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J Korean Cancer Assoc > Volume 31(4); 1999 > Article
Journal of the Korean Cancer Association 1999;31(4): 773-783.
Effects of New Nultidrug - Resistance Reversing Agent, KR-30035, on Tumoral Uptake of Tc-99m MIBI In-vitro and In-vivo
Ihn Ho Cho, Jaetae Lee, Jang Soo Suh, Byung Ho Lee, Sang Woon Choi, Sang Kyun Sohn, Chong Ock Lee, Sung Eun Yoo, June Key Chung, Kyu Bo Lee
1Department of Nuclear Medicine, School of Medicine Kyungpook National University, Taegu, Korea.
2Cancer Research Institute, School of Medicine Kyungpook National University, Taegu, Korea.
3Bioorganic Science Division Korea Institute of Chemical Technology, Taejon, Korea.
4Department of Nuclear Medicine, Seoul National University Hospital, Seoul, Korea.
Verapamil is one of the most extensively characterized modulators of P-glyco- protein (P-gp) mediated multi-drug resistance (MDR), but its plasma concentration required to reverse MDR can cause cardiovascular toxicity. KR-30035 is a newly synthesized verapamil analogue with more potent cytostatic effects, but has lower cardiovascular effects than verapamil. We have assessed the MDR reversing effects of KR-30035 by measuring Tc-99m MIBI uptake in cultured tumor cells and in nude mice bearing human tumor xenografts.
In-vitro uptake of Tc-99m MIBI was measured in murine leukemia cells (L-1210) and those MDR-positive variants after incubation with different concentrations of KR-30035. Results were compared to those with verapamil. Organ and tumoral uptake of Tc-99m MIBI was compared between P-gp (+) human colon cancer (HCT15 cells) and P-gp (-) lung cancer (A549 cells) in nude mice, treated with either KR-30035 or verapamil.
There was no significant difference in in-vitro uptake of Tc-99m MIBI between verapamil and KR-30035 group at any concentrations. MIBI uptake in P-gp (+) cells continuously increased either with verapamil or KR-30035 in a dose-dependent manner. Tc-99m MIBI uptake ratios of the tumor [P-gp (+' tumor uptake divided by P-gp (-) uptake] were significantly higher with KR-30035 than with verapamil in tumor bearing nude mice. Washout rate of Tc-99m MIBI from P-gp (+) HCT15 cells was lower in verapamil or KR-30035 groups than in the control group, which was 0.19, 0.19 and 0.27 respectively.
These studies revealed that KR-30035 can potentially be used as an active modulator of MDR, with its significantly lesser cardiovascular toxicity than verapamil. Our results warrants further evaluation of this novel agent.
Key words: KR-30035;Verapamil;Multi-drug resistance;Tc-99m MIBI
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