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[Dose escalation strategies of molecular target drugs]
1Division of GI Oncology/Digestive Endoscopy, National Cancer Center Hospital East, Kashiwa, Japan.
Abstract:
During the last decade, advances in cell biology and molecular biology have produced molecular targets for cancer treatment, and many molecular targeted drugs, or "cytostatic agents," have been clinically evaluated. Dose limiting toxicities are not always observed with these drugs and there is little relationship between drug dose and biological effect. Therefore, the traditional strategy used in the clinical development of cytotoxic drugs may not be appropriate for evaluation of these cytostatic agents. In order to determine the optimum dose for these agents, new clinical strategies must be developed on the basis of the following considerations: 1. the relationship between the effective plasma concentration in preclinical data and mean trough plasma levels in clinical trials, 2. changes in plasma concentration in the tumor or expression of molecular targets according to dose escalation, and 3. application of surrogate markers for biological activity.
Insights
New clinical strategies are needed for evaluating cytostatic cancer drugs. Traditional methods for cytotoxic drugs are unsuitable due to the unique dose-response of molecular targeted therapies.
Area of Science:
- Molecular biology
- Cell biology
- Cancer research
Context:
- Recent advances in cell and molecular biology have identified novel molecular targets for cancer therapy.
- Numerous molecular targeted drugs, termed cytostatic agents, have undergone clinical evaluation.
- These agents often lack dose-limiting toxicities and show minimal correlation between dose and biological effect.
Purpose:
- To address the inadequacy of traditional cytotoxic drug development strategies for cytostatic agents.
- To propose new clinical strategies for determining optimal dosing of molecular targeted therapies.
- To guide the clinical development of novel cancer treatments.
Summary:
- Traditional clinical development strategies for cytotoxic drugs may not be appropriate for cytostatic agents.
- New strategies are required to determine optimal doses for molecular targeted therapies.
- Considerations include relating preclinical effective plasma concentrations to clinical trough levels, monitoring target engagement in tumors, and utilizing surrogate markers for biological activity.
Impact:
- Facilitates the development of more effective and personalized cancer treatments.
- Optimizes the clinical evaluation of molecular targeted drugs.
- Improves patient outcomes by ensuring appropriate dosing of novel cancer therapies.