Human Tumor Xenografts as Predictive Preclinical Models for Anticancer Drug Activity in Humans: Better than Commonly Perceived—But They Can Be Improved
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Notice bibliographique
Résumé
It is not uncommon for new anti-cancer drugs or therapies to show highly effective, and sometimes even spectacular anti-cancer treatment results using transplantable tumors in mice. These models frequently involve human tumor xenografts grown subcutaneously in immune deficient hosts such as athymic (nude) or severe combined immune deficient (SCID) mice. Unfortunately, such preclinical results are often followed by failure of the drug/therapy in clinical trials, or, if the drug is successful, it usually has only modest efficacy results, by comparison. Not surprisingly, this has provoked considerable skepticism about the value of using such preclinical models for early stage in vivo preclinical drug testing. As a result, a shift has occurred towards developing and using spontaneous mouse tumors arising in transgenic and/or knockout mice engineered to recapitulate various genetic alterations thought to be causative of specific types of respective human cancers. Alternatively, the opinion has been expressed of the need to refine and improve the human tumor xenograft models, e.g., by use of orthotopic transplantation and therefore promotion of metastatic spread of the resultant "primary" tumors. Close inspection of retrospective and prospective studies in the literature, however, reveals that human tumor xenografts-even non metastatic ectopic/subcutaneous "primary" tumor transplants-can be remarkably predictive of cytotoxic chemotherapeutic drugs that have activity in humans, when the drugs are tested in mice using pharmacokinetically clinically equivalent or "rational" drug doses. What may be at variance with clinical activity, however, is the magnitude of the benefit observed in mice, both in terms of the degree of tumor responses and overall survival. It is argued that this disparity can be significantly minimized by use of orthotopic transplant/metastatic tumor models in which treatment is initiated after the primary tumor has been removed and the distant metastases are well established and macroscopic-i.e., the bar is raised and treatment is undertaken on advanced, high volume, metastatic disease. In such circumstances, survival should be used as an endpoint; changes in tumor burden using surrogate markers or micro-imaging techniques can be used as well to monitor effects of therapies on tumor response. Adoption of such procedures would more accurately recapitulate the phase I/II/III clinical trial situation in which treatment is initiated on patients with advanced, high-volume metastatic disease.
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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) | 0,000 | 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 | 0,000 |
| 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 découle