Tumor Chemotherapy Sun Yet-san University Cancer Center Rui-Hua Xu, Zhi-Ming Li E-mail: xurh@mail.sysu.edu.cn [email_addre...
<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 ...
Definition <ul><li>√ Tumor chemotherapy </li></ul><ul><ul><li>A  systemic  therapy, kill cancer cells with  anticancer dru...
Basic theories of chemotherapy <ul><li>History of chemotherapy and the role it plays in the cancer treatment </li></ul><ul...
Development of Chemo-drugs Nitrogen Mustard for lymphoma 40s 50s MTX for   hematological malignancies   & children’s ALL 7...
Milestones of anticancer therapy <ul><li>The latter half of the 20th century  </li></ul><ul><li>Cytotoxic drugs   took the...
Achievements of chemotherapy <ul><li>A. Several diseases may be cured from incurable </li></ul><ul><li>diseases   :  Lymph...
Basic theories of chemotherapy <ul><li>History of chemotherapy and the role it plays in the cancer treatment </li></ul><ul...
<ul><li>Tumor </li></ul><ul><li>Body   Drug </li></ul>
<ul><li>Tumor </li></ul><ul><li>Body   Drug </li></ul>
  Cell cycle kinetics <ul><li>Cell cycle   G1  DNA pre-synthetic phase  </li></ul><ul><li>S  DNA  synthetic phase  </li></...
Tumor biology   — growth kinetics   <ul><li>Non-proliferation group  Proliferation group </li></ul>cells without  prolifer...
Tumor biology   — growth kinetics   <ul><li>Different types of tumor cells have different GF </li></ul><ul><li>The higher ...
Tumor biology     -  growth kinetics   <ul><li>Doubling time </li></ul><ul><li>(DT):  The time tumor cells need to increas...
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 ...
Tumor biology—loss of tumor cells <ul><li>Lack of blood supply, offspring cells’ genetic variation, cells shedding from th...
<ul><li>Tumor </li></ul><ul><li>Body  Drug </li></ul>
Tumor biology     Total  kill <ul><li>“ To cure cancer patient, we must eliminate all the tumor cells in the body”—the imp...
Complexity of tumor’s drug resistance <ul><li>Pseudo-resistance : Blood-brain Barrier 、 Blood-testis barrier </li></ul><ul...
Tumor multiple drug resistance (MDR) <ul><li>MDR : </li></ul><ul><ul><li>Def : When it resists to one anticancer drug, tum...
Mechanism of MDR <ul><li>Extra cellular Intracellular </li></ul>ATP P-glycoprotein 170   ATP Drug Drug Cell membrane
NEJM 2003 348:538-549 Target enzyme and  efficacy of anticancer drug
Clin Cancer Res 4139 2006;12(14) July 15, 2006
Basis theories of chemotherapy <ul><li>History of chemotherapy and the role it plays in the cancer treatment  </li></ul><u...
<ul><li>Tumor </li></ul><ul><li>Body   Drug </li></ul>
Drug <ul><li>Classification : </li></ul><ul><ul><li>(1) According to cell cycle: </li></ul></ul><ul><ul><li>Cell cycle non...
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)
Cell cycle specific agents 100  S  细 胞 存 活  R 率 %  剂量  S: Slow growth (normal cell)   R: Rapid growth (tumor cell)
The connection of anticancer drug’s effect and cell cycle <ul><li>Antimetabolite </li></ul><ul><li>Antibiotic </li></ul>S ...
Classification of anticancer drugs <ul><li>(2) According to mechanism : </li></ul><ul><ul><ul><li>Alkylating agent   </li>...
Alkylating agent <ul><li>Nitrogen mustards : HN2 、 CTX , IFO , chlorambucil ( leukeran ), L-PAM( Melphalan ) </li></ul><ul...
Alkylating agent <ul><li>Mechanism : </li></ul><ul><li>Alkylating agent has active  R-CH2- , it forms a cross linking with...
Alkylating agent  Cyclophosphamide <ul><li>CTX </li></ul>4-OH CTX aldophosphamide   phospho ramide mustard   4-keto cyclop...
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 + ...
Platinum drugs <ul><li>DDP  side effects : </li></ul><ul><li>Kidney toxicity ( dose limiting): Mainly causes the renal tub...
Anti-metabolite   anticancer drugs <ul><li>folic acid antagonist   : MTX </li></ul><ul><li>miazines : 5-Fu , fluorofur , <...
Anti-metabolite   anticancer drugs <ul><li>Mechanism </li></ul><ul><ul><li>-Has similar structure to the normal metabolite...
Anti-metabolite   anticancer drugs Dihydrofolate Reductase   METHOTREXATE   (MTX) FH 2 FH 4 Uracil   + N 5-10  methylene F...
Antibiotic anticancer drugs Double strand dissociation Interfere DNA transcription  and mRNA  synthesis Anthracycline  ant...
Antibiotic anticancer drugs <ul><li>Side effects of anthracycline : cardiac toxicity (dose-limiting toxicity)  </li></ul><...
Antibiotic anticancer drugs <ul><li>Others: dactinomycin, bleomycin, mitomycin  </li></ul><ul><li>Bleomycin may cause the ...
Tubulin inhibitor <ul><li>Vinblastine category </li></ul><ul><ul><li>Antimitotic —binding with tubulin ,  block tubulin po...
Tubulin inhibitor Interfere tubulin polymerization   :   colchicine   Vinblastine block tubulin depolymerization   :   Tax...
Anti-mitosis anticancer drugs <ul><li>Centromere   </li></ul><ul><li>Soluble tubulin dimer </li></ul><ul><li>Nuclear membr...
Topoisomerase inhibitors <ul><li>Topoisomerase  I  inhibitors : camptothecin: </li></ul><ul><li>CPT-11, Topotecan  </li></...
Topoisomerase inhibitors <ul><li>Topoisomerase II inhibitors :  etoposide : teniposide </li></ul><ul><li>B reak the double...
Topoisomerase   <ul><li>Cells in S-phase </li></ul>DNA DNA replication DNA rotating  along its axis interfere DNA replicat...
Topoisomerase Attached double-stranded DNA , cut through the DNA  strand transiently , the torsion disappeared , then catc...
Topoisomerase  I  inhibitors Topoisomerase  I  inhibitors combined with TOPO I-DNA  complex
Topoisomerase  I  inhibitors combination of replication fork &  Breaking of DNA single strand  Interruption of the cell cy...
Mechanism of anticancer drugs
Molecular target drugs <ul><li>Specifically act on the key molecular in cancer cells’ lives 、 proliferation 、 invasion and...
Common target drugs Name Trade name Main targets Structure Indication Imatinib Gleeve Bcr/Abl, c-kit, PDEFR Small Molecule...
Gefitinib erlotinib Anti-EGFR 2: Herceptin Anti-EGFR 1: Cetuximub
Basis theories of chemotherapy <ul><li>History of chemotherapy and the role it plays in the cancer treatment   </li></ul><...
<ul><li>Tumor </li></ul><ul><li>Body   Drug </li></ul>
Adverse effect of anticancer drugs <ul><li>Short term </li></ul><ul><ul><li>Generality </li></ul></ul><ul><ul><ul><li>① My...
Adverse effect of anticancer drugs <ul><li>Long term </li></ul><ul><li>⑴  Carcinogenesis    ⑵  Infertility    (3) Growth r...
Basis theories of chemotherapy <ul><li>History of chemotherapy and the role it plays in the cancer treatment </li></ul><ul...
Clinical application of chemotherapy goals of chemotherapy <ul><li>Curative Chemotherapy </li></ul><ul><li>Adjuvant Chemot...
Clinical application—curative chemotherapy <ul><li>Tumors can be cured by chemotherapy  : </li></ul><ul><li>Acute leukemia...
Clinical application—curative chemotherapy <ul><li>Applicable to those tumors which may be cured by chemotherapy </li></ul...
Clinical application—adjuvant chemotherapy <ul><li>Radical surgery, eliminating sub-clinical micro-metastasis, is part of ...
Clinical application—neo-adjuvant chemotherapy <ul><li>Neo-Adjuvant Chemotherapy before surgery or radiation therapy  </li...
Clinical application—palliative chemotherapy <ul><li>To relief symptoms  , prolong survival, improve quality of life for t...
Balance of c hemotherapy efficacy and toxicity  Efficacy Safety Strategy for the reasonable application  of chemotherapy
Patient’s survival time and quality of life after treatment
Clinical application---- investigative chemotherapy <ul><li>Definition  :  Clinical investigations of new drugs or new reg...
Clinical application of chemotherapy —the principle of Rational Drug Use <ul><li>The principle for selecting regimen   : s...
Research for enhancing the effect of systemic chemotherapy  <ul><li>Development of new cytotoxic drugs </li></ul><ul><li>A...
PROGRESS IN MEDICAL ONCOLOGY 1975 -> 2000 -> 2025 MOLECULAR MEDICINE EVIDENCE-BASED MEDICINE SMALL, PILOT TRIALS P R O G R...
Conclusions <ul><li>Definition of chemotherapy </li></ul><ul><li>Cancer Biology :  cell cycle  、  growth fraction(GF)  、  ...
Thank you!
Upcoming SlideShare
Loading in...5
×

9 Tumor+Chemotherapy English +Version Imp

3,719

Published on

0 Comments
4 Likes
Statistics
Notes
  • Be the first to comment

No Downloads
Views
Total Views
3,719
On Slideshare
0
From Embeds
0
Number of Embeds
0
Actions
Shares
0
Downloads
244
Comments
0
Likes
4
Embeds 0
No embeds

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
  • 9 Tumor+Chemotherapy English +Version Imp

    1. 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. 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. 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. 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. 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. 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. 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. 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. 9. <ul><li>Tumor </li></ul><ul><li>Body Drug </li></ul>
    10. 10. <ul><li>Tumor </li></ul><ul><li>Body Drug </li></ul>
    11. 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. 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. 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. 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. 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. 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. 17. <ul><li>Tumor </li></ul><ul><li>Body Drug </li></ul>
    18. 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. 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. 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. 21. Mechanism of MDR <ul><li>Extra cellular Intracellular </li></ul>ATP P-glycoprotein 170 ATP Drug Drug Cell membrane
    22. 22. NEJM 2003 348:538-549 Target enzyme and efficacy of anticancer drug
    23. 23. Clin Cancer Res 4139 2006;12(14) July 15, 2006
    24. 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. 25. <ul><li>Tumor </li></ul><ul><li>Body Drug </li></ul>
    26. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 43. Tubulin inhibitor Interfere tubulin polymerization : colchicine Vinblastine block tubulin depolymerization : Taxoids tubulin tubule 20nm  
    44. 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. 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. 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. 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. 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. 49. Topoisomerase I inhibitors Topoisomerase I inhibitors combined with TOPO I-DNA complex
    50. 50. Topoisomerase I inhibitors combination of replication fork & Breaking of DNA single strand Interruption of the cell cycle Cell death
    51. 51. Mechanism of anticancer drugs
    52. 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. 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. 54. Gefitinib erlotinib Anti-EGFR 2: Herceptin Anti-EGFR 1: Cetuximub
    55. 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. 56. <ul><li>Tumor </li></ul><ul><li>Body Drug </li></ul>
    57. 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. 58. Adverse effect of anticancer drugs <ul><li>Long term </li></ul><ul><li>⑴ Carcinogenesis ⑵ Infertility (3) Growth retardation </li></ul>
    59. 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. 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. 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. 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. 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. 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. 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. 66. Balance of c hemotherapy efficacy and toxicity Efficacy Safety Strategy for the reasonable application of chemotherapy
    67. 67. Patient’s survival time and quality of life after treatment
    68. 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. 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. 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. 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. 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. 73. Thank you!
    1. A particular slide catching your eye?

      Clipping is a handy way to collect important slides you want to go back to later.

    ×