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.
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Authors | Byung Ho Lee, Chong Ock Lee, Myung-Ja Kwon, Kyu Yang Yi, Sung-Eun Yoo, Sang-Un Choi |
Journal | Anti-cancer drugs
(Anticancer Drugs)
Vol. 14
Issue 2
Pg. 175-81
(Feb 2003)
ISSN: 0959-4973 [Print] England |
PMID | 12569305
(Publication Type: Journal Article)
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Copyright | Copyright 2003 Lippincott Williams & Wilkins |
Chemical References |
- ATP Binding Cassette Transporter, Subfamily B, Member 1
- Antineoplastic Agents
- Calcium Channel Blockers
- KR30031
- Doxorubicin
- Verapamil
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Topics |
- ATP Binding Cassette Transporter, Subfamily B, Member 1
(metabolism)
- Animals
- Antineoplastic Agents
(adverse effects, pharmacology)
- Aorta
(drug effects)
- Blood Pressure
(drug effects)
- Calcium Channel Blockers
(toxicity)
- Colorectal Neoplasms
(metabolism, pathology, prevention & control)
- Doxorubicin
(adverse effects, pharmacology)
- Drug Resistance, Multiple
- Drug Resistance, Neoplasm
- Female
- Humans
- Isomerism
- Male
- Rats
- Rats, Sprague-Dawley
- Tumor Cells, Cultured
(drug effects, metabolism, pathology)
- Uterine Neoplasms
(metabolism, pathology, prevention & control)
- Vasodilation
(drug effects)
- Ventricular Function, Left
(drug effects)
- Verapamil
(analogs & derivatives, toxicity)
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