logo_lf_mu PharmDr. Ondřej Zendulka, Ph.D. Pharmacology of anticancer drugs Anticancer drugs •Definition: •drugs used in therapy of all types of cancer disease • •synonyms = •chemoterapeutics, cytostatic or cytotoxic drugs • •chemoprotective substances – protect somatic cells against toxic effect of chemoterapeutics (mesna, AcCys, dexrazoxane etc.) • Anticancer drugs •Carcinogenesis •!! multistage process !! •process of transformation of somatic cell to malignant •3 phases: • initiation • carcinogens, mutagens and mutation • promotion • expansion of cells • progression • final transformation to malignancy • Anticancer drugs •Carcinogenesis •Factors related to tumours •exogenic: tobacco, ethanol, infections, diet, radiation • International Agency for Research on Cancer (IARC) http://www.iarc.fr •endogenic: genetic predisposition (Xeroderma pig.) • defects of immune system • Anticancer drugs •Tumors •Types of tumours: 1.Benign •multiplication of differenciated cells, danger of localization and size 2.Malignant •invasivness, dedifferentiation, metastasis, uncontrolled proliferation 3.Transitional states •characteristics of 1. and 2. • • • Anticancer drugs •Characteristics of malignant cell •Uncontrolled proliferation •the clonal expansion, defect in proliferation controlling mechanisms •speed of proliferation, cell cycle, apoptosis •mechanisms: extracellular signals, receptors, intracellular signaling pathways, intracelular signals •Dediferentiation and loss of function •↓degree of differentiation = ↑speed of proliferation • Anticancer drugs •Characteristics of malignant cell •Invasiveness •proteolytic enzymes, angiogenesis •Metastases •secondary tumours • Anticancer drugs •Anticancer treatment •Surgical excision •Radiation: ionizing radiation •Chemotherapy: curative • palliative: adjuvant • neoadjuvant • • 1012 1010 time death diagnosis symptoms surgery Anticancer drugs •Sites of action 1.interference with DNA (RNA) : alkylating and intercalating agents, inhibitors of topoisomerase, radiomimetics 2.antimetabolites: pyrimidine and purine analogues, folate antagonists 3.interference with microtubules 4.hormones 5.others Anticancer drugs •Sites of action ANTIMETABOLITES METHOTREXATE Nitrosoureas Taxanes Vinca alcaloids Alkylating agents Antibiotics Cisplatin Sex steroids Topoisomerase I METHOTREXATE Anticancer drugs •Classification •with regard to: 1.the cell cycle: cell cycle specific (CCS) • cell cycle nonspecific (CCNS) 2. 2. 2.chemical structure 3.principle of action phase specific phase nonspecific Anticancer drugs •fast proliferating cells – mid.speed of proliferation – slow proliferating cells • stem cells, germ-cells-- hair foliculs, skin cells -- liver, kidneys • Burkitt‘s carcinom -- acute leukemia -- Ca of colon • M S G2 G0 G1 G1 time G1 Anticancer drugs 8_Cyclophosphamide_Doxorubicin_prednisolone_vincristine vincristin cyclophosphamide prednisone doxorubicin Anticancer drugs Adverse effects • •Early •nausea, vomitus •fever •sweating •allergic reaction • • •Retarded •myelotoxicity •GIT toxicity •secondary malignity •alopecia •local toxicity •development of resistance •reproductive toxicity Anticancer drugs • extravazál1 extravazál 4 extravazál2 extravazál3 Anticancer drugs •Classification •with regard to: principle of action 1.alkylating agents and related compounds 2.intercalating agents 3.antimetabolites 4.inhibitors of topoisomerases I and II 5.hormones 6.miscellaneous agents Anticancer drugs 1.Alkylating agents and related compounds •Principle of action • Mech úč tecka 5 Anticancer drugs 1.Alkylating agents and related compounds •Principle of action: covalent bounds to cell structures (DNA) •Adverse effects: myelotoxicity, vomitus, second. malignity •Members: nitrogen mustards: cyclophosphamide, ifosfamide, chlorambucil, melphalan • nitrosoureas: carmustine (BCNU), lomustine (CCNU), streptozocine • platin complexes: cisplatin, carboplatin, oxaliplatin • procarbazine, dacarbazine • busulphan acrolein phosphoramide Anticancer drugs 2.Intercalating agents •Principle of action: noncovalent bounds •Adverse effects •Members: anthracyclines: doxorubicin (adriamycin), daunorubicin (daunomycin), idarubicin, epirubicin • mitoxantrone • actinomycin D interkalace 2 Anticancer drugs 3.Inhibitors of topoisomerases •Principle of action •Adverse effects •Members: Topoisomerase I • irinotecan, topotecan • Topoisomerase II • etoposid, teniposid (from mayapple) kamptotecin topoizomeráza izomeráza II Anticancer drugs 3.Inhibitors of topoisomerases mayap2 mbloom Anticancer drugs 4.Antimetabolites 1.Folate antagonists •metotrexate metotrexát MTX- methotrexate DHFR- dihydrofolate reductase SHMT- serin OHCH3transferase TS-thymidylate syntase • • folatecycle Anticancer drugs 4.Antimetabolites 1.Folate antagonists •Principles of action •Adverse effects: nephrotoxicity, hepatotoxicity •Members: metotrexate (MTX), trimetrexate •leucovorin ( folinic acid) – antagonist of MTX •immunosuppressive therapy • Anticancer drugs 4.Antimetabolites 2.Purine analogues •Principles of action: antagonism of purine bases and enzymes = defect of transcription and replication of NA • + functionaless proteins •Adverse effects: nephrotoxicity, myelosuppression • •Members: 6-mercaptopurin, 6-thioguanin, azathioprin (immunosupression), fludarabine, cladribine, pentostatin •↑of effect by inactivating xantinoxidase • • merkaptopurin fludarabin Anticancer drugs 4.Antimetabolites 3.Pyrimidine analogues •Principle of action: incorporation to DNA or inhibition of replication enzymes • •Adverse effects: myelosuppression, myelotoxicity • •cytarabine,5-fluorouracil, gemcitabine, floxuridine, tegafur • •synergisms of flourouracil and MTX • fluorouracil Anticancer drugs •Inhibitors of mitosis •Principle of action: interaction with mitotic spindle •Vinca alkaloids (from periwinkle plant) •Adverse effects: neurotoxicity, myelotoxicity •vincristine, vinblastine, vindesine, vinorelbine •M phase specific •Taxanes ( from Pacific yew) •Adverse effects: neurotoxicity, bradycardia, granulocytopenia •docetaxel, paclitaxel Anticancer drugs •Inhibitors of mitosis vinca-rosea Tbrevifbark Tbreviffruit Tbrevifleaf Anticancer drugs •Inhibitors of protein synthesis •Asparaginase – cristantaspase • •Principle of action: Asn Asp and NH3 • •Adverse effects: allergic reaction, neurotoxicity, hepatotoxicity, pancreatitis • •!! IS NOT myelosuppresive and not toxic for GIT !! • Anticancer drugs 5. Hormons and hormon antagonists •Androgens •Antiandrogens •Oestrogens •Antioestrogens •Gestagens • • • • •Inhibitors of gonadoliberin •Inhibitors of aromatases •Glucocorticoids •Octreotid •Estramustin, prednimustin • Anticancer drugs 5. Hormons and hormon antagonist •Androgens •Principle of action: antagonism of oestrogens •Adverse effects: retention of Na+, hepatotoxicity, virilisation •testosterone, fluoxymesterone •combinations with antioestrogens •Antioestrogens •Principle of action: •Adverse effects: flush syndrome, nausea •tamoxifen • • Anticancer drugs 5. Hormons and hormon antagonists •Antiandrogens •Principle of action: antagonism of androgens •Adverse effects: gynecomastia •cyproteron, flutamid, nilutamid, bikalutamid •Oestrogens •Principle of action •Adverse effects: gynecomastia, trombembolia, retention of Na+ •ethinylestradiol • • Anticancer drugs 5. Hormons and hormon antagonists •Inhibitors of gonadoliberin (gonadotrophin – releasing hormone) •Principle of action: ↓ releasing of sex hormones •Adverse effects: flush s., myalgia, osteoporosis •leuprolid acetate, goserelin, buserelin • •Inhibitors of aromatases •Principle of action: inhibition of aromatases •Adverse effects: swellings, myalgia, artralgia •aminoglutethimide, anastrozole • Anticancer drugs 5. Hormons and hormon antagonist •Glucocorticoids •Principle of action: inhibition of lymphocyte proliferation •Adverse effects: •prednisone, dexametazone •symptomatic treatment - swellings • • Anticancer drugs 6. Others •Radiomimetics •Principle of action: production of ROS •Adverse effects: pulmonary fibrosis,hyperpyrexia, allergic reactions •bleomycin •low myelotoxicity radiomimetika Anticancer drugs 6. Others •Radioisotopes •i.e. 131I in therapy of cancers of thyroid gland •Immunomodulators and others •monoclonal antibodies •inhibitors of angiogenesis •interferons