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[Place of in vitro models in preclinical evaluation of anticancer drugs]
1Institut Bergonié, Bordeaux, France.
Abstract:
In vitro models have been intensively developed for several years for selecting new anticancer agents. The National Cancer Institute has even chosen as a primary screen of new molecules a panel of 60 human tumor cell lines. However, it may seem hazardous to rely too much on in vitro models for the discovery and selection of new anticancer drugs: (1 because no metabolism of the compounds occurs in cell culture; (2 because an in vitro cell line cannot be representative of an in situ tumor cell population; (3 because antiproliferative activity is only part of antitumor activity; (4 because the toxicologic properties of the molecules are not taken into account by in vitro systems; (5 because cell cultures do not allow any selectivity study between tumor cells and normal cells. With examples drawn from three different therapeutic classes, anthracyclines, taxoids and camptothecin derivatives, we show that in vitro tests are insufficiently predictive of antitumor potential. The excess of confidence allowed to these models may lead to premature decisions which are not after that justified by clinical trials.
Insights
In vitro cancer models are widely used but may inaccurately predict drug effectiveness. These models lack crucial factors like metabolism and toxicity, potentially leading to flawed anticancer drug selection.
Area of Science:
- Oncology
- Pharmacology
- Drug Discovery
Background:
- In vitro models, including the National Cancer Institute's 60 human tumor cell lines, are standard for anticancer agent screening.
- However, limitations exist regarding their predictive value for in vivo efficacy.
Purpose of the Study:
- To critically evaluate the predictive accuracy of in vitro models for anticancer drug discovery.
- To highlight the shortcomings of relying solely on in vitro data for selecting novel therapeutic agents.
Main Methods:
- Analysis of in vitro test limitations, including lack of metabolism, inability to represent in situ tumors, and absence of toxicity assessment.
- Case examples using anthracyclines, taxoids, and camptothecin derivatives to illustrate predictive discrepancies.
Main Results:
- In vitro models fail to account for critical factors such as drug metabolism and toxicological properties.
- Cell line models do not accurately reflect the complexity of in situ tumor microenvironments or allow for selectivity studies.
- Antiproliferative activity in vitro does not fully correlate with overall antitumor efficacy.
Conclusions:
- In vitro screening models provide insufficient predictive power for the actual antitumor potential of drug candidates.
- Over-reliance on in vitro data can result in premature decisions, leading to clinical trial failures.
- A more comprehensive approach is needed to bridge the gap between in vitro findings and clinical outcomes in anticancer drug development.