(DNA).The specific type of chemical bonding involved is alkylation.After alkylation,DNA is unable to replicate and therefore can no longer synt
16、hesize proteins and other essential cell metabolites.Consequently,cell reproduction is inhibited and the cell eventually dies from the inability to maintain its metabolic functions.Resistance of Alkylating AgentsResistance to alkylating agents has severalcauses:Membrane transport may be decreased.Th
17、e drug may be bound by glutathione(GSH)via GSH-S-transferase or metallothioneins in the cytoplasm and inactivated.The drug may be metabolized to inactive species.Adverse Effects of Alkylating AgentsMyelosuppression is the dose-limiting adverse effect for alkylating agents.Nausea and vomiting are com
18、mon as are teratogenesis and gonadal atrophy,although in the latter cases these are variable,according to the drug,its schedule,and route of administration.Treatment also carries a major risk of leukemogenesis and carcinogenesis.Alkylating AgentsMustineMustine must be injected intravenously because
19、it is highly reactive.It disappears very rapidly from the blood,the activity of Mustine lasts only a few minutes.The main indication for Mustine is in treatment of Hodgkins disease and lymphomas,but it may also be useful in other malignancies.Alkylating AgentsCyclophosphamideCyclophosphamide can als
20、o be given orally.Indications：It is used in the treatment of chronic lymphocycticleukemia,non-Hodgkinslymphomas,breastandovarian cancer,and a variety of other cancers.It is also a potent immunosuppressant,it is used inthemanagementofrheumatoiddisordersandautoimmune nephritis.Adverse Effects:Alopecia
21、,nausea,vomiting,myelosuppression,andhemorrhagic cystitis.Alkylating AgentsNitrosoureasCarmustine,Lomustine,SemustinePharmacokinetics:Nitrosoureas are highly lipophilic and reach cerebrospinal fluid concentrations that are about 30%of plasma concentrations.Indications:Because of their excellent CNS
22、penetration,carmustine and lomustine have been used to treat brain tumors.Alkylating AgentsAlkysulfonatesBusulfan MyleranIndications:Busulfan is administered orally to treat chroic granulocytic leukemia and other myeloproliferative disorders.Adverse Effects:Busulfan produces advers effects related t
23、o myelosuppression.It only occasionally produces nausea and vomitting.In high doses,it produces a rare but sometimes fatal pulmonary fibrosis,”busulfan lung”.Alkylating AgentsThiotepaThiotepa is converted rapidly by liver mixed-function oxidases to its active metabolite triethylenephosphoramide(TEPA
24、);it is active in bladder cancer.AntimetabolitesGeneral Characteristics：Antimetabolites are S phase-specific drugs that are structural analogues of essential metabolites and that interfere with DNA synthesis.Myelosuppression is the dose-limiting toxicity for all drugs in this class.Classification of
25、 Antimetabolites Folic acidAntagonists:MTXPurine Antagonists:6MP6TG Pyrimidine Antagonists：5FUaraCHUAntimetabolitesFolic Acid AntagonistMethotrexate（MTX）Mechanism of Action：The structures of MTX and folic acid are similar.MTX is actively transported into mammalian cells and inhibits dihydrofolate re
26、ductase,the enzyme that normally converts dietary folate to the tetrahydrofolate form required for thymidine and purine synthesis.AntimetabolitesFolic Acid AntagonistMethotrexate（MTX）Indications：The use of MTX in the treatment of choriocarinoma,a trophoblastic tumor,was the first demonstration of cu
27、rative chemotherapy.It is especially effective for treating acute lymphocytic leukemia and for treating the meningeal metastases of a wide range of tumors.AntimetabolitesFolic Acid AntagonistMethotrexate（MTX）Adverse Effects：MTX is myelosuppressive,producing severe leukopenia,bone marrow aplasia,and
28、thrombocytopenia.This agent may produce severe gastrointestinal disturbances.Renal toxicity may occur because of precipitation(crystalluria)of the 7-OH metabolite of MTX.AntimetabolitesPurine Antagonists6-Mercapapurine（6-MP）The drugs are believed to act similarly to inhibit purine base synthesis,alt
29、hough their exact mechanisms of action are still uncertain.Indications:Mercaptopurine is used primarily for the maintenance of remission in patients with acute lymphocytic leukemia and is given in combination with MTX for this purpose.Adverse Effects:Well tolerate.Myelosuppression is generally mild
30、with thioguanine.Long-term mercaptopurine use may cause hepatotoxicity.AntimetabolitesPyrimidine Antagonists5-Fluorouracil(5-FU)Mechanism of Action：Fluorouracil is an analogue of thymine in which the methyl group is replaced by a fluorine atom.It has two active metabolites:5-FdUMP and 5-FdUTP.5-FdUM
31、P inhibits thymidylate synthetases and prevents the synthesis of thymidine,a major building block of DNA.5-FdUTP is incorporated into RNA by RNA polymerase and interferes with RNA function.AntimetabolitesPyrimidine Antagonists5-Fluorouracil(5-FU)Indications：Fluorouracil is exclusively used to treat
32、solid tumors,especially breast,colorectal,and gastric tumors and squamous cell tumors of the head and neck.AntimetabolitesPyrimidine Antagonists5-Fluorouracil(5-FU)Adverse Effects：Fluorouracil may cause nausea and vomiting,myelosuppression,and oral and gastrointestinal ulceration.Nausea and vomittin
33、g are usually mild.With fluorouracil,myelosuppression is more problematic after bolus injections,whereas mucosal damage is dose-limiting with continuous infusions.AntimetabolitesPyrimidine AntagonistsCytarabineIndications：Cytarabine has a narrow clinical spectrum and is primarily used in combination
34、 with daunorubicin or thioguanine for the treatment of acute nonlymphocytic leukemia.Adverse Effects:High doses of cytarabine can damage the liver,heart,andother organs.AntibioticsClassification of Antibiotics:Adriamycin(Anthracyaline Antibiotics)Mitomycin CBleomycinActinomycin DAntibioticsAdriamyci
35、n and Daunorubicin：Properties:Adriamycin and Daunorubicin are tetracycline rings with the sugar daunosamine.They are DNA intercalating agents that block the synthesis of DNA and RNA.These agents are primarily toxic during the S phase of cell cycle.These agents imparts a red tinge to the urine.Adramy
36、cin is used to treat acute leukemias,lymphoma,and a number of solid tumors.AntibioticsMitomycin C:Mechanism:Mitomycin C is an antineoplastic antibiotic that alkylates DNA and thereby causes strand breakage and inhibition of DNA synthesis.Indications:It is primarily used in combination with vinvristi
37、ne as salvage therapy for breast cancer.Adverse Effects:Mitomycinproducesdelaysandprolongedmyelosuppressionthatpreferentiallyaffectsplatelets and leukocytes.AntibioticsActinomycin D:Actinomycin D intercalates DNA and thereby prevents DNA transcription and messenger RNA synthesis.The drug is given in
38、travenously,and its clinical use is limited to the treatment of trophoblastic(gestational)tumors and the treatment of pediatric tumors,such as Wilms tumor and Ewings sarcoma.AntibioticsBleomycin:Mechanism:The drug has its greatest effect on neoplastic cell in the G2 phase of the cell replication cyc
39、le.Although bleomycin intercalates DNA,the major cytotoxicity is believed to result from ironcatalyzed free radical formation and DNA strand breakage.Indications:It is useful in Hodgkins and non-Hodgkins lymphomas,testicular cancer,and several other solid tumors.Adverse Effects:Bleomycin produces ve
40、ry little myelosuppression.ThemostserioustoxicitiesofBleomycinarepulmonary and mucocutaneous reactions.Anti-Cancer Plant Allaloids Tubulin-Binding AgentsVinca Alkaloids:The cellular mechanism of action of vinca alkaloids is the prevention of microtubule assembly,causing cells to arrest in the late G
41、2 phase by preventing formation of mitotic filaments for nuclear and cell division.Anti-Cancer Plant Allaloids Tubulin-Binding Agents Vinca alkaloids:Vinblastine,vincristin,vindesine and vinorelbine are all alkaloids derived from the periwinkle plant(Vinca rosea).Indications:Vinblastine is used in c
42、ombination with Bleomycin and Cisplatin for metastatic testicular tumors.Vincristine is used in combination with prednisone to induce remission in childhood leukemia.Vinorelbine is used to treat non-small-cell lung cancer and breast cancer.Anti-Cancer Plant Allaloids Tubulin-Binding Agents Paclitaxe
43、l:Taxanes enhance all aspects of tubulin polymerization,an action that is the opposite to that of vinca alkaloids,but they are also cytotoxic,emphasizing the dynamic importance of tubulin polymerization as a target for cytotoxic drugs.Paclitaxel,TaxotereAnti-Cancer Plant AllaloidsInterfere the Funct
44、ion of Ribosome:Cephalotaxus Alkaloids:HarringtonineHomoharringtoninePlatinum CompoundCisplatin:Mechanism of Action:Cisplatin binds to guanine in DNA and RNA,and the interaction is stabilized by hydrogen bonding.The molecular mechanism of action is unwinding and shortening of the DNA helix.Platinum
45、CompoundCisplatin:Indications:Cisplatin has efficacy against a wide range of neoplasms.It is given intravenously as a first-line drug for testicular,ovarian,and bladder cancer,and it is also useful in the treatment of melanoma and a number of other soild tumors.Adverse Effect:Cisplatin produces rela
46、tively little myelosuppression but can cause severe nausea,vomiting,and nephrotoxicity.Platinum CompoundCarboplatin:Indication:Carboplatin has a similar spectrum of activity,but it is approved only as a second-line drug for ovarian cancer.Hormones Several types of hormone-dependent cancer(especially
47、 breast,prostate,and endometrial cancer)respond to treatment with their corresponding hormone antagonists.Estrogen antagonists are primarily used in the treatment of breast cancer,whereas androgen antagonists are used in the treatment of prostate cancer.Corticosteroids are particularly useful in tre
48、ating lymphocytic leukemias and lymphomas.HormonesAntiestrogen:Tamoxifen Tamoxifen is the drug of choice in postmenopausal women with or recovering from metastatic breast cancer.It is most effective in patients who have estrogen receptor-positive tumors.Tamoxifen is also used as adjunvctive therapy
49、to oophorectomy to leuprolide or goserelin in premenopausal women with estrogen receptor-positive tumors.HormonesGlucocorticoids:They are integral components of curative therapy for acute lymphoblastic leukemia,non-Hodgkins lymphoma,and Hodgkins disease.Glucocorticoids have essential roles in the pr
50、evention of allergic reaction,emesis control,relief of intracranial hypertension or spinal cord compression in neurologic complications,and pain relief.Types of molecular targeted agents Tyrosine kinase inhibitorsIressaEFGR inhibitorTacevaEFGR inhibitorGleevecbcr/abl inhibitor Monoclonal antibodiesH