1 / 84

CHEMOT H ERAPEUTI CS OF MALIGNANT DISEASES

CHEMOT H ERAPEUTI CS OF MALIGNANT DISEASES. A. Kohút. C arcinogen esis. DNA mut ation heredit a r y acquired radiation v i rus es chemi ca l s drugs. a) ina c tiv ation of tumor supre s sor g e n es : mut ation binding to a v i rus prote i n

nyx
Download Presentation

CHEMOT H ERAPEUTI CS OF MALIGNANT DISEASES

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript


  1. CHEMOTHERAPEUTICSOF MALIGNANT DISEASES A. Kohút

  2. Carcinogenesis DNA mutation • hereditary • acquired radiation viruses chemicalsdrugs

  3. a) inactivation of tumorsupressor genes: mutation binding to a virus protein binding to amutated cellular protein b) activationof protooncogenesto oncogenes: point mutation (single nucleotide polymorphisms-SNPs) gene amplification chromosome translocation virus interaction Categoriesof genetic changes resulting in malignity

  4. 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

  5. Characteristics of tumour cells • uncontrolled proliferation • dedifferentiation  loss of function • invasiveness • metastatic potential

  6. 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).

  7. „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

  8. SENSITIVITY OF TUMOURS TO CHEMOTHERAPY • chemosensitive tumours • intermediary chemosensitive tumours • chemoresistanttumours

  9. Chemosensitive tumours • generally sensitive to several drugs • combined chemotherapy is prefered • chemotherapy is always indicated

  10. 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)

  11. Chemoresistant tumours • low response rate (about 20%) • complete remission is rare • chemotherapy has only adjuvant role • neoadjuvant therapy

  12. 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

  13. Mechanisms of resistance I. • Defect activation • cyclophosphamide needs metabolic activation • metothrexate needs conversion toMTX-polyglutamate in cells • Increased inactivation • sulfhydryl substances - glutathion, metalothionein – scavenge reactive molecules • aldehyde dehydrogenase – inactivation of cyclophosphamide • Increased nucleotidelevels • can affect the effectiveness of antimetabolites • Changes in DNA repare •  repare mechanisms, elimination of cross-links • bleomycine otherDNA-interfering drugs

  14. Mechanisms of resistance II. • Changes in target structure • active enzyme with lower drug affinity:DFR-metothrexate • Reduced quantity of target structure • amount of topoII:etoposide • Gene amplification • metothrexate:  DFR requires more MTX to block the activity

  15. Mechanisms of resistance III. • Decreased accumulation • Decreased uptake • MTX-protein transporter • melphalan/leucine transport • Increased efflux • multidrug resistance (MDR): - most often for natural drugsdoxorubicine, etoposide, actinomycine D, vinca alcaloids - Pgpis normally expressedinsome cells, e.g. stem cells in bone marrow

  16. 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 damageappear in cancer cells

  17. 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)

  18. 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

  19. PRACTICAL USE OF ANTICANCER DRUGS • the doses are expressed in mg per m2 of body surface (more precise dose/effect ratio)

  20. 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 Toxic effects of anticancer chemotherapeutics

  21. ANTICANCER DRUGS

  22. Mechanism of action - cell cycle • intercalation • blockade of metabolic steps in DNAsynthesis •  of enzymes regulating cell cycle •  RNAsynthesis •  protein synthesis •  microtubular functions

  23. Cell cycle intervals &anticancer drugs interferrence

  24. Anticancer drugs • alkylating agents(cyclophosphamide, cisplatin) • antimetabolites(methotrexate) • cytotoxic ATB (antracyclines) • mitosisinhibitors (vincristine, taxans) • topoinhibitors (topotecan, etoposide) • hormones(corticoids, tamoxifen, flutamide) • enzymes & other drugs(asparaginase, procarbazine, hydroxyurea) • PTKinhibitors (imatinib) • monoclonal antibodies (rituximab,trastuzumab)

  25. I. Alkylating agents • cyclophosphamide • platinum derivatives • derivatives of nitrosourea (lomustine, carmustine) • estramustin • melphalan • chlorambucil • busulphan • dacarbazine

  26. Mechanism of action • inter- or intra-chain cross-linking • interference with transcription & replication (S phase & G2 block) • apoptosis

  27. Alkylating agents • Side effects • myelosuppresion • GIT toxicity • inhibition of gametogenesis (sterility-males) • secondary malignities • (acute leukemias)

  28. Cyclophosphamide(mustard gas) • frequently used • also as immunosupressive agent • P-450 activation • p.o., i.v, i.m. • derivative - ifosfamide

  29. Cyclophosphamide • Side effects • myelosuppression • GIT toxicity • hemorrhagic cystitis – acroleine •  • N-acetylcyst.,mesna

  30. Cisplatin, carboplatin • platinum complex 2 chlorid ions 2 amonium groups • cross-linking, DNA denaturation • solid tumors - testes & ovarial

  31. Cisplatin • Kinetics • slow i.v. perfusion • (water soluble) • Side effects • myelosuppression • GIT toxicity • nephrotoxicity • emetogenity • ototoxicity • neuropathies

  32. II. Antimetabolites • Antagonists of folic acid • Pyrimidine derivatives (thymine, cytosine, uracil) DNA RNA • Purine derivatives (adenine, guanine)

  33. 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

  34. 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 Methothrexate

  35. Mechanism of action interference with thymidylate & DNA synthesis fluorodeoxyuridine monophosphate formation (FDUMP) parenteral application mainly solid tumors (GI) Side effects GI epithelial damage myelotoxicity Fluorouracil (5-FU)(pyrimidine (uracile) derivative)

  36. 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 Cytarabine (pyrimidine (cytidine) derivative)

  37. III. Cytotoxic ATB • Anthracyclines (daunorubicine, doxorubicine,epirubicine, idarubicine) • Bleomycines

  38. 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 cardio- toxity (free radicals) alopecia local necrosis (extravascular appl.) Daunorubicine (anthracycline)

  39. Mechanism of action intercalating ATB inhibition of topo II much broader indication spectrum asdau 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 Doxorubicine(anthracycline)

More Related