Therapy of cancer disease This study material is recommended specifically for practical courses from Pharmacology II for students of general medicine and stomatology. These brief notes could be used to prepare for the lesson and as a base for own notes during courses. Addititonal explanations and information are given in single lessons. Definition chemiotherapeutics = chemoprotectives – Cytostatics Cancer disease Classification: 1.Benign 2. 2.Malign Cytostatics Cabcerogenesis •process of change of somatic cell to cancer cell •3 phases: initiation promotion progression Cytostatics Exogenous factors involved in cancerogenesis 1. • • • • • • • Cytostatics Endogenous factors involved in cancerogenesis 2. Cytostatics Modes of action Target sites: • • • • Cytostatics 1. Early • • • • Adverse effects 2.Delayed • • • • • • • Nežádoucí účinky cytostatik Adverse effects Adverse effects Adverse effects Adverse effects Analgesics •basic analgesics are NSAIDs •in strong pain opioids •bone pain – kalcitonin, bisphosphonates •combination with corticoids and psychoactive agents (antidepressants, neuroleptics, anxiolytics) Adverse effects Bisphosphonates • • • ibandronate clodronate pamidronate zoledronate Adverse effects Particularity of cancer pharmacotherapy •DDF • •„nonspecificity“ of target site • •combination with othrt types of therapy • •dosing, administration routes and combinations Cytostatics Classification with regard to cell cycle •cycle specific/nonspecific • •phase specific/nonspecific Cytostatics Classification •monoclonal antibodies and other drugs of „biological“ (targeted) therapy •alkylating •platin cytostatics •cytotoxic antibiotics •antimetabolites •herbal alkaloids •hormones •others Cytostatics Mode of action •alkylation of cellular structures, namely DNA → loss of function and cellular death Alkylating cytostatics •β-chloretylamines (N-yperite derivatives): chlorambucil, melphalan • • •oxazaphosphorines: cyclophosphamide, ifosfamide • • •methanesulphonic acid derivatives: busulphan Alkylating cytostatics nitrosourea derivatives: lomustine, carmustine, fotemustine, streptozocine • • triazenes: procarbazine, dacarbazine • • platin compounds: cisplatin, carboplatin, oxaliplatin • mitomycin Alkylating cytostatics MofA •bounds between DNA strands with non-covalent binding (Van der Waals forces, hydrogen bonds) doxorubicine daunorubicine mitoxantrone Intercalating agents Folic acid antagonists MofA: dihydrofolate reductase inhibition methotrexate Antimetabolites Purine antagonists 6-merkaptopurine 6-thioguanine azathioprine cladribine fludarabine Antimetabolites Pyrimidine antagonists cytarabine 5-fluorouracil gemcitabine Antimetabolites irinotecan, topotecan MofA: topoisomerase I inhibition Herbal alkaloids etoposid, teniposid MofA: topoisomerase II inhibition • Herbal alkaloids Vinca alkaloids MofA: destruction of mitotic spindle vincristine vinblastine vindesine vinorelbine • Herbal alkaloids Taxans MofA: inhibition of tubulin depolymerization = block of mitotic spindle paclitaxel docetaxel Herbal alkaloids •Androgens •Antiandrogens •Oestrogens •Antioestrogens •Gestagens • • • • •Gonadoliberin inhibitors •Aromatase inhibitors •Glucocorticoids •Octreotide •Estramustine, prednimustine • Hormones and theit antagonists bleomycine, (peplomycine) MofA: ROS production→ DNA fragmentation AE: pyretic reactions, pulmonary fibrosis •low myelosuppression • hydroxycarbamid arsenic trioxide celekoxib anagrelide asparaginase Others