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Therapeutic index: a vital component in selection of anticancer agents for clinical trial
1Clinical Oncology Unit, University of Bradford, West Yorkshire, United Kingdom.
Abstract:
In an attempt to identify anticancer agents more active in the major groups of solid cancers, the National Cancer Institute has replaced the primary murine tumor systems with an in vitro system using human cancer cell lines. A broader approach is being followed in Europe, where considerable reliance will still be placed on data from animal tumor systems. We argue the case for broader preclinical evaluation using animal model systems that are resistant to standard anticancer agents and thus reflect the clinical disease. Selection of compounds for clinical trials should be based on a therapeutic index that will give a more realistic representation of the margin between antitumor activity and toxicity to normal cells. Furthermore, preclinical evaluation can establish understanding of the factors responsible for treatment efficacy, including pharmacokinetics, metabolism, and drug bioavailability.
Insights
New preclinical models are needed to find better anticancer agents for solid cancers. Evaluating drug resistance and therapeutic index in animal models offers a more realistic approach to clinical trial selection.
Area of Science:
- Oncology
- Pharmacology
- Preclinical Research
Background:
- The National Cancer Institute (NCI) now uses in vitro human cancer cell lines for anticancer agent screening.
- European research continues to rely on animal tumor systems for preclinical evaluation.
- Current preclinical models may not accurately reflect the complexity of human solid cancers and drug resistance.
Purpose of the Study:
- To advocate for broader preclinical evaluation of anticancer agents.
- To emphasize the importance of using animal models resistant to standard therapies.
- To improve the selection process for compounds entering clinical trials.
Main Methods:
- Utilizing animal model systems resistant to standard anticancer agents.
- Assessing the therapeutic index for a realistic margin of antitumor activity versus normal cell toxicity.
- Investigating factors influencing treatment efficacy, including pharmacokinetics, metabolism, and bioavailability.
Main Results:
- Preclinical models resistant to standard agents better reflect clinical disease.
- Therapeutic index provides a more realistic measure of drug efficacy and safety.
- Understanding drug pharmacokinetics, metabolism, and bioavailability is crucial for treatment success.
Conclusions:
- Broader preclinical evaluation using resistant animal models is essential for identifying effective anticancer agents.
- Selection for clinical trials should prioritize compounds with a favorable therapeutic index.
- Comprehensive preclinical assessment enhances the understanding of drug efficacy in solid cancers.