Synthesis and biological evaluation of taxinine analogues as orally active multidrug resistance reversal agents in cancer.

Abstract

Three novel taxinine analogues were prepared and tested for their activity as multidrug resistance (MDR) reversal agents in comparison with verapamil. In vitro testing demonstrated that compounds 8-10 possess MDR-reversal activity in the KB/V cell line. Half-hour after treatment with 5, 10, and 20 micromol/L compound 9, the intracellular rhodamine123 concentration increased 2.3, 2.9, and 3.2-fold, respectively, higher than 1.88-fold of 10 micromol/L verapamil in KB/V cell line. In vivo studies with VCR-resistant KB/V tumor xenografts showed that compound 9 in combination with VCR significantly inhibited tumor growth. Treatment with VCR or 9 alone did not result in growth inhibition. These results reveal that three taxinine analogues are good modifiers of MDR in tumor cells.

• Authors: Xin Zhao, Jun Gu, Dali Yin, Xiaoguang Chen
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 14 Issue 18 Pg. 4767-70 (Sep 20 2004) ISSN: 0960-894X [Print] England
• PMID: 15324905 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Taxoids
• Vincristine
• taxinine

Topics

• Administration, Oral
• Animals
• Antineoplastic Agents (administration & dosage, chemical synthesis, pharmacology)
• Carcinoma, Squamous Cell (drug therapy)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Dose-Response Relationship, Drug
• Drug Resistance, Multiple (drug effects)
• Drug Resistance, Neoplasm (drug effects)
• Humans
• Mice
• Mice, Nude
• Taxoids (administration & dosage, chemical synthesis, pharmacology)
• Time Factors
• Vincristine (pharmacology)
• Xenograft Model Antitumor Assays