9 Tumor+Chemotherapy English +Version Imp

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

Tumor chemotherapy? 1.Know about it . 2.Just heard. 3.Never heard. Survey

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. ）

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

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

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

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

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

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

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.

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

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

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.

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

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

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.

Mechanism of MDR Extra cellular Intracellular 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 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

Drug Classification ： (1) According to cell cycle: Cell cycle non-specific agents 2. Cell cycle specific agents

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 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

Classification of anticancer drugs (2) According to mechanism ： Alkylating agent Antimetabolite Antibiotic Tubulin inhibitor Topoisomerase inhibitor Hormones Molecular target drug

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

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+

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

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

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.

Anti-metabolite anticancer drugs folic acid antagonist ： MTX miazines ： 5-Fu ， fluorofur ， furtuion ， Capacitabine cytidine ： Ara-C ， Gemcitabine purines ： 6-MP ， 6-TG

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

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

Antibiotic anticancer drugs Double strand dissociation Interfere DNA transcription and mRNA synthesis Anthracycline antibotics insert to the base pair near the DNA double strand

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.

Antibiotic anticancer drugs Others: dactinomycin, bleomycin, mitomycin Bleomycin may cause the pulmonary fibrosis, the cumulative dose

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.

Tubulin inhibitor Interfere tubulin polymerization : colchicine Vinblastine block tubulin depolymerization : Taxoids tubulin tubule 20nm  

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

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

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

Topoisomerase Cells in S-phase DNA DNA replication DNA rotating along its axis interfere DNA replication Double-strand torsion increased

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

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 cycle Cell death

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

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

Gefitinib erlotinib Anti-EGFR 2: Herceptin Anti-EGFR 1: Cetuximub

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

Adverse effect of anticancer drugs Long term ⑴ Carcinogenesis ⑵ Infertility (3) Growth retardation

Clinical application of chemotherapy goals of chemotherapy Curative Chemotherapy Adjuvant Chemotherapy Neoadjuvant Chemotherapy Palliative Chemotherapy Investigative Chemotherapy √ √ √ √ √

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.

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

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.

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

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.

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 Definition ： Clinical investigations of new drugs or new regimens. Content ： purpose ， scheme ， observation, evaluation Principles: low toxicity, effective and comply with medical ethics

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 √

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

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

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

9 Tumor+Chemotherapy English +Version Imp

More Related Content

What's hot (20)

Viewers also liked (20)

Similar to 9 Tumor+Chemotherapy English +Version Imp (20)

More from Sumit Prajapati (20)

9 Tumor+Chemotherapy English +Version Imp

Editor's Notes