Abstract A9: Potent preclinical impact of metronomic low-dose oral topotecan combined with the antiangiogenic drug pazopanib for the treatment of ovarian cancer
Notice bibliographique
Résumé
Abstract Low dose metronomic (LDM) chemotherapy has shown promising activity in many preclinical as well as some phase II clinical studies involving various tumor types. It involves chronic but close, regular administration of chemotherapeutic drugs without prolonged breaks. Combination of LDM chemotherapy with targeted biologic agents such as antiangiogenic drugs can sometimes induce striking anti-tumor effects in preclinical models, with minimal toxicity. The most encouraging clinical results thus far involve patients with metastatic breast cancer and recurrent metastatic ovarian cancer. Regarding the ovarian cancer trials, all have involved daily low-dose oral cyclophosphamide using a fixed dose of 50mg, combined with bevacizumab. However, there may be much more effective chemotherapy drugs for LDM chemotherapy-based treatments of ovarian cancer. Here we evaluated the impact of optimal biologic doses (OBDs) of LDM oral topotecan, a topo-isomerase-1 inhibitor already approved for refractory ovarian cancer, in combination with oral pazopanib, a receptor tyrosine kinase inhibitor which targets VEGF and PDGF receptors. Clones of the SKOV-3 human ovarian carcinoma cell line expressing secretable β-subunit of human choriogonadotropic (β-hCG) protein and firefly luciferase were generated, and evaluated for growth after orthotopic (intraperitoneal) injection into immune deficient SCID mice, and a highly aggressive clone, SKOV-3-13, was selected for further study. Treatments were initiated 14 days after injection of 3×106 cells when evidence of carcinomatosis-like disease in the peritoneum was established as assessed by imaging analysis. The drug concentrations were 1mg/kg for oral topotecan by daily gavage, 150mg/kg pazopanib daily gavage or 25mg/kg twice/day, and combinations of oral topotecan+pazopanib. These doses were based on suppressive effects on circulating endothelial progenitor cells, a method we have used previously to determine the OBD for other LDM chemotherapy regimens. Metronomic oral topotecan showed excellent anti-tumor activity, the extent of which was significantly enhanced by concurrent pazopanib, which itself had modest activity. The median survival value of mice in the control group was 34 days after start of treatment compared with 73 days for MTD topotecan, 41 days for 25mg/kg pazopanib, 41 days for 150mg/kg pazopanib, 90 days for oral topotecan, whereas all of the mice in the two oral topotecan/pazopanib combination treatment groups were still alive 150 days after initiation of treatment. Overt toxic side effect was not observed throughout the treatment period. Metronomic topotecan in combination with an antiangiogenic VEGF-pathway targeting drug, such as pazopanib should be considered for evaluation in clinical trials involving patients with advanced, recurrent epithelial ovarian cancer. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A9.
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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) | 0,001 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 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) | 0,002 | 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 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 ».