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Novel multidrug-resistance modulators, KR-30026 and KR-30031, in cancer cells.

Abstract
The present study was performed to evaluate the ability of KR-30026 and KR-30031 to overcome multidrug resistance (MDR) by measuring the cytotoxicity of paclitaxel and the rate of rhodamine accumulation, which were then compared with verapamil. KR-30026 potentiated the paclitaxel-induced cytotoxicity of HCT15 to over 60 fold greater than that of verapamil, and KR-30031 was equipotent with verapamil (EC50: 0.00066, 0.04 and 0.05 nM at 4.0 micrograms/ml, respectively). KR-30026 and KR-30031 were without effect on paclitaxel-induced cytotoxicity to SK-OV-3 cells, as well as on tamoxifen-induced cytotoxicity to HCT15, HCT15/CL02 and SK-OV-3 cells. Maximal rhodamine accumulation by KR-30026, KR-30031 and verapamil were similar in HCT15 cells, while KR-30026 was more potent than verapamil in HCT15/CL02 cells (721 and 440%, respectively). To evaluate the cardiac toxicity of KR-30026 and KR-30031, the changes of tension in isolated rat aorta and left ventricular pressure (LVP) in guinea pig heart were determined; KR-30026 and KR-30031 were 15-40 and 25-70 fold less potent than verapamil, respectively. These results suggest that KR-30026 and KR-30031 are active modulators of MDR with potentially minimal cardiovascular toxicity.
AuthorsS U Choi, B H Lee, K H Kim, E J Choi, S H Park, H S Shin, S E Yoo, N P Jung, C O Lee
JournalAnticancer research (Anticancer Res) 1997 Nov-Dec Vol. 17 Issue 6D Pg. 4577-82 ISSN: 0250-7005 [Print] Greece
PMID9494571 (Publication Type: Journal Article)
Chemical References
  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Rhodamines
  • Verapamil
  • Paclitaxel
Topics
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 (biosynthesis)
  • Animals
  • Aorta, Thoracic (physiology)
  • Cell Survival (drug effects)
  • Colorectal Neoplasms
  • Drug Resistance, Multiple
  • Female
  • Guinea Pigs
  • Heart (drug effects, physiology)
  • Humans
  • In Vitro Techniques
  • Kinetics
  • Male
  • Molecular Structure
  • Muscle, Smooth, Vascular (drug effects, physiology)
  • Ovarian Neoplasms
  • Paclitaxel (toxicity)
  • Rats
  • Rats, Sprague-Dawley
  • Rhodamines (pharmacokinetics)
  • Tumor Cells, Cultured
  • Vasodilation (drug effects)
  • Verapamil (pharmacology)

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