Related Experiment Videos
[New taxanes and epothilone derivatives in clinical trials]
1Société française du cancer, 6, rue Louis-Thuillier, 75005 Paris, France. francois.lavelle@wanadoo.fr
Abstract:
This review describes the experimental and clinical properties of new taxanes and epothilones. Six new taxanes are currently in clinical trials: BMS 184476, BMS 188797, BMS 275183, IDN 5109/BAY 598862, RPR 109881A et RPR 116258 All these derivatives share the same feature which is a decreased recognition by Pgp-170, the product of the MDR1 gene. This confers innovative properties such as in vitro and in vivo activities on tumors expressing the Pgp-170, activity by the oral route. Identification of other families of molecules bearing the same mechanism of action as taxol has been a goal pursued by many groups. The discovery of epothilones led to the pharmaceutical development of two molecules: EPO 906 (which corresponds to the natural compound epothilone B) and BMS 247550. Phase I clinical trials have established that all these investigational drugs (taxanes and epothilones) can be safely administered in patients, the limiting toxicity being most of the time febrile neutropenia. Many tumor responses have been noted.
Insights
New taxanes and epothilones show promise in cancer treatment. These drugs overcome multidrug resistance and demonstrate efficacy, with manageable toxicities in early clinical trials.
Area of Science:
- Pharmacology and Experimental Therapeutics
- Oncology
- Medicinal Chemistry
Background:
- Taxanes and epothilones are crucial chemotherapeutic agents.
- Multidrug resistance (MDR), mediated by P-glycoprotein (Pgp-170), limits treatment efficacy.
- Development of novel agents overcoming MDR is a significant challenge in cancer therapy.
Purpose of the Study:
- To review the experimental and clinical properties of new taxane and epothilone derivatives.
- To highlight agents designed to overcome Pgp-170-mediated multidrug resistance.
- To assess the safety, efficacy, and therapeutic potential of these novel anticancer drugs.
Main Methods:
- Review of preclinical data and Phase I clinical trial results for new taxanes and epothilones.
- Analysis of molecular mechanisms, including Pgp-170 recognition and drug resistance profiles.
- Evaluation of in vitro and in vivo antitumor activity and pharmacokinetic properties.
Main Results:
- Six new taxane derivatives (e.g., BMS 184476, IDN 5109) exhibit reduced Pgp-170 recognition, enabling activity against resistant tumors.
- Epothilone derivatives (EPO 906, BMS 247550) have been developed, showing therapeutic potential.
- Investigational taxanes and epothilones demonstrate favorable safety profiles in Phase I trials, with febrile neutropenia as a common dose-limiting toxicity.
- Significant tumor responses have been observed across multiple studies.
Conclusions:
- Novel taxanes and epothilones represent a promising class of anticancer agents, particularly for MDR-positive tumors.
- These agents offer potential for oral administration and demonstrate significant antitumor activity.
- Further clinical development is warranted to establish their role in cancer treatment regimens.