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CHEMOTHERAPEUTICS OF MALIGNANT DISEASES A. Kohút Carcinogenesis DNA mutation • hereditary • acquired radiation viruses chemicals drugs Categories of genetic changes resulting in malignity a) inactivation of tumor supressor genes: • mutation • binding to a virus protein • binding to a mutated cellular protein b) activation of protooncogenes to oncogenes: • point mutation (single nucleotide polymorphisms-SNPs) • gene amplification • chromosome translocation • virus interaction Oncogenes – autonomy of cell growth Oncogenes interfere with: • mechanisms of proliferation • mechanisms of differentiation • • • • by means of: production secretion of autocrine growth factors receptors for growth factors cytosolic nuclear signal pathways transduction systems controling cell cycle Characteristics of tumour cells • uncontrolled proliferation • dedifferentiation loss of function • invasiveness • metastatic potential Therapeutic effect of anticancer drugs a. The therapeutic effect of anticancer drugs may require total tumor cell kill, which is the of all neoplastic cells. b. Achievement of a therapeutic effect often involvs drugs that have a narrow therapeutic index (TI). c. A therapeutic effect is usually achieved by killing activelly growing cells, which are most sensitive to this class of agents. d. Because normal cells and cancer cells have similar sensitivity to chemotherapeutic agents, adverse effects are mostly seen in normally dividing non-neoplastic cells, sach as: hair follicles, bone marrow, sperm. e. To minimize the adverse effects and resistance, often is used combination of several agents with different mechanism of action. f. Achievement of a therapeutic effect may involve the use of drugs, sometimes sequentially (at specific stages of cell cycle). „PRODRUGS“ 1. Cyclophosphamide 4-Hydroxyphosphamide (liver) 2. Procarbazíne dacarbazine (liver) 3. Merkaptopurine 6-merkaptopurine ribozophosphate 4. Tioquanín 6-tioquanín-ribózophosphate 5. Fluorouracil 5-fluoro-deoxy- uracil monophosphate 7. Mitomycin (only at the hypoxic tissue of tumors) 8. Doxorubicin idarubicin SENSITIVITY OF TUMOURS TO CHEMOTHERAPY • chemosensitive tumours • intermediary chemosensitive tumours • chemoresistant tumours Chemosensitive tumours • generally sensitive to several drugs • combined chemotherapy is prefered • chemotherapy is always indicated Intermediary chemosensitive tumours • complete remission rate about 10% • high partial response (about 50%) • combined chemotherapy is slightly more effective • chemotherapy could be used (no as first-choice therapy) Chemoresistant tumours • low response rate (about 20%) • complete remission is rare • chemotherapy has only adjuvant role • neoadjuvant therapy Factors influencing chemotherapy response • fraction of proliferating cells • cell cycle rate • synchronisation of cell cycle within tumour • tumour mass large tumours are relatively less sensitive: 1. a lot of cells in G0 2. penetration of drugs • kinetics of cell killing cytotoxic drugs kill only a part of cells of certain type • resistance of tumour cells Mechanisms of resistance I. • Defect activation – cyclophosphamide needs metabolic activation – metothrexate needs conversion to MTXpolyglutamate in cells • Increased inactivation – sulfhydryl substances - glutathion, metalothionein – scavenge reactive molecules – aldehyde dehydrogenase – inactivation of cyclophosphamide • Increased nucleotide levels – can affect the effectiveness of antimetabolites • Changes in DNA repare – repare mechanisms, elimination of cross-links – bleomycine other DNA-interfering drugs Mechanisms of resistance II. • Changes in target structure – active enzyme with lower drug affinity: DFR-metothrexate • Reduced quantity of target structure – amount of topo II: etoposide • Gene amplification – metothrexate: DFR requires more MTX to block the activity Mechanisms of resistance III. • Decreased accumulation – Decreased uptake • MTX - protein transporter • melphalan/leucine transport – Increased efflux • multidrug resistance (MDR): - most often for natural drugs doxorubicine, etoposide, actinomycine D, vinca alcaloids - Pgp is normally expressed in some cells, e.g. stem cells in bone marrow Combination chemotherapy • tumours have tendency to be resistant to some drug (cell heterogeneity) • resistance is often required during therapy with only one drug (proliferation of mutated cells) • several sites of effect are possible with drugs with different side effects • cummulative biochemical damage appear in cancer cells MODALITIES OF ANTICANCER CHEMOTHERAPY 1. Intermittent application • • period for bone marrow regeneration period for immunity regeneration 2. Continual therapy • during maintenance therapy (chlorambucil in CLL, busulfan in CML, hormones or antagonists in prostate or breast carcinoma) 3. Special applications • • instilation in malignant secretions (bleomycine, thiotepa) (can be palliative by volume reduction) intrathecal (metothrexate) (infiltration of CNS in leukemia) INDIVIDUALISATION OF CANCER THERAPY Type of tumour: • selection of anticancer drug • combination (or not) Repeated evaluation of clinical status: • continuation (or not) in agressive therapy Continual monitoring of bone marrow: • before & during therapy • reduction (or not) of therapeutic regimen intensity The use of drugs modifying unwanted side effects: • antiemetics, colony-stimulating factors • increase in therapeutic:toxic ratio PRACTICAL USE OF ANTICANCER DRUGS • the doses are expressed in mg per m2 of body surface (more precise dose/effect ratio) Toxic effects of anticancer chemotherapeutics • myelotoxicity • alopecia • loss of appetite & weight • nausea & vomitus • taste change • stomatitis, esophagitis, constipation, diarrhea • fatigue • • • • • • • • cardiotoxicity neurotoxicity lung damage sterility & teratogenicity hepatotoxicity & nefrotoxicity ↓ wound healing ↓ growth (children) carcinogenicity ANTICANCER DRUGS Mechanism of action - cell cycle • intercalation • blockade of metabolic steps in DNA synthesis • of enzymes regulating cell cycle • RNA synthesis • protein synthesis • microtubular functions Cell cycle intervals & anticancer drugs interferrence Anticancer drugs 1. 2. 3. 4. 5. 6. 7. alkylating agents (cyclophosphamide, cisplatin) antimetabolites (methotrexate) cytotoxic ATB (antracyclines) mitosis inhibitors (vincristine, taxans) topo inhibitors (topotecan, etoposide) hormones (corticoids, tamoxifen, flutamide) enzymes & other drugs (asparaginase, procarbazine, hydroxyurea) PTK inhibitors (imatinib) 8. 9. monoclonal antibodies (rituximab,trastuzumab) I. Alkylating agents • • • • • • • • cyclophosphamide platinum derivatives derivatives of nitrosourea (lomustine, carmustine) estramustin melphalan chlorambucil busulphan dacarbazine Mechanism of action • inter- or intra-chain cross-linking • interference with transcription & replication (S phase & G2 block) • apoptosis Alkylating agents Side effects • myelosuppresion • GIT toxicity • inhibition of gametogenesis (sterility-males) • secondary malignities (acute leukemias) Cyclophosphamide (mustard gas) • frequently used • also as immunosupressive agent • P-450 activation • p.o., i.v, i.m. • derivative - ifosfamide Cyclophosphamide Side effects • myelosuppression • GIT toxicity • hemorrhagic cystitis – acroleine N-acetylcyst., mesna Cisplatin, carboplatin • platinum complex 2 chlorid ions 2 amonium groups • cross-linking, DNA denaturation • solid tumors - testes & ovarial Cisplatin Kinetics slow i.v. perfusion (water soluble) Side effects • myelosuppression • GIT toxicity • nephrotoxicity • emetogenity • ototoxicity • neuropathies II. Antimetabolites • Antagonists of folic acid • Pyrimidine derivatives (thymine, cytosine, uracil) DNA • RNA Purine derivatives (adenine, guanine) Methothrexate (antifolate) Mechanism of action • folates – purine nucleotides – thymidilate – DNA • reduction to FH4 • DHFR - high affinitt for FH4 - key enzyme • transport of monocarbon groups • uracile methylation to 2-deoxyuridylate (DUMP) & thymidylate (DTMP) • DNA synthesis Methothrexate Kinetics • low liposolubility • p.o., i.v., i.m., i.t. • folate transport (in the cell) • polyglutamation (intracellular) • higher affinity to DHFR as FH2 • FH4 depletion Side effects • myelosuppression, GIT, pneumonitis, nephrotoxicity (tubular precipitation - hydratation) • high doses – followed by folic acid Fluorouracil (5-FU) (pyrimidine (uracile) derivative) Mechanism of action • interference with thymidylate & DNA synthesis • fluorodeoxyuridine monophosphate formation (FDUMP) • parenteral application • mainly solid tumors (GI) Side effects • GI epithelial damage • myelotoxicity Cytarabine (pyrimidine (cytidine) derivative) Mechanism of action • intracellular phosphorylation • DNA & RNA incorporation • DNA polymerase inhibition • Inhibition of replication & reparation Kinetics & indications • s.c. (myelodysplastic syndrome), i.v., i.t. • AML, CML remission, lymphoma, myelodysplast. sy Side effects • myelosuppression, GIT, nausea, vomiting III. Cytotoxic ATB • Anthracyclines (daunorubicine, doxorubicine, epirubicine, idarubicine) • Bleomycines Daunorubicine (anthracycline) Mechanism of action • intercalating ATB • topo II inhibition Indications • induction therapy ALL, AML, CML blast. trans. Kinetics • i.v. infusion • metab. & excretion (mainly liver) Side effects • myelotoxicity • accumulative cardiotoxity (free radicals) • alopecia • local necrosis (extravascular appl.) Doxorubicine (anthracycline) Mechanism of action • intercalating ATB • inhibition of topo II • much broader indication spectrum as dau • Hodgkin, NHL, myeloma, at least all localizations of solid tumors • i.v. perfusion, intravesically Side effects • myelotoxicity • cardiotoxicity (dexrazoxan) • alopecia, mucositis, necroses in mouth & if applied paravenously Bleomycines (glycopeptide ATB-radiomimetic) • Fe ion chelatation, interaction with O2 • superoxide & hydroxyl radicals • degradation of preformed DNA • chain fragmentation • radiomimetic effect • most effective in G2 & M phase, as well as G0 • testicular tumors & malignant lymphomas • orofacial tumors, ca vulvae, penis, skin • i.v., i.m. • • • • Side effects shivering, fever lung fibrosis allergies, mucocutaneous reactions low hemat. tox. IV. Mitosis inhibitors • Vinca alcaloids (vincristine, vinblastine, vinorelbine) • Taxans (paclitaxel, docetaxel) Mechanism of action Inhibition of polymerisation: colchicin vinca alcaloids Tubuline Microtubulus Stimulation of polymerisation taxans Inhibition of depolymerisation Vincristine (vinblastine, vinorelbine) (mitosis inhibitors) Mechanism of action • inhibition of tubuline polymerisation • inhibition of mitotic spindle formation • effective in G2/M phase • • • • Side effects myelosuppression phagocytosis, chemotaxy of leukocytes axonal transport in neurons paresthesies, neuromuscular abnormalities Vincristine, vinblastine Indications Vincristine • ALL & AML • Hodgkin lymphoma, NHL • multiple myeloma • combination therapy in some solid tumors Vinblastine • • • • Hodgkin lymphoma, NHL testicular tumors choriocarcinoma Grawitz tumor Paclitaxel, docetaxel (mitosis inhibitors) Mechanism of action • microtubular stabilisation • final effect like vinca alcaloids Kinetics • very low water solubility • only as i.v. perfusion Paclitaxel, docetaxel Side effects • myelosuppression • neurotoxicity • hypersensitivity (premedication with steroids & antihistaminics) Indications • metastatic tumors (breast) • progressive ovarial tumors • NSCLC • Kaposi sarcoma (AIDS) V. Topoisomerase inhibitors • topo I inhibitors (topotecan, irinotecan) • topo II inhibitors (etopozide, tenipozide) Topotecan (irinotecan) (topo I inhibitors) Mechanism of action • topo I inhibition • its levels are during the whole cell cycle Side effects • diarrhea, reversible myelosuppression • relatively low toxicity Indications • metastatic ovarial tumors in case of first line therapy failure (topotecan) • colorectal ca in progress (irinotecan) Etopozide (tenipozide) (topo II inhibitors) Mechanism of action • Inhibition of mitochondrial functions & nucleoside transport • topo II inhibition Side effects • nausea, vomitus • myelosuppression, alopecia Indications • solid tumors (lung-SCLC, testicular, trophoblast, ovarial, urinary blader) • malignant lymphoma, acute non-lymphatic leukemia VI. Hormones • Glucocorticoids (prednisolone, dexamethasone) • Antihormones (tamoxifen, flutamid) Tamoxifen (toremifen) Mechanism of action • nonsteroidal antiestrogene • inhibits estradiol binding to receptors Indications • p.o. appl. in breast cancer with positive estrogene receptors Side effects • • • • • metrorhagies thrombophlebitis flush alopecia estrogene endometrial effect VII. Enzymes & other chemotherapeutics • Enzyme (asparaginase) • Other chemotherapeutics (procarbazine, hydroxyurea) Asparaginase (enzyme) • • • • Mechanism of action, kinetics, indications cleaves asparagine, useful in malignities where the cells lost possibility of its synthesis i.m., i.v. in ALL Side effects weak myelosuppression, GIT toxicity & alopecia nausea, vomiting, CNS depression, anaphylaxis, hepatotoxicity VIII. PTK inhibitors (imatinib mesylate) Mechanism of action, kinetics, indications • PTK inhibition • phosphate group transport from ATP & phosphorylation of tyrozine residues in substrate proteins • Inhibition of transduction signals transmission • p.o. appl. in therapy of CML & GIST Side effects • nausea, vomiting, diarrhea • edema, headache & muscle pain • neutropenia & thrombocytopenia IX. Monoclonal antibodies (rituximab, trastuzumab) Rituximab • monoclonal antibody only for i.v. appl. • indicated in lymphoma therapy Trastuzumab • monoclonal antibody only for i.v. appl. • indicated in HER2 Neu positive breast ca therapy Side effects • • • • pseudoinfluenza sy. fever headache, chest, abdominal, muscle & joint pain nausea, vomiting, diarrhea & exanthema Angiogenesis in cancer Vasculogenesis vs Angiogenesis Vasculogenesis Formation of blood vessels from differentiating angioblasts and their organization into a primordial vascular network, consisting of the major blood vessels of the embryo Agiogenesis Formation of vascular sprouts from preexisting vessels Physiological versus pathological angiogenesis Physiological angiogenesis Pathological angiogenesis Therapeutic goal Embryogenesis Female reproductive system Development of follicles Corpus luteum formation Embryo implantation Successful wound healing Inhibition of angiogenesis Stimulation of angiogenesis Hemangiomas Psoriasis Kaposi's sarcoma Ocular neovascularization Rheumatoid arthritis Endometriosis Atherosclerosis Myocardial ischemia Peripheral ischemia Cerebral ischemia Wound healing Reconstructive surgery Ulcer healing Tumor growth and metastasis Progression of Cancer Established tumor 1 kg 1g Dormant in situ Cancer 1 mg Initiation Promotion Hypoxia crosstalk Dormant cancer cells regain tumorigenic potential 1 mg Suzuki M et al AJP 169: 673-681 Accessory cells Angiogenic switch 1 ng The balance hypothesis for the angiogenic switch VEGF family FGF family PDGF TGF family Angiogenin Angiopoietin-1/Tie2 TNF-a HGF/scatter factor IGF family IL-8 Nitric oxide Prostaglandins Tissue factor MMPs . . . Hanahan D & Folkman J. Cell. 86:353, 1996 Angiostatin/other plasminogen kringles Antithrombin (cleaved) Endostatin Fibronectin fragments PEX 16-kDa Prolactin Prothrombin kringle-2 Maspin Restin Vasostatin IL-1, -4, -10, -12, -18 IFNs TIMPs 1,25-(OH)2-vitamin D 2-Methoxyestradiol Angiopoietin-2 EMAP-II gro-b IP-10 . . . Normal Blood Vessels vs Tumor Blood Vessels McDonald & Choyke Nat Med 2003 Bevacizumab • Recombinant, humanized monoclonal antibody that binds to VEGF-A • Approved for first-line treatment of Non-Small Cell Lung Cancer in combination with Carboplatin and Paclitaxel • Adding bevacizumab to chemotherapy results in increased median Progression Free Survival by 33% Concerns • Since bevacizumab is expected to inhibit new angiogenic growth, concerns have been raised regarding postoperative wound-healing and bleeding complications in patients who undergo surgery within 1 to 2 months of Bevacizumab therapy Side efects • Gastrointestinal (GI) perforation • Wound healing complication • Hemorrhage • Neutropenia Immunosuppressant drugs - inhibit interleukin-2 production or action cyclosporin, tacrolimus, sirolimus - inhibit cytokine gene expression corticosteroids - inhibit purine and pyrimidine synthesis azathioprine - block the T cell surface molecules involved in signalling polyclonal and monoclonal antibodies - act by cytotoxic mechanisms cyclophosphamide, chlorambucil Usage in therapy: - autoimmune disease (some forms of haemolytic anaemia, glomerulonephritis…) - prevention /or therapy of transplant rejection (kidneys, bone marrow, heart, liver, etc.) Hazard: - decreased response to infections - facilitation of emergence of malignant cells Cyclosporin -a fungal polypeptide with potent immunosuppresive activity Pharmacokinetics - i.v., oral absorption - hepatic metabolism-metabolites excreted in the bile -accumulation in most tissues at conc. 3 to 4 times that seen in the plasma Unwanted reactions: - nephrotoxicity - hepatotoxicity - hypertension Tacrolimus - a macrolide antibiotic - i.v., orally - metabolized by the liver Unwanted reactions: - neurotoxicity - GIT upsets, metabolic disturbances (hyperglycaemia) reversible by reducing the dosage Glucocorticoids - restrain the clonal proliferation of Th cells through decreasing transcription of the gene for IL-2 - decrease the transcription of many other cytokine genes in both the induction and effector phases of the immune response Azathioprine is activated to 6-mercaptopurine (a pure analogue – antimetabolite - that inhibits DNA synthesis) by a cytotoxic action on dividing cells inhibits clonal proliferation in the induction phase of the immune response Unwanted reactions: - depression of the bone marrow, - nausea and vomiting Mycophenolate mofetil A semisynthetic derivative of a fungal antibiotic bioactivated to mycophenolic acid Action (fairly selective): - restrains proliferation of both T and B lymphocytes - reduces the production of cytotoxic T cells Kinetics: Well absorbed from the GIT Enterohepatic circulation-inactive glucuronides