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9   Tumor+Chemotherapy English  +Version Imp
9   Tumor+Chemotherapy English  +Version Imp
9   Tumor+Chemotherapy English  +Version Imp
9   Tumor+Chemotherapy English  +Version Imp
9   Tumor+Chemotherapy English  +Version Imp
9   Tumor+Chemotherapy English  +Version Imp
9   Tumor+Chemotherapy English  +Version Imp
9   Tumor+Chemotherapy English  +Version Imp
9   Tumor+Chemotherapy English  +Version Imp
9   Tumor+Chemotherapy English  +Version Imp
9   Tumor+Chemotherapy English  +Version Imp
9   Tumor+Chemotherapy English  +Version Imp
9   Tumor+Chemotherapy English  +Version Imp
9   Tumor+Chemotherapy English  +Version Imp
9   Tumor+Chemotherapy English  +Version Imp
9   Tumor+Chemotherapy English  +Version Imp
9   Tumor+Chemotherapy English  +Version Imp
9   Tumor+Chemotherapy English  +Version Imp
9   Tumor+Chemotherapy English  +Version Imp
9   Tumor+Chemotherapy English  +Version Imp
9   Tumor+Chemotherapy English  +Version Imp
9   Tumor+Chemotherapy English  +Version Imp
9   Tumor+Chemotherapy English  +Version Imp
9   Tumor+Chemotherapy English  +Version Imp
9   Tumor+Chemotherapy English  +Version Imp
9   Tumor+Chemotherapy English  +Version Imp
9   Tumor+Chemotherapy English  +Version Imp
9   Tumor+Chemotherapy English  +Version Imp
9   Tumor+Chemotherapy English  +Version Imp
9   Tumor+Chemotherapy English  +Version Imp
9   Tumor+Chemotherapy English  +Version Imp
9   Tumor+Chemotherapy English  +Version Imp
9   Tumor+Chemotherapy English  +Version Imp
9   Tumor+Chemotherapy English  +Version Imp
9   Tumor+Chemotherapy English  +Version Imp
9   Tumor+Chemotherapy English  +Version Imp
9   Tumor+Chemotherapy English  +Version Imp
9   Tumor+Chemotherapy English  +Version Imp
9   Tumor+Chemotherapy English  +Version Imp
9   Tumor+Chemotherapy English  +Version Imp
9   Tumor+Chemotherapy English  +Version Imp
9   Tumor+Chemotherapy English  +Version Imp
9   Tumor+Chemotherapy English  +Version Imp
9   Tumor+Chemotherapy English  +Version Imp
9   Tumor+Chemotherapy English  +Version Imp
9   Tumor+Chemotherapy English  +Version Imp
9   Tumor+Chemotherapy English  +Version Imp
9   Tumor+Chemotherapy English  +Version Imp
9   Tumor+Chemotherapy English  +Version Imp
9   Tumor+Chemotherapy English  +Version Imp
9   Tumor+Chemotherapy English  +Version Imp
9   Tumor+Chemotherapy English  +Version Imp
9   Tumor+Chemotherapy English  +Version Imp
9   Tumor+Chemotherapy English  +Version Imp
9   Tumor+Chemotherapy English  +Version Imp
9   Tumor+Chemotherapy English  +Version Imp
9   Tumor+Chemotherapy English  +Version Imp
9   Tumor+Chemotherapy English  +Version Imp
9   Tumor+Chemotherapy English  +Version Imp
9   Tumor+Chemotherapy English  +Version Imp
9   Tumor+Chemotherapy English  +Version Imp
9   Tumor+Chemotherapy English  +Version Imp
9   Tumor+Chemotherapy English  +Version Imp
9   Tumor+Chemotherapy English  +Version Imp
9   Tumor+Chemotherapy English  +Version Imp
9   Tumor+Chemotherapy English  +Version Imp
9   Tumor+Chemotherapy English  +Version Imp
9   Tumor+Chemotherapy English  +Version Imp
9   Tumor+Chemotherapy English  +Version Imp
9   Tumor+Chemotherapy English  +Version Imp
9   Tumor+Chemotherapy English  +Version Imp
9   Tumor+Chemotherapy English  +Version Imp
9   Tumor+Chemotherapy English  +Version Imp
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9 Tumor+Chemotherapy English +Version Imp

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  • electrophiles
  • 2 2 Simplified diagram of the EGFR pathway consisting of the EGFR signal transduction cascade, and cellular effects of stimulation through the EGFR. 5 The ligand binding site serves as the receptor for ligands such as EGF and TGF-  Upon ligand binding, subsequent receptor signaling, including autophosphorylation of the receptor and phosphorylation of target proteins, occurs downstream in the signal transduction cascade. 2 • EGFR is expressed in a significant percentage of human tumors. Expression has been correlated with poor prognosis, decreased survival, and/or increased metastases. 2 • EGFR plays a critical role in cellular growth, repair, and survival and has been demonstrated to function as a key pathway for the regulation of growth in many tumor types. 2 • Current therapies have significant therapeutic and safety limitations in the management of solid tumors. The use of EGFR targeted therapy is a potentially important addition to standard anticancer therapy. 2 • It has been postulated that EGFR inhibitors may synergize with radiation and certain chemotherapeutic agents, possibly through apoptotic, antiangiogenic, and/or cell cycle effects. 2
  • Transcript

    • 1. Tumor Chemotherapy Sun Yet-san University Cancer Center Rui-Hua Xu, Zhi-Ming Li E-mail: xurh@mail.sysu.edu.cn [email_address] Tel: 8734 3356
    • 2. <ul><li>Tumor chemotherapy? </li></ul><ul><li>1.Know about it . </li></ul><ul><li>2.Just heard. </li></ul><ul><li>3.Never heard. </li></ul>Survey
    • 3. Definition <ul><li>√ Tumor chemotherapy </li></ul><ul><ul><li>A systemic therapy, kill cancer cells with anticancer drugs . </li></ul></ul><ul><ul><li>Narrow-sense : cytotoxic drugs </li></ul></ul><ul><ul><li>Broad-sense : medical oncology ( chemotherapy, endocrine therapy, immunotherapy etc. ) </li></ul></ul>
    • 4. Basic theories of chemotherapy <ul><li>History of chemotherapy and the role it plays in the cancer treatment </li></ul><ul><li>Tumor cell cycle kinetics </li></ul><ul><li>Classification and mechanism of anticancer drugs </li></ul><ul><li>Adverse effects of anticancer drugs </li></ul><ul><li>Clinical application of chemotherapy </li></ul>
    • 5. Development of Chemo-drugs Nitrogen Mustard for lymphoma 40s 50s MTX for hematological malignancies & children’s ALL 70s DDP 、 ADM—palliative chemotherapy transition to curative chemotherapy, medical oncology established 80s Adjuvant/Neo-adjuvant chemotherapy 90s 21 st Biological Response Modifier , supportive care , High dose chemotherapy + HSCT Molecular target drug
    • 6. Milestones of anticancer therapy <ul><li>The latter half of the 20th century </li></ul><ul><li>Cytotoxic drugs took the predominant position with a continuous appearance of new agents. </li></ul><ul><li>The late 19th century ~ 21st century </li></ul><ul><li>Cytotoxic drugs kept developing </li></ul><ul><li>Molecular target drugs </li></ul><ul><li>Biotherapy and gene therapy develop rapidly </li></ul>
    • 7. Achievements of chemotherapy <ul><li>A. Several diseases may be cured from incurable </li></ul><ul><li>diseases : Lymphoma, testicular cancer, acute lymphocytic leukemia, chorio carcinoma, etc . </li></ul><ul><li>B. Solid tumor’s palliative chemotherapy is still unsatisfied, but keeps improving : Breast cancer, NSCLC, gastric cancer, colon cancer, NPC, etc. </li></ul><ul><li>C. Adjuvant chemotherapy reduces the relapse rate and improve the efficacy: Breast cancer, colorectal cancer, NSCLC, osteosarcoma, etc. </li></ul><ul><li>D. Neo-adjuvant chemotherapy increase resection rate, reduce disability: breast cancer, rectal cancer, Laryngeal cancer,etc. </li></ul>Comparison of children’s ALL Hodgkin’ Lymphoma Testicular tumor 100 80 60 40 20 0 0 6 12 18 CT BSC Chemotherapy of Advanced NSCLC Progress of mCRC BSC 1980s 5-FU/LV 1990s 5-FU/LV Civ 1990s 5-FU/LV/Irino 2000 5-FU/LV/Oxal 2000 FOLFOX/ FOLFIRI FUFOX 200 1 FOLFOX/IRI+Target Therapy 2004 Adjuvant chemotherapy of breast cancer Adjuvant chemotherapy of NSCLC MOSAIC trial for CRC Adjuvant chemotherapy of colorectal cancer
    • 8. Basic theories of chemotherapy <ul><li>History of chemotherapy and the role it plays in the cancer treatment </li></ul><ul><li>Tumor cell cycle kinetics </li></ul><ul><li>Classification and mechanism of anticancer drugs </li></ul><ul><li>Adverse effects of anticancer drugs </li></ul><ul><li>Clinical application of chemotherapy </li></ul>
    • 9. <ul><li>Tumor </li></ul><ul><li>Body Drug </li></ul>
    • 10. <ul><li>Tumor </li></ul><ul><li>Body Drug </li></ul>
    • 11. Cell cycle kinetics <ul><li>Cell cycle G1 DNA pre-synthetic phase </li></ul><ul><li>S DNA synthetic phase </li></ul><ul><li>G2 DNA post synthetic phase </li></ul><ul><li>M mitotic phase </li></ul>Cells without proliferation ability G0 ( resting phase ) Death Cells in proliferation cycle Refers to a process from the former ending of mitosis to the next ending. Regulated by cyclins ( CKDs 、 CDKIs ) G1 M G2 S
    • 12. Tumor biology — growth kinetics <ul><li>Non-proliferation group Proliferation group </li></ul>cells without proliferation capacity G0 ( quiescent cell ) √ Growth fraction ( GF ) : The percentage of the cells in active proliferation phase in total cells. Growth part
    • 13. Tumor biology — growth kinetics <ul><li>Different types of tumor cells have different GF </li></ul><ul><li>The higher the GF , the more sensitive tumor to chemotherapy, it will be much easier to cure the tumor. (Lymphoma’s GF is 90% ) </li></ul><ul><li>Effective treatment decreases the number of proliferating cells , but cells in G 0 phase may re-enter the proliferation phase that causes the tumor relapse. </li></ul>
    • 14. Tumor biology - growth kinetics <ul><li>Doubling time </li></ul><ul><li>(DT): The time tumor cells need to increase twice of the total amount and volume </li></ul>Normal cell Dividing Malignant transformation 2 cancer cells Doubling 4 cells Doubling 8 cells Doubling 16 cells 1 million cells (20 doublings) undetectable 1 billion cells (30 doublings) lump appears 1 trillion cells (40 doublings – 2 lb/1kg) 41 – 43 doublings — Death
    • 15. 时间 指数生长 癌瘤 正常 细胞产生 = 细胞丢失 稳定态 Gompertzian 生长 对数细胞数 时间 指数生长 癌瘤 正常 细胞产生 = 细胞丢失 稳定态 Gompertzian 生长 对数细胞数 时间 指数生长 癌瘤 正常 细胞产生 = 细胞丢失 稳定态 Gompertzian 生长 对数细胞数 Time Exponential Growth tumor normal cell produce=cell loss Stable state Gompertzian growth cell produce > cell loss l Log of Cells
    • 16. Tumor biology—loss of tumor cells <ul><li>Lack of blood supply, offspring cells’ genetic variation, cells shedding from the surface of tumor—loss of tumor cells. </li></ul><ul><li>Unlike the normal tissue, tumor’s growth always exceeding its loss , which leads to tumor progression. </li></ul><ul><li>Severity of tumor loss various in different types of tumor. The more it loss, the slower it grows and vice versa. </li></ul>
    • 17. <ul><li>Tumor </li></ul><ul><li>Body Drug </li></ul>
    • 18. Tumor biology Total kill <ul><li>“ To cure cancer patient, we must eliminate all the tumor cells in the body”—the important basic theory of curative chemotherapy. </li></ul><ul><li>Anticancer drugs kill tumor cells followed the “first order kinetics” : kill a proportion, not a number of tumor cells each time. So multiple courses are needed to kill the tumor. </li></ul><ul><li>Clinical complete remission does not equal to cure. </li></ul>10 12 10 6 10 12 10 11 10 10 10 9 10 8 10 7 10 6 Anticancer drug’s killing kinetics The number of tumor cells in vivo 10 12 ( 1kg) 10 9 ( 1g) 10 6 ( 1mg) 10 3 ( 1ug) 1 Clinical detection Clinical cure Host immune clearance Induce Consolidation Maintenance Cure Tumor reaction to anticancer drugs
    • 19. Complexity of tumor’s drug resistance <ul><li>Pseudo-resistance : Blood-brain Barrier 、 Blood-testis barrier </li></ul><ul><li>Tumor biology </li></ul><ul><li>MDR </li></ul><ul><li>Congenital Interstitial pressure </li></ul><ul><li>Hypoxia </li></ul><ul><li>Tumor </li></ul><ul><li>factors </li></ul><ul><li>Goldie-Coldman </li></ul><ul><li>Acquired Simon-Norton </li></ul><ul><li>True resistance MDR </li></ul><ul><li>Tumor heterogeneity </li></ul><ul><li>Body factors : Drug targeting enzyme, </li></ul><ul><li>metabolic enzyme </li></ul>Tumor drug resistance
    • 20. Tumor multiple drug resistance (MDR) <ul><li>MDR : </li></ul><ul><ul><li>Def : When it resists to one anticancer drug, tumor cells will show cross resistance to many other types of drugs , not only those shared similar mechanism. </li></ul></ul><ul><ul><li>Often seen in those naturally originated drugs, like the botanical alkaloids and antibiotics. </li></ul></ul>
    • 21. Mechanism of MDR <ul><li>Extra cellular Intracellular </li></ul>ATP P-glycoprotein 170 ATP Drug Drug Cell membrane
    • 22. NEJM 2003 348:538-549 Target enzyme and efficacy of anticancer drug
    • 23. Clin Cancer Res 4139 2006;12(14) July 15, 2006
    • 24. Basis theories of chemotherapy <ul><li>History of chemotherapy and the role it plays in the cancer treatment </li></ul><ul><li>Tumor cell cycle kinetics </li></ul><ul><li>Classification and mechanism of anticancer drugs </li></ul><ul><li>Adverse effect of anticancer drugs </li></ul><ul><li>Clinical application of chemotherapy </li></ul>
    • 25. <ul><li>Tumor </li></ul><ul><li>Body Drug </li></ul>
    • 26. Drug <ul><li>Classification : </li></ul><ul><ul><li>(1) According to cell cycle: </li></ul></ul><ul><ul><li>Cell cycle non-specific agents </li></ul></ul><ul><ul><li>2. Cell cycle specific agents </li></ul></ul>
    • 27. Cell cycle non-specific agents 100 S 细 胞 存 活 R 率 % 剂量 S: Slow growth (normal cell) R: Rapid growth (tumor cell)
    • 28. Cell cycle specific agents 100 S 细 胞 存 活 R 率 % 剂量 S: Slow growth (normal cell) R: Rapid growth (tumor cell)
    • 29. The connection of anticancer drug’s effect and cell cycle <ul><li>Antimetabolite </li></ul><ul><li>Antibiotic </li></ul>S (2-6h) G 2 (2-32h) M (0.5-2h) Alkylating agent G 1 (2-  h) G 0 Vinblastine Anti-mitosis drugs Taxoids
    • 30. Classification of anticancer drugs <ul><li>(2) According to mechanism : </li></ul><ul><ul><ul><li>Alkylating agent </li></ul></ul></ul><ul><ul><ul><li>Antimetabolite </li></ul></ul></ul><ul><ul><ul><li>Antibiotic </li></ul></ul></ul><ul><ul><ul><li>Tubulin inhibitor </li></ul></ul></ul><ul><ul><ul><li>Topoisomerase inhibitor </li></ul></ul></ul><ul><ul><ul><li>Hormones </li></ul></ul></ul><ul><ul><ul><li>Molecular target drug </li></ul></ul></ul>
    • 31. Alkylating agent <ul><li>Nitrogen mustards : HN2 、 CTX , IFO , chlorambucil ( leukeran ), L-PAM( Melphalan ) </li></ul><ul><li>Nitrosoureas : CCNU , BCNU , Me-CCNU </li></ul><ul><li>Alkyl sodium sulfonate : myleran </li></ul><ul><li>Triazine : DTIC </li></ul><ul><li>Ethyleneimine : TSPA </li></ul><ul><li>Metallic salts : cisplatine , carboplatine , </li></ul><ul><li>oxaliplatine </li></ul>
    • 32. Alkylating agent <ul><li>Mechanism : </li></ul><ul><li>Alkylating agent has active R-CH2- , it forms a cross linking with DNA molecular or between DNA molecular and protein by foralkylation, which causes cell death 、 gene mutation or carcinogenesis. </li></ul><ul><li>Destroy DNA structure directly, has strong toxicity to both proliferate or non-proliferate cells — Cell cycle non-specific agents </li></ul><ul><li>Important to the slow growth tumor , with precipitous dose-response curve. </li></ul>DNA double strands inhibit DNA replication C+ C+
    • 33. Alkylating agent Cyclophosphamide <ul><li>CTX </li></ul>4-OH CTX aldophosphamide phospho ramide mustard 4-keto cyclophosphamide Carboxyl phosphamide Acrolein Hepatic Cytochrome P 450 activated Cell toxicity Toxicity inactivate Acetaldehyde dehydrogenase
    • 34. Platinum drugs Pt(II) NH 3 NH 3 Pt(II) NH 3 NH 3 + 2H 2 O Cisplatin Reactive complex + 2Cl - Pt G G Cl Cl H 2 O + H 2 O + DNA Strand
    • 35. Platinum drugs <ul><li>DDP side effects : </li></ul><ul><li>Kidney toxicity ( dose limiting): Mainly causes the renal tubular damage. Large dose usage needs hydration and diuresis. </li></ul><ul><li>Severe vomiting , but less myelosuppression. </li></ul><ul><li>Ototoxicty and peripheral neurotoxicity. </li></ul><ul><li>Indication : common used broad-spectrum anticancer drug , important composition in many combination chemotherapies. </li></ul>
    • 36. Anti-metabolite anticancer drugs <ul><li>folic acid antagonist : MTX </li></ul><ul><li>miazines : 5-Fu , fluorofur , </li></ul><ul><li>furtuion , Capacitabine </li></ul><ul><li>cytidine : Ara-C , Gemcitabine </li></ul><ul><li>purines : 6-MP , 6-TG </li></ul>
    • 37. Anti-metabolite anticancer drugs <ul><li>Mechanism </li></ul><ul><ul><li>-Has similar structure to the normal metabolites, competitively </li></ul></ul><ul><ul><li>inhibits the main enzymes of nucleic acid metabolism </li></ul></ul><ul><ul><li>and replace the precursor materials for DNA or RNA synthesis, </li></ul></ul><ul><ul><li>thus affect DNA synthesis </li></ul></ul><ul><ul><li>-- Interference with nucleic acid synthesis, most effective in </li></ul></ul><ul><ul><li>Phase S — cell cycle specific , little effect on non-proliferating </li></ul></ul><ul><ul><li>cells </li></ul></ul><ul><li>-- The curve flattened when dose increased. No effect on stem </li></ul><ul><li>cells, short and slight myelosuppression </li></ul>
    • 38. Anti-metabolite anticancer drugs Dihydrofolate Reductase METHOTREXATE (MTX) FH 2 FH 4 Uracil + N 5-10 methylene FH 4 deoxynucleotide ( dUMP ) 5- fluorouracil (5-FU) Purine Nucleotide thymidine deoxynucleotide (dTMP) Thymidylate Synthase (TS) fluorouracil deoxynucleotide ( F dUMP ) DNA DNApolymerase Cytarabine (Arac) Gemcitabine 6MP 、 6TG
    • 39. Antibiotic anticancer drugs Double strand dissociation Interfere DNA transcription and mRNA synthesis Anthracycline antibotics insert to the base pair near the DNA double strand
    • 40. Antibiotic anticancer drugs <ul><li>Side effects of anthracycline : cardiac toxicity (dose-limiting toxicity) </li></ul><ul><li>Cumulative dose of doxorubicin incidence of congestive heart failure </li></ul><ul><li>450-550mg/ M 2 1-2% </li></ul><ul><li>550mg/ M 2 1-4% </li></ul><ul><li>600mg/ M 2 30% </li></ul><ul><li>With a history of mediastinal radiotherapy or hypertension, the application of CTX will increase the cardiac toxicity. </li></ul><ul><li>Monitoring Methods: cardiac nuclide scan or cardiac ultrasound to observe the changes of left ventricular ejection index. </li></ul>
    • 41. Antibiotic anticancer drugs <ul><li>Others: dactinomycin, bleomycin, mitomycin </li></ul><ul><li>Bleomycin may cause the pulmonary fibrosis, the cumulative dose </li></ul>
    • 42. Tubulin inhibitor <ul><li>Vinblastine category </li></ul><ul><ul><li>Antimitotic —binding with tubulin , block tubulin polymerization , stop the cell mitosis at the mid phase. </li></ul></ul><ul><ul><li>Include : Vinblastine, Vincristine, Vindesine,etc . </li></ul></ul><ul><ul><li>Common side effects are bone marrow toxicity and neurotoxicity </li></ul></ul><ul><li>Taxadiene category : </li></ul><ul><li>: </li></ul><ul><ul><li>Antimitotic - block tubulin depolymerization , interfere with mitosis </li></ul></ul><ul><ul><li>Include : Taxol, Taxotere </li></ul></ul><ul><ul><li>Side effects : allergy, bone marrow suppression, neurotoxicity, hair loss, etc. </li></ul></ul>
    • 43. Tubulin inhibitor Interfere tubulin polymerization : colchicine Vinblastine block tubulin depolymerization : Taxoids tubulin tubule 20nm  
    • 44. Anti-mitosis anticancer drugs <ul><li>Centromere </li></ul><ul><li>Soluble tubulin dimer </li></ul><ul><li>Nuclear membrane fragments </li></ul>Taxoids Promote tubulin polymerization Prevent tubulin depolymerization Vinblastine inhibit spindle fibers’ formation Prometaphase of mitosis
    • 45. Topoisomerase inhibitors <ul><li>Topoisomerase I inhibitors : camptothecin: </li></ul><ul><li>CPT-11, Topotecan </li></ul><ul><li>Break the DNA single strand, interfere DNA replication </li></ul><ul><li>Side effects : CPT-11 causes acetylcholine syndrome, delayed diarrhea, nausea, vomiting, bone marrow suppression </li></ul><ul><li>Indication : colon cancer, SCLC, ovarian cancer </li></ul>
    • 46. Topoisomerase inhibitors <ul><li>Topoisomerase II inhibitors : etoposide : teniposide </li></ul><ul><li>B reak the double strands of DNA, interfere with DNA replication </li></ul><ul><li>The main toxicity is myelosuppression, transient hypotension may occur during rapid infusion . </li></ul><ul><li>Indication : broad-spectrum anti-cancer drugs , testicular tumor, SCLC, refractory NHL </li></ul>
    • 47. Topoisomerase <ul><li>Cells in S-phase </li></ul>DNA DNA replication DNA rotating along its axis interfere DNA replication Double-strand torsion increased
    • 48. Topoisomerase Attached double-stranded DNA , cut through the DNA strand transiently , the torsion disappeared , then catch the rotated DNA again , re-adhesion the DNA strand
    • 49. Topoisomerase I inhibitors Topoisomerase I inhibitors combined with TOPO I-DNA complex
    • 50. Topoisomerase I inhibitors combination of replication fork & Breaking of DNA single strand Interruption of the cell cycle Cell death
    • 51. Mechanism of anticancer drugs
    • 52. Molecular target drugs <ul><li>Specifically act on the key molecular in cancer cells’ lives 、 proliferation 、 invasion and metastasis. (High selectivity ) </li></ul><ul><li>Broad targeting: cell membrane antigen, EGFR, VEGFR, tyrosine kinase, Farnesyltransferase ... ... </li></ul><ul><li>Various of structures: small-molecule compounds, monoclonal antibodies (anti-rat, chimeric, humanized), antisense oligonucleotide , natural products; low toxicity, cooperate with chemotherapy, radiotherapy </li></ul>
    • 53. Common target drugs Name Trade name Main targets Structure Indication Imatinib Gleeve Bcr/Abl, c-kit, PDEFR Small Molecule Compounds CML GIST Retuximab MabThera CD-20( B limphocyte) Chimeric Antibody NHL Transtuzumab Herceptin HER2/neu Human antibody Breast cancer Gefitinib Iressa EGFR-TK Small Molecule Compounds NSCLC Cetuximab Erbitux EGFR Chimeric Antibody Colorectal, head & neck Erlotinib Tarceva EGFR-TK Small Molecule Compounds 非小细胞肺癌 NSCLC Bevacizumab Avastin VEGF Human antibody Colorectal Ca
    • 54. Gefitinib erlotinib Anti-EGFR 2: Herceptin Anti-EGFR 1: Cetuximub
    • 55. Basis theories of chemotherapy <ul><li>History of chemotherapy and the role it plays in the cancer treatment </li></ul><ul><li>Tumor cell cycle kinetics </li></ul><ul><li>Classification and mechanism of anticancer drugs </li></ul><ul><li>Adverse effect of anticancer drugs </li></ul><ul><li>Clinical application of chemotherapy </li></ul>
    • 56. <ul><li>Tumor </li></ul><ul><li>Body Drug </li></ul>
    • 57. Adverse effect of anticancer drugs <ul><li>Short term </li></ul><ul><ul><li>Generality </li></ul></ul><ul><ul><ul><li>① Myelosuppression suppression </li></ul></ul></ul><ul><li>Individuality </li></ul><ul><ul><ul><li>② Gastrointestinal-tract side effect </li></ul></ul></ul><ul><ul><ul><li>③ Hair loss </li></ul></ul></ul><ul><ul><ul><li>④ Local stimulation ( drug extravasation ) </li></ul></ul></ul><ul><ul><ul><li>⑤   Allergic Reaction </li></ul></ul></ul><ul><ul><ul><li>① Cardiac toxicity </li></ul></ul></ul><ul><ul><ul><li>② Lung toxicity </li></ul></ul></ul><ul><ul><ul><li>③ Neurological toxicity </li></ul></ul></ul><ul><ul><ul><li>④ Liver toxicity </li></ul></ul></ul><ul><ul><ul><li>⑤ Kidney toxicity </li></ul></ul></ul><ul><ul><li>Leukopenia: infection (anti-bacterial treatment and the application of G-CSF) </li></ul></ul><ul><ul><li>Erythrocytopenia: anemia (RBC infusion and the application of Epo) </li></ul></ul><ul><ul><li>Thrombocytopenia: haemorrhage (platelet infusion and the application of TPO) </li></ul></ul><ul><ul><li>Nausea, vomiting :5-HT3 receptor antagonist </li></ul></ul><ul><ul><li>Oral Ulcer: mouthwash, anti-bacterial treatment </li></ul></ul><ul><ul><li>Diarrhea, abdominal pain: anti-bacterial treatment, water-electrolyte balance </li></ul></ul>
    • 58. Adverse effect of anticancer drugs <ul><li>Long term </li></ul><ul><li>⑴ Carcinogenesis ⑵ Infertility (3) Growth retardation </li></ul>
    • 59. Basis theories of chemotherapy <ul><li>History of chemotherapy and the role it plays in the cancer treatment </li></ul><ul><li>Tumor cell cycle kinetics </li></ul><ul><li>Classification and mechanism of anticancer drugs </li></ul><ul><li>Adverse effect of anticancer drugs </li></ul><ul><li>Clinical application of chemotherapy </li></ul>
    • 60. Clinical application of chemotherapy goals of chemotherapy <ul><li>Curative Chemotherapy </li></ul><ul><li>Adjuvant Chemotherapy </li></ul><ul><li>Neoadjuvant Chemotherapy </li></ul><ul><li>Palliative Chemotherapy </li></ul><ul><li>Investigative Chemotherapy </li></ul>√ √ √ √ √
    • 61. Clinical application—curative chemotherapy <ul><li>Tumors can be cured by chemotherapy : </li></ul><ul><li>Acute leukemia, non-Hodgkin's lymphoma, HD, testicular germ cell cancer, ovarian cancer, child nephroblastoma, embryonal rhabdomyosarcoma, Ewing's tumor etc. </li></ul>
    • 62. Clinical application—curative chemotherapy <ul><li>Applicable to those tumors which may be cured by chemotherapy </li></ul><ul><li>Select the recognized standard combination chemotherapy </li></ul><ul><li>Adequate course and full dosages </li></ul><ul><li>Do not arbitrarily extend the intervals of chemotherapy </li></ul><ul><li>Intensive supportive care, prevent and treat the complications of chemotherapy </li></ul>
    • 63. Clinical application—adjuvant chemotherapy <ul><li>Radical surgery, eliminating sub-clinical micro-metastasis, is part of the curative treatment. </li></ul><ul><li>Postoperative chemotherapy should be given as soon as possible </li></ul><ul><li>Choose standard regimens </li></ul><ul><li>Breast cancer , osteosarcoma, lung cancer, colorectal cancer and other solid tumors of children, etc. </li></ul>
    • 64. Clinical application—neo-adjuvant chemotherapy <ul><li>Neo-Adjuvant Chemotherapy before surgery or radiation therapy </li></ul><ul><li>Increase resection rates, reduce the surgical injury, eliminate the sub-clinical metastasis, investigate the body reaction of chemotherapy </li></ul><ul><li>Choose standard regimens </li></ul><ul><li>Suit for the head and neck cancers, rectal cancer, osteosarcoma </li></ul>
    • 65. Clinical application—palliative chemotherapy <ul><li>To relief symptoms , prolong survival, improve quality of life for terminal patients </li></ul><ul><li>Non-curative chemotherapy, must balance the advantages and disadvantages of chemotherapy </li></ul><ul><li>Advanced non-small cell lung cancer, gastric cancer, liver cancer, colorectal cancer, renal cancer, malignant melanoma, pancreatic cancer, etc. </li></ul>
    • 66. Balance of c hemotherapy efficacy and toxicity Efficacy Safety Strategy for the reasonable application of chemotherapy
    • 67. Patient’s survival time and quality of life after treatment
    • 68. Clinical application---- investigative chemotherapy <ul><li>Definition : Clinical investigations of new drugs or new regimens. </li></ul><ul><li>Content : purpose , scheme , observation, evaluation </li></ul><ul><li>Principles: low toxicity, effective and comply with medical ethics </li></ul>
    • 69. Clinical application of chemotherapy —the principle of Rational Drug Use <ul><li>The principle for selecting regimen : standard regimen as first choice . </li></ul><ul><li>Principle of Combination Chemotherapy </li></ul><ul><ul><li>Effective single drug </li></ul></ul><ul><ul><li>Various mechanisms and phases </li></ul></ul><ul><ul><li>Various toxicity </li></ul></ul><ul><ul><li>Proven to be effective in clinical application </li></ul></ul>√
    • 70. Research for enhancing the effect of systemic chemotherapy <ul><li>Development of new cytotoxic drugs </li></ul><ul><li>Application of molecular target drugs </li></ul><ul><li>Raise the dosage of chemotherapy drugs </li></ul><ul><li>Overcome drug-resistance of tumor cells </li></ul><ul><li>Biological Treatment </li></ul><ul><li>Gene Therapy </li></ul>
    • 71. PROGRESS IN MEDICAL ONCOLOGY 1975 -> 2000 -> 2025 MOLECULAR MEDICINE EVIDENCE-BASED MEDICINE SMALL, PILOT TRIALS P R O G R E S S 1975 1980 2000
    • 72. Conclusions <ul><li>Definition of chemotherapy </li></ul><ul><li>Cancer Biology : cell cycle 、 growth fraction(GF) 、 doubling time (DT) </li></ul><ul><li>Classification of anticancer drugs : cycles and mechanism </li></ul><ul><li>Adverse effect of anticancer drugs </li></ul><ul><li>Clinical application of anticancer drugs </li></ul>
    • 73. Thank you!

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