Obiettivo The present project is a logical pursuit of our BIOMED-1 programme (CT93-1500). During this programme we developed new anti-ras oligonucleotides. In the present programme we will carry out the necessary experiments to bring this new potential anti-cancer treatment to the clinic.We have shown that antisense oligonucleotides directed to a point mutation in codon 12 of the Ha-ras mRNA selectively inhibited the proliferation of cells expressing the mutated Ha-ras gene. Tumour growth of these cells in nude mice was markedly inhibited after subcutaneous injection of antisense dodecamer absorbed to nanoparticles. The predominant nuclease activity which degrades oligonucleotides intracellularly and extracellularly are 3'-exonucleases. By attaching short alkyl chains connected to the 3'-position of antisense dodecamer, we have enhanced stability of the dodecamer towards nucleases and lowered tumour growth inhibition dose by 100-fold. The discovery of these highly active and selective oligonucleotide analogues prompts us to propose pharmaceutical and medical applications. Activated mutated Ha-ras has been found in several cancers including bladder carcinomas. Oligonucleotides could be instilled intravesically, as an adjuvant therapy, in order to prevent progression or relapse after endoscopie resection. Therapeutic applications of antisense oligonucleotides to cancer treatment require information concerning the in vivo behaviour of olignonucleotides. Therefore, this proposal will focus on the in vivo evaluation of Ha-ras targeted 3'-end modified antisense oligonucleotides. The proposal contains three main lines of investigation : 1. In vitro and in vivo evaluation of the efficacy of antisense oligonucleotides : Evaluation of original modifications which could improve the stability and the uptake of oligonucleotides.2. Pharmacological studies : organ distribution, clearance kinetics and toxicity of modified dodeacamers will be studied in mammalians.3. Collection of clinical samples and characterisation : the aim is to collect bladder carcinomas samples exhibiting ras mutation in order to establish primary culture and derived cell lines. At the same time antisense oligonucleotide activity will be evaluated and clinical trials will be started in the most optimal conditions. Campo scientifico natural sciencesbiological sciencesgeneticsmutationmedical and health sciencesclinical medicineoncologyengineering and technologynanotechnologynano-materials Programma(i) FP4-BIOMED 2 - Specific research, technological development and demonstration programme in the field of biomedicine and health, 1994-1998 Argomento(i) 4.1.3 - Cell-selective targeting Invito a presentare proposte Data not available Meccanismo di finanziamento CSC - Cost-sharing contracts Coordinatore Muséum National d'Histoire Naturelle Contributo UE Nessun dato Indirizzo 43,Rue Cuvier 43 75231 Paris Francia Mostra sulla mappa Costo totale Nessun dato Partecipanti (4) Classifica in ordine alfabetico Classifica per Contributo UE Espandi tutto Riduci tutto Centre Antoine Lacassagne Francia Contributo UE Nessun dato Indirizzo 36,Voie Romaine 06054 NICE Mostra sulla mappa Costo totale Nessun dato Katholieke Universiteit Leuven Belgio Contributo UE Nessun dato Indirizzo 10,Minderbroederstraat 3000 LEUVEN Mostra sulla mappa Costo totale Nessun dato Rijksuniversiteit Leiden Paesi Bassi Contributo UE Nessun dato Indirizzo 72,Wassenaaerseweg 2300 RA LEIDEN Mostra sulla mappa Costo totale Nessun dato Università di Napoli Federico II Italia Contributo UE Nessun dato Indirizzo Via S. Pansini 5 80131 Napoli Mostra sulla mappa Costo totale Nessun dato
