Differential effects of the optical isomers of KR30031 on cardiotoxicity and on multidrug resistance reversal activity
- 1 February 2003
- journal article
- Published by Ovid Technologies (Wolters Kluwer Health) in Anti-Cancer Drugs
- Vol. 14 (2), 175-181
- https://doi.org/10.1097/00001813-200302000-00012
Abstract
The present study was performed to compare the cardiovascular adverse effects of verapamil, KR30031 and their optical isomers, and also to measure their ability to overcome multidrug resistance (MDR). The R-isomer of KR30031 (R-KR30031) was equipotent with the S-isomer of KR30031 (S-KR30031) and 25-fold less potent than the R-isomer of verapamil (R-verapamil) in relaxing the aorta isolated from rat (EC50: 11.8, 10.2 and 0.46 microM, respectively). The effect of R-KR30031 in decreasing left ventricular pressure of heart isolated from rat was 2- and 267-fold smaller than those of S-KR30031 and R-verapamil, respectively (EC50: 23.9, 9.4 and 0.089 mM, respectively). The hypotensive effect of R-KR30031 in rat was about 2- and 23-fold smaller than those of S-KR30031 and R-verapamil, respectively (ED20: 1.15, 0.60 and 0.05 mg/kg, respectively). On the other hand, R-KR30031 elicited potency similar to those of S-KR30031 and R-verapamil in enhancing the paclitaxel-induced cytotoxicity to HCT15/CL02 and MES-SA/DX5 cells that reveal high levels of P-glycoprotein expression (IC50: 3.11, 3.04 and 2.58 microM, respectively). In addition, the intrinsic cytotoxicity of R-KR30031 in HCT15/CL02 and MES-SA/DX5 cells was observed only at the very high concentration of 100 microM. All these results suggest that R- and racemic KR30031 are active modulators of MDR with potentially minimal cardiovascular adverse activity.Keywords
This publication has 11 references indexed in Scilit:
- Verapamil increases the survival of patients with anthracycline-resistant metastatic breast carcinomaAnnals Of Oncology, 2000
- Effects of the optical isomers of verapamil on electrophysiological properties of the heart in conscious dogs.European Journal of Pharmacology, 1998
- Reversal of multidrug resistance by novel verapamil analogs in cancer cellsAnti-Cancer Drugs, 1998
- Establishment of doxorubicin-resistant subline derived from HCT15 human colorectal cancer cellsArchives of Pharmacal Research, 1996
- Phase I/II trial of dexverapamil plus vinblastine for patients with advanced renal cell carcinoma.Journal of Clinical Oncology, 1995
- Effects of cyclosporin A and a non-immunosuppressive analogue, O-acetyl cyclosporin A, upon the growth of parent and multidrug resistant human lung cancer cells in vitroBritish Journal of Cancer, 1992
- D‐verapamil and L‐verapamil are equally effective in increasing vincristine accumulation in leukemic cells in vitroInternational Journal of Cancer, 1988
- Homology between P-glycoprotein and a bacterial haemolysin transport protein suggests a model for multidrug resistanceNature, 1986
- The effect of dextro-, levo-, and racemic verapamil on atrioventricular conduction in humansAmerican Heart Journal, 1985
- Coronary Vasodilator and Cardiac Effects of Optical Isomers of Verapamil in the DogJournal of Cardiovascular Pharmacology, 1980