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LLC e MM oggi: un paradigma per nuovi standard nelle neoplasie ematologiche

LLC e MM oggi: un paradigma per nuovi standard nelle neoplasie ematologiche. Ruolo di bendamustina: un nuovo standard?. Annamaria Rauco UO Oncologia Medica Ospedale S.Camillo de Lellis, Rieti Lorenzo Falchi SC Oncoematologia con Autotrapianto, Az. Osp. S.Maria Terni

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LLC e MM oggi: un paradigma per nuovi standard nelle neoplasie ematologiche

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  1. LLC e MM oggi: un paradigma per nuovi standard nelle neoplasie ematologiche Ruolo di bendamustina: un nuovo standard? Annamaria Rauco UO Oncologia Medica Ospedale S.Camillo de Lellis, Rieti Lorenzo Falchi SC Oncoematologia con Autotrapianto, Az. Osp. S.Maria Terni Università degli studi di Perugia MediterraneanSchoolofOncology Orvieto, Palazzo Coelli 20-22 Novembre 2009

  2. BENDAMUSTINE HISTORY

  3. BENDAMUSTINE CHEMICAL STRUCTURE BENZIMIDAZOLE RING ALKYLATINGGROUP BUTYRIC ACID SIDE CHAIN

  4. BENDAMUSTINE CHEMICAL STRUCTURE BENDAMUSTINE CHLORAMBUCIL CICLOFOSFAMIDE MELPHALAN

  5. DNA Alkylation BENDAMUSTINE ALKYLATING ACTIVITY Cross-links DNA single and double stands inhibiting DNA replication, repair and transcription Significantly more double strand breaks when compared to cyclophosphamide and carmustine Double strand breaks more durable when compared to cyclophosphamide and carmustine Extent and durability of effect results in ‘mitotic catastrophe’

  6. BENDAMUSTINE APOPTOSIS PATHWAYS BENDAMUSTINE UNIQUELY REGULATES APOPTOSIS PATHWAYS COMPARED WITH OTHER ALKYLATORS p21,wip1,NOXA,DR5/KILLER,BTG2 PROAPOPTOTICI PRESENTANO p53-RESPONSE ELEMENTS NELLE LORO REGIONI PROMOTER E SONO DEFINITI p53-DIPENDENTI MICROARRAYS GENI ATTIVATI DALLA BENDAMUSTINA

  7. BENDAMUSTINE APOPTOSIS PATHWAYS Q-PCR validation was used to confirm the effects of bendamustine on p21 and NOXA both genes were induced in SU-DHL-1 cells after 8 h of exposure to bendamutine genes were also induced by equitoxic concentration of phosphoramide mustard and chlorambucil but to a much lower extent

  8. BENDAMUSTINE APOPTOSIS PATHWAYS immunoblotting analysis, using antibodies that specifically recognize Ser15 - phosphorilated p53 shows that bendamustine led to an 8-fold up-regulation of Ser15 - phosphorilated p53 in SU-DHL-1 cells when testing the proapoptotic mitochondrial protein Bax, Bendamustine, but not chloramucil or phosphoramide caused an appreciable increase in the protein expression of Bax

  9. BENDAMUSTINE DNA REPAIR PATHWAYS the DNA repairenzyme APE isanapurinic/apyrimidinicendonucleasethatplays a criticalrole in the base excisionrepairpathway APE isinhibitedbymethoxyamine, a drugthatspecificallybindstoabasicsites in DNA and reduces APE activityby 300-fold The cytotoxic activities of bendamustine and phosphoramide were assessed The IC50 of bendamustine was reduced 6-fold with methoxyamine addition The IC50 of phosphoramide mustard did not change with methoxyamine addition BENDAMUSTINE UNIQUELY INDUCES A BASE EXCISION REPAIR PATHWAY RESPONSE

  10. BENDAMUSTINE DNA REPAIR PATHWAYS DNA repair enzyme O6-alkylguanine-DNA alkyltransferase is an important DNA-repair protein that protects cells from the toxic effects of DNA alkylators The activity of bendamustine and phosphoramide was examined in presence of an alkylguanyl transferase inhibitor, O6-benzylguanine The cytotoxicity of bendamustine was not enhanced by the addition of O6 -benzylguanine OTHER ALKYLATORS BUT NOT BENDAMUSTINE INDUCE AN ALKYLTRANSFERASE MECHANISM OF DNA REPAIR

  11. BENDAMUSTINE MITOTIC CATASTROPHE Bendamustine inhibits mitotic checkpoints and induces mitotic catastrophe Treatment withbendamustineresulted in a 60-80% down-regulationof the mRNAexpressionofallthreegenes Phosphoramidemustard or chlorambucil had more modestinhibitoryeffects on thesegenestranscript

  12. BENDAMUSTINE MITOTIC CATASTROPHE To determine whether bendamustine can cause mitotic catastrophe it was tested in cell lines with deficiencies in apoptotic pathways Increasedincidenceofchromatincondensation and multinucleation/micronucleation, hallmarksofmitoticcatastrophe, in bothcelllines Micronucleationcompared withonly 6% in DMSO controlcells

  13. CONCLUSIONI • Meccanismo d’azione unico • Attivazione apoptosi p53-dipendente • Alti livelli di attivazione p53 e dei geni p53 dipendenti • Inibizione numerosi checkpoint mitotici • Danno esteso al DNA/innesco catastrofe mitotica ATTIVITÀ NEI PAZIENTI RESISTENTI AGLI ALCHILANTI TRADIZIONALI

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