We report here that a tetra-substituted naphthalene-diimide derivative (MM41) has significant in vivo anti-tumour activity against the MIA PaCa-2 pancreatic cancer xenograft model. IV administration with a twice-weekly 15 mg/kg dose produces ca 80% tumour growth decrease in a group of tumour-bearing animals. Two animals survived tumour-free after 279 days. High levels of MM41 are rapidly transported into cell nuclei and were found to accumulate in the tumour. MM41 is a quadruplex-interactive compound which binds strongly to the quadruplexes encoded in the promoter sequences of the BCL-2 and k-RAS genes, both of which are dis-regulated in many human pancreatic cancers. Levels of BCL-2 were reduced by ca 40% in tumours from MM41-treated animals relative to controls, consistent with BCL-2 being a target for MM41. Molecular modelling suggests that MM41 binds to a BCL-2 quadruplex in a manner resembling that previously observed in co-crystal structures with human telomeric quadruplexes. This supports the concept that MM41 (and by implication other quadruplex-targeting small molecules) can bind to quadruplex-forming promoter regions in a number of genes and down-regulate their transcription. We suggest that quadruplexes within those master genes that are up-regulated drivers for particular cancers, may be selective targets for compounds such as MM41.

• MeSH
• exprese genu MeSH
• G-kvadruplexy MeSH
• genetická transkripce MeSH
• imidy chemie   farmakologie   MeSH
• injekce intravenózní MeSH
• lidé MeSH
• myši nahé MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• nádory slinivky břišní farmakoterapie   genetika   metabolismus   patologie   MeSH
• naftaleny chemie   farmakologie   MeSH
• promotorové oblasti (genetika) * MeSH
• protinádorové látky chemie   farmakologie   MeSH
• protoonkogenní proteiny c-bcl-2 antagonisté a inhibitory   chemie   genetika   metabolismus   MeSH
• protoonkogenní proteiny p21(ras) genetika   metabolismus   MeSH
• rozvrh dávkování léků MeSH
• simulace molekulární dynamiky MeSH
• tumor burden účinky léků   MeSH
• xenogenní modely - testy protinádorové aktivity MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• Bcl2 protein, mouse MeSH Prohlížeč
• Hras protein, mouse MeSH Prohlížeč
• imidy MeSH
• naftaleny MeSH
• naphthalenediimide MeSH Prohlížeč
• protinádorové látky MeSH
• protoonkogenní proteiny c-bcl-2 MeSH
• protoonkogenní proteiny p21(ras) MeSH