9 Tumor+Chemotherapy English +Version Imp

  • 3,504 views
Uploaded on

 

  • Full Name Full Name Comment goes here.
    Are you sure you want to
    Your message goes here
    Be the first to comment
No Downloads

Views

Total Views
3,504
On Slideshare
0
From Embeds
0
Number of Embeds
0

Actions

Shares
Downloads
239
Comments
0
Likes
4

Embeds 0

No embeds

Report content

Flagged as inappropriate Flag as inappropriate
Flag as inappropriate

Select your reason for flagging this presentation as inappropriate.

Cancel
    No notes for slide
  • 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.
    • 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!