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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
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    • 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.
      • Tumor chemotherapy?
      • 1.Know about it .
      • 2.Just heard.
      • 3.Never heard.
      Survey
    • 3. Definition
      • √ Tumor chemotherapy
        • A systemic therapy, kill cancer cells with anticancer drugs .
        • Narrow-sense : cytotoxic drugs
        • Broad-sense : medical oncology ( chemotherapy, endocrine therapy, immunotherapy etc. )
    • 4. Basic theories of chemotherapy
      • History of chemotherapy and the role it plays in the cancer treatment
      • Tumor cell cycle kinetics
      • Classification and mechanism of anticancer drugs
      • Adverse effects of anticancer drugs
      • Clinical application of chemotherapy
    • 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
      • The latter half of the 20th century
      • Cytotoxic drugs took the predominant position with a continuous appearance of new agents.
      • The late 19th century ~ 21st century
      • Cytotoxic drugs kept developing
      • Molecular target drugs
      • Biotherapy and gene therapy develop rapidly
    • 7. Achievements of chemotherapy
      • A. Several diseases may be cured from incurable
      • diseases : Lymphoma, testicular cancer, acute lymphocytic leukemia, chorio carcinoma, etc .
      • B. Solid tumor’s palliative chemotherapy is still unsatisfied, but keeps improving : Breast cancer, NSCLC, gastric cancer, colon cancer, NPC, etc.
      • C. Adjuvant chemotherapy reduces the relapse rate and improve the efficacy: Breast cancer, colorectal cancer, NSCLC, osteosarcoma, etc.
      • D. Neo-adjuvant chemotherapy increase resection rate, reduce disability: breast cancer, rectal cancer, Laryngeal cancer,etc.
      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
      • History of chemotherapy and the role it plays in the cancer treatment
      • Tumor cell cycle kinetics
      • Classification and mechanism of anticancer drugs
      • Adverse effects of anticancer drugs
      • Clinical application of chemotherapy
    • 9.
      • Tumor
      • Body Drug
    • 10.
      • Tumor
      • Body Drug
    • 11. Cell cycle kinetics
      • Cell cycle G1 DNA pre-synthetic phase
      • S DNA synthetic phase
      • G2 DNA post synthetic phase
      • M mitotic phase
      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
      • Non-proliferation group Proliferation group
      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
      • Different types of tumor cells have different GF
      • The higher the GF , the more sensitive tumor to chemotherapy, it will be much easier to cure the tumor. (Lymphoma’s GF is 90% )
      • 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.
    • 14. Tumor biology - growth kinetics
      • Doubling time
      • (DT): The time tumor cells need to increase twice of the total amount and volume
      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
      • Lack of blood supply, offspring cells’ genetic variation, cells shedding from the surface of tumor—loss of tumor cells.
      • Unlike the normal tissue, tumor’s growth always exceeding its loss , which leads to tumor progression.
      • Severity of tumor loss various in different types of tumor. The more it loss, the slower it grows and vice versa.
    • 17.
      • Tumor
      • Body Drug
    • 18. Tumor biology Total kill
      • “ To cure cancer patient, we must eliminate all the tumor cells in the body”—the important basic theory of curative chemotherapy.
      • 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.
      • Clinical complete remission does not equal to cure.
      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
      • Pseudo-resistance : Blood-brain Barrier 、 Blood-testis barrier
      • Tumor biology
      • MDR
      • Congenital Interstitial pressure
      • Hypoxia
      • Tumor
      • factors
      • Goldie-Coldman
      • Acquired Simon-Norton
      • True resistance MDR
      • Tumor heterogeneity
      • Body factors : Drug targeting enzyme,
      • metabolic enzyme
      Tumor drug resistance
    • 20. Tumor multiple drug resistance (MDR)
      • MDR :
        • 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.
        • Often seen in those naturally originated drugs, like the botanical alkaloids and antibiotics.
    • 21. Mechanism of MDR
      • Extra cellular Intracellular
      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
      • History of chemotherapy and the role it plays in the cancer treatment
      • Tumor cell cycle kinetics
      • Classification and mechanism of anticancer drugs
      • Adverse effect of anticancer drugs
      • Clinical application of chemotherapy
    • 25.
      • Tumor
      • Body Drug
    • 26. Drug
      • Classification :
        • (1) According to cell cycle:
        • Cell cycle non-specific agents
        • 2. Cell cycle specific agents
    • 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
      • Antimetabolite
      • Antibiotic
      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
      • (2) According to mechanism :
          • Alkylating agent
          • Antimetabolite
          • Antibiotic
          • Tubulin inhibitor
          • Topoisomerase inhibitor
          • Hormones
          • Molecular target drug
    • 31. Alkylating agent
      • Nitrogen mustards : HN2 、 CTX , IFO , chlorambucil ( leukeran ), L-PAM( Melphalan )
      • Nitrosoureas : CCNU , BCNU , Me-CCNU
      • Alkyl sodium sulfonate : myleran
      • Triazine : DTIC
      • Ethyleneimine : TSPA
      • Metallic salts : cisplatine , carboplatine ,
      • oxaliplatine
    • 32. Alkylating agent
      • Mechanism :
      • 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.
      • Destroy DNA structure directly, has strong toxicity to both proliferate or non-proliferate cells — Cell cycle non-specific agents
      • Important to the slow growth tumor , with precipitous dose-response curve.
      DNA double strands inhibit DNA replication C+ C+
    • 33. Alkylating agent Cyclophosphamide
      • CTX
      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
      • DDP side effects :
      • Kidney toxicity ( dose limiting): Mainly causes the renal tubular damage. Large dose usage needs hydration and diuresis.
      • Severe vomiting , but less myelosuppression.
      • Ototoxicty and peripheral neurotoxicity.
      • Indication : common used broad-spectrum anticancer drug , important composition in many combination chemotherapies.
    • 36. Anti-metabolite anticancer drugs
      • folic acid antagonist : MTX
      • miazines : 5-Fu , fluorofur ,
      • furtuion , Capacitabine
      • cytidine : Ara-C , Gemcitabine
      • purines : 6-MP , 6-TG
    • 37. Anti-metabolite anticancer drugs
      • Mechanism
        • -Has similar structure to the normal metabolites, competitively
        • inhibits the main enzymes of nucleic acid metabolism
        • and replace the precursor materials for DNA or RNA synthesis,
        • thus affect DNA synthesis
        • -- Interference with nucleic acid synthesis, most effective in
        • Phase S — cell cycle specific , little effect on non-proliferating
        • cells
      • -- The curve flattened when dose increased. No effect on stem
      • cells, short and slight myelosuppression
    • 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
      • Side effects of anthracycline : cardiac toxicity (dose-limiting toxicity)
      • Cumulative dose of doxorubicin incidence of congestive heart failure
      • 450-550mg/ M 2 1-2%
      • 550mg/ M 2 1-4%
      • 600mg/ M 2 30%
      • With a history of mediastinal radiotherapy or hypertension, the application of CTX will increase the cardiac toxicity.
      • Monitoring Methods: cardiac nuclide scan or cardiac ultrasound to observe the changes of left ventricular ejection index.
    • 41. Antibiotic anticancer drugs
      • Others: dactinomycin, bleomycin, mitomycin
      • Bleomycin may cause the pulmonary fibrosis, the cumulative dose
    • 42. Tubulin inhibitor
      • Vinblastine category
        • Antimitotic —binding with tubulin , block tubulin polymerization , stop the cell mitosis at the mid phase.
        • Include : Vinblastine, Vincristine, Vindesine,etc .
        • Common side effects are bone marrow toxicity and neurotoxicity
      • Taxadiene category :
        • Antimitotic - block tubulin depolymerization , interfere with mitosis
        • Include : Taxol, Taxotere
        • Side effects : allergy, bone marrow suppression, neurotoxicity, hair loss, etc.
    • 43. Tubulin inhibitor Interfere tubulin polymerization : colchicine Vinblastine block tubulin depolymerization : Taxoids tubulin tubule 20nm  
    • 44. Anti-mitosis anticancer drugs
      • Centromere
      • Soluble tubulin dimer
      • Nuclear membrane fragments
      Taxoids Promote tubulin polymerization Prevent tubulin depolymerization Vinblastine inhibit spindle fibers’ formation Prometaphase of mitosis
    • 45. Topoisomerase inhibitors
      • Topoisomerase I inhibitors : camptothecin:
      • CPT-11, Topotecan
      • Break the DNA single strand, interfere DNA replication
      • Side effects : CPT-11 causes acetylcholine syndrome, delayed diarrhea, nausea, vomiting, bone marrow suppression
      • Indication : colon cancer, SCLC, ovarian cancer
    • 46. Topoisomerase inhibitors
      • Topoisomerase II inhibitors : etoposide : teniposide
      • B reak the double strands of DNA, interfere with DNA replication
      • The main toxicity is myelosuppression, transient hypotension may occur during rapid infusion .
      • Indication : broad-spectrum anti-cancer drugs , testicular tumor, SCLC, refractory NHL
    • 47. Topoisomerase
      • Cells in S-phase
      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
      • Specifically act on the key molecular in cancer cells’ lives 、 proliferation 、 invasion and metastasis. (High selectivity )
      • Broad targeting: cell membrane antigen, EGFR, VEGFR, tyrosine kinase, Farnesyltransferase ... ...
      • Various of structures: small-molecule compounds, monoclonal antibodies (anti-rat, chimeric, humanized), antisense oligonucleotide , natural products; low toxicity, cooperate with chemotherapy, radiotherapy
    • 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
      • History of chemotherapy and the role it plays in the cancer treatment
      • Tumor cell cycle kinetics
      • Classification and mechanism of anticancer drugs
      • Adverse effect of anticancer drugs
      • Clinical application of chemotherapy
    • 56.
      • Tumor
      • Body Drug
    • 57. Adverse effect of anticancer drugs
      • Short term
        • Generality
          • ① Myelosuppression suppression
      • Individuality
          • ② Gastrointestinal-tract side effect
          • ③ Hair loss
          • ④ Local stimulation ( drug extravasation )
          • ⑤   Allergic Reaction
          • ① Cardiac toxicity
          • ② Lung toxicity
          • ③ Neurological toxicity
          • ④ Liver toxicity
          • ⑤ Kidney toxicity
        • Leukopenia: infection (anti-bacterial treatment and the application of G-CSF)
        • Erythrocytopenia: anemia (RBC infusion and the application of Epo)
        • Thrombocytopenia: haemorrhage (platelet infusion and the application of TPO)
        • Nausea, vomiting :5-HT3 receptor antagonist
        • Oral Ulcer: mouthwash, anti-bacterial treatment
        • Diarrhea, abdominal pain: anti-bacterial treatment, water-electrolyte balance
    • 58. Adverse effect of anticancer drugs
      • Long term
      • ⑴ Carcinogenesis ⑵ Infertility (3) Growth retardation
    • 59. Basis theories of chemotherapy
      • History of chemotherapy and the role it plays in the cancer treatment
      • Tumor cell cycle kinetics
      • Classification and mechanism of anticancer drugs
      • Adverse effect of anticancer drugs
      • Clinical application of chemotherapy
    • 60. Clinical application of chemotherapy goals of chemotherapy
      • Curative Chemotherapy
      • Adjuvant Chemotherapy
      • Neoadjuvant Chemotherapy
      • Palliative Chemotherapy
      • Investigative Chemotherapy
      √ √ √ √ √
    • 61. Clinical application—curative chemotherapy
      • Tumors can be cured by chemotherapy :
      • Acute leukemia, non-Hodgkin's lymphoma, HD, testicular germ cell cancer, ovarian cancer, child nephroblastoma, embryonal rhabdomyosarcoma, Ewing's tumor etc.
    • 62. Clinical application—curative chemotherapy
      • Applicable to those tumors which may be cured by chemotherapy
      • Select the recognized standard combination chemotherapy
      • Adequate course and full dosages
      • Do not arbitrarily extend the intervals of chemotherapy
      • Intensive supportive care, prevent and treat the complications of chemotherapy
    • 63. Clinical application—adjuvant chemotherapy
      • Radical surgery, eliminating sub-clinical micro-metastasis, is part of the curative treatment.
      • Postoperative chemotherapy should be given as soon as possible
      • Choose standard regimens
      • Breast cancer , osteosarcoma, lung cancer, colorectal cancer and other solid tumors of children, etc.
    • 64. Clinical application—neo-adjuvant chemotherapy
      • Neo-Adjuvant Chemotherapy before surgery or radiation therapy
      • Increase resection rates, reduce the surgical injury, eliminate the sub-clinical metastasis, investigate the body reaction of chemotherapy
      • Choose standard regimens
      • Suit for the head and neck cancers, rectal cancer, osteosarcoma
    • 65. Clinical application—palliative chemotherapy
      • To relief symptoms , prolong survival, improve quality of life for terminal patients
      • Non-curative chemotherapy, must balance the advantages and disadvantages of chemotherapy
      • Advanced non-small cell lung cancer, gastric cancer, liver cancer, colorectal cancer, renal cancer, malignant melanoma, pancreatic cancer, etc.
    • 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
      • Definition : Clinical investigations of new drugs or new regimens.
      • Content : purpose , scheme , observation, evaluation
      • Principles: low toxicity, effective and comply with medical ethics
    • 69. Clinical application of chemotherapy —the principle of Rational Drug Use
      • The principle for selecting regimen : standard regimen as first choice .
      • Principle of Combination Chemotherapy
        • Effective single drug
        • Various mechanisms and phases
        • Various toxicity
        • Proven to be effective in clinical application
    • 70. Research for enhancing the effect of systemic chemotherapy
      • Development of new cytotoxic drugs
      • Application of molecular target drugs
      • Raise the dosage of chemotherapy drugs
      • Overcome drug-resistance of tumor cells
      • Biological Treatment
      • Gene Therapy
    • 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
      • Definition of chemotherapy
      • Cancer Biology : cell cycle 、 growth fraction(GF) 、 doubling time (DT)
      • Classification of anticancer drugs : cycles and mechanism
      • Adverse effect of anticancer drugs
      • Clinical application of anticancer drugs
    • 73. Thank you!