The original hypothesis for Iressa was that in a number of tumours EGFR expression was associated with a poor prognosis and that inhibition of the enzyme would have a number of effects that would impact on tumour growth. This hypothesis was supported by preclinical data.
Principles of Systemic Therapy in Cancer N. PAVLIDIS PROFESSOR OF MEDICAL ONCOLOGY UNIVERSITY OF IOANNINA GREECE ESO COURSE IOANNINA, JULY 2011
ALKYLATING AGENTS Mechanism of action : Target DNA, produce alkylation through formation of intermediates. No phase-specific drugs Busulfan Chlorambucil Cisplatin, Carboplatin, Oxaliplatin Cyclophosphamide, Ifosfamide Dacarbazine Mechlorethamine (Nitrogen Mustard) Melphalan Nitrosoureas Procarbazine Streptozotocin Temozolomide Thiotepa
ANTIMETABOLITES Mechanism of action : Interfere with DNA synthesis. They are structural analogs or they inhibit several enzymes. S-phase specific Aracytidine Cytarabin Fludarabine Fluorouracil Leucovorin Capecitabine Gemcitabine Hydroxyurea Mercaptopurine Methotrexate Pemetrexed Pentostatin Raltitrexed Thioguanine Trimetrexate Uracil / Tegafur (UFT)
ANTITUMOR ANTIBIOTICS Mechanism of action : A variety of mechanisms. They are derived from microorganisms. Cell cycle specific drugs Actinomycin-D Bleomycin Daunorubicin Doxorubicin Doxorubicin Liposomal Epirubicin Idarubicin Mitomycin Mitoxantrone
MITOTIC SPINDLE AGENTS Mechanism of action : Bind to microtubular proteins, thus inhibit microtubule assembly resulting in dissolution of the mitotic assembly structure. M- phase specific drugs. Docetaxel Paclitaxel Vinblastine Vincristine Vindesine Vinorelbine
TOPOISOMERASE INHIBITORS Mechanism of action : DNA Topoisomerases I and II are essential enzymes for transcription, replication and mitosis. The following drugs are able to inhibit these enzymes. Topoisomerease I inhibitors Irinotecan Topotecan Topoisomerase II inhibitors Etoposide Teniposide
Marrow-ablative doses of chemotherapy to increase tumor cell-kill, while rescuing the host with:
(i) autologous bone marrow
(ii) donor bone marrow
(iii) peripheral stem-cells
Oral chronic administration of chemotherapy (i.e. cyclophosphamide, etoposide, vinorelbine) has both antitumorigenic and antiangiogenic effect on tumor endothelial tumor cell. Endothelial cells are 10-100 times more susceptible to chemotherapy.
PARAMETERS TO BE EVALUATED IN SYSTEMIC TREATMENTS
CHEMOTHERAPY TOXICITIES ( I ) Bone m arrow s uppression (anemia, leucopenia, thrombocytopenia) Almost all Erythropoietin, G-CSF, blood transfusions TOXICITY DRUG INDUCED ANTIDOTE Nausea- v omiting Platinum Anthracyclines Alkylating s Centrones (serotonin block): granisetron , ondasetron Alopecia Anthracyclines Taxanes Scalp-cooling techniques (not universally accepted) Cardiotoxicity Anthracyclines Cyclophosphamide 5-FU Early detection . Dexrazoxane
CHEMOTHERAPY TOXICITIES ( II ) Pulmonary toxicity Bleom y c i n Alkylating s Gemcitabine Early detection . Corticosteroids Nephrotoxicity Platinum Methotrexate (↑dose) Adequate hydration Neurotoxicity Alkaloids Platinum Taxanes Early detection Gonadal d amage Alkylatings Others Sperm preservation Second m alignancies Alkylating s Avoid if possible responsible drugs and/or RT in curable diseases
INTRODUCTION TO ENDOCRINE THERAPY (HORMONAL AGENTS)
Potent selective inhibitor of the P210 BCR-ABL tyrosine kinase (occupies the ATP binding site of the BCR-ABL protein resulting in induction of apoptosis). Inhibits also receptor kinases for PDGFR, stem cell factor and c-kit .