Abstract 3314: Sensitization of human tumor cells to chemotherapy drugs by antisense downregulation of BRCA2 and thymidylate synthase (TS): Induction of synthetic lethality by targeting DNA repair.
Notice bibliographique
Résumé
Abstract Although genomic instability contributes to tumor progression and development of drug resistance, molecular events underlying instability could also lead to selective sensitivity of tumor cells to certain treatments. Deficiencies in specific mechanisms of DNA repair, with resultant dependence on other repair pathways, have been exploited in therapeutic strategies. For example, BRCA1 and BRCA2, which are involved in homologous recombination repair, have been implicated in hereditary and sporadic carcinomas of the breast, ovary, and other sites. Notably, individuals with BRCA2 mutations respond more favourably to conventional chemotherapy. It is hypothesized that in the absence of functional BRCA2 protein, tumor cells are unable to efficiently repair DNA damage induced by anticancer agents. This "synthetic lethality" can be exploited to selectively kill BRCA1- or BRCA2-deficient tumor cells both in vitro (Nature 434: 913, and 917, 2005) and in patients (NEJM 361: 123, 2009). To advance the utility of this phenomenon to selectively kill cancer cells, it may be possible to use antisense technology to create synthetic lethal situations in tumors. siRNA knockdown of BRCA2 in human A549 non-small cell lung cancer cells inhibited proliferation and induced sensitization to cisplatin (DNA cross-linker), melphalan (alkylating agent), the poly(ADP-ribose) polymerase inhibitor olaparib, and the thymidylate synthase (TS)-targeting agent 5-fluorodeoxyuridine. Three novel oligodeoxynucleotides (ODNs) were synthesized to target the BRCA2 mRNA, 2 against the coding region (ODNs BR1 and BR2) and the other in the 3′-untranslated region (BR3). All three ODNs sensitized A549 cells to cisplatin by up to 80%, and BR1 synergistically inhibited proliferation in combination with an antisense ODN targeting TS, SARI-083. A combination of siRNA treatments that knocked down both BRCA2 and TS sensitized cells to a combination of alkylating agents (cisplatin or melphalan) and a TS-targeting drug (5-FUdR). This combination was more effective at inhibiting proliferation than would be predicted by knockdown of TS and BRCA2 followed by treatment with any single drug (5-FUdR, cisplatin, or melphalan). These data suggest that: (1) targeting BRCA2 is a viable strategy to increase the effectiveness of common chemotherapeutic drugs; and (2) it is possible to use antisense-mediated targeting of both TS and a DNA repair protein to sensitize the same cell to two different drugs, and thus potentiate overall therapeutic effectiveness. This is progressing towards human trials. Supported by a grant from the Canadian Institutes of Health Research (CIHR) to JK and MDV. MR is a scholar of the CIHR Strategic Training Program in Cancer Research and Technology Transfer (CaRTT) and a recipient of the Queen Elizabeth II Scholarship in Science and Technology. Citation Format: Peter J. Ferguson, Mateusz Rytelewski, Mark D. Vincent, René Figueredo, James Koropatnick. Sensitization of human tumor cells to chemotherapy drugs by antisense downregulation of BRCA2 and thymidylate synthase (TS): Induction of synthetic lethality by targeting DNA repair. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3314. doi:10.1158/1538-7445.AM2013-3314
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 machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,004 | 0,001 |
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 source (Gemma direct ou Codex distillé), 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 ».