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What is the optimal rodent model for anti-tumor drug testing?
1Division of Cancer Biology Research, Sunnybrook Health Science Centre, Toronto, Ontario. kerbel@scrl.sunnybrook.utoronto.ca
Abstract:
One of the most serious obstacles facing investigators involved in the development and assessment of new anti-cancer drugs is the failure of preclinical rodent tumor models to predict in a reliable way whether a given drug will have anti-tumor activity and acceptable toxicity in humans. Most previous investigations for assessing drug activity in vivo have utilized rapidly growing non-metastatic transplantable mouse or human tumors injected ectopically in syngeneic or nude mice, respectively. Some of the reasons for the inadequacy of such models are well known and, as a result, there has been a gradual movement toward the use of transgenic oncomouse models for anti-cancer drug testing. It is too early to conclude, one way or the other, whether these will be superior to transplantable tumor models. Moreover, such transgenic models have a number of limitations which are not widely appreciated. It is argued that transplantable tumor models, with various modifications, might be made significantly more predictive than current models, and would thus constitute a more economic alternative to the use of large numbers of transgenic oncomice. These modifications include the use of slower growing and genetically tagged (e.g. LacZ or GFP) tumors which are transplanted initially into orthotopic organ sites. These methods would facilitate the growth and detection of distant microscopic and macroscopic metastases, the response of which to anti-cancer drugs, using 'clinically equivalent doses,' could be evaluated.
Insights
Preclinical anti-cancer drug testing models often fail to predict human outcomes. Modified transplantable tumor models may offer a more reliable and economical alternative to transgenic models for evaluating drug efficacy.
Area of Science:
- Oncology
- Pharmacology
- Translational Medicine
Background:
- Preclinical anti-cancer drug development relies heavily on rodent tumor models.
- Current models, primarily transplantable tumors, often fail to accurately predict human drug efficacy and toxicity.
- Transgenic oncomouse models are increasingly used but have limitations and are costly.
Purpose of the Study:
- To evaluate the predictive value of preclinical anti-cancer drug testing models.
- To propose modifications to transplantable tumor models to enhance their predictive accuracy.
- To compare the utility of modified transplantable models versus transgenic models.
Main Methods:
- Review of existing preclinical anti-cancer drug testing methodologies.
- Analysis of limitations in current transplantable and transgenic rodent tumor models.
- Proposal for modified transplantable tumor models using genetically tagged, slower-growing tumors in orthotopic sites.
Main Results:
- Current preclinical models show poor correlation with human clinical outcomes.
- Transgenic models show promise but have unappreciated limitations and high costs.
- Modified transplantable models with genetic tagging and orthotopic implantation can better detect metastases.
Conclusions:
- Transplantable tumor models, when modified, can be significantly more predictive than current models.
- Modified transplantable models offer a more economical alternative to transgenic models for anti-cancer drug evaluation.
- Orthotopic transplantation of genetically tagged tumors facilitates metastasis assessment for improved drug response evaluation.