18. Comparison of Antitumor Activity of Cytosine Deaminase::Uracil Phosphoribosyl Transferase (CD::UPRT) and Purine Nucleoside Phosphorylase (PNP) Suicide Genes Using Replicative but Non-Disseminative Adenovirus Vectors
Notice bibliographique
Résumé
Cancer gene therapy using suicide genes has shown great potential in tumor models. To improve efficacy, recent attention has focused on the use of oncolytic vectors. To date this strategy has not resulted in vectors with anti-tumor activities sufficiently potent to sustain complete tumor regression. In this study, we pursued a modified approach that makes use of viral DNA replication but not of oncolysis. This approach is based on the protease-deleted adenovirus vector (AdV) (Oualikene et al. 2000). Such vectors are designed to convert transduced cells into mega-factories for suicide genes. To evaluate this strategy, we compared the activity in vitro of two suicide genes: CD::UPRT and PNP in the Replicative but Non-Disseminative (RND) AdVs. In AdVs the CD::UPRT or PNP transgene and the E1A gene were introduced as a bicistronic cassette under the control of the CMV5 promoter. Adenoviruses were generated by introducing the expression cassette in the E1 region of an AdV backbone deleted for E1, E3, and the protease gene. Due to the protease deletion, these AdVs can no longer form viral particles, even following replication resulting from E1A expression. The resulting Ad(dPS)C::U-IRES-E1A, and Ad(dPS)PNP-IRES-E1A were grown in protease-complementing 293 cells. When tested for anti-tumor activities in two human and one murine glioblastoma cell lines and one ovarian cancer cell line, Ad(dPS)PNP-IRES-E1A outperformed its counterpart, the Ad(dPS)C::U-IRES-E1A, by up to 16-fold in human glioblastoma and 5 fold in human ovarian cancer cells. Both RND virus performed better than non replicative counterparts. In bystander assays, the number of transduced cells sufficient to convey the anti-tumor activity to the entire cell population could be reduced by more than 10-and 8-fold when comparing Ad(dPS)PNP-IRES-E1A to Ad(dPS)C::U-IRES-E1A on glioblastoma and ovarian cancer cells respectively. In a three-dimensional spheroid culture model, when both RND AdVs were compared, anti-tumor activity was significantly better (ANOVA p<0.001) for Ad(dPS)PNP-IRES-E1A in all cancer cell models, ranging from 3-fold in ovarian cancer up to 10-fold in glioblastoma spheroids. In conclusion, the RND AdV platform substantially improves anti-tumor activity of suicide gene therapy. Using this strategy, the suicide gene PNP performed better than CD::UPRT in both glioblastoma and ovarian cancer cells. This work demonstrates that the protease-deleted AdV platform can provide vectors that are potentially safer than conditional oncolytic AdVs and yet generate sufficient anti-tumor activity to eradicate large tumors. Results with Ad(dPS)PNP-IRES-E1A are promising and work with animal models is in progress.
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,001 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,000 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule tête enseignante, pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».