J Korean Cancer Assoc.
1999 Aug;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
- Affiliations
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- 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.
Abstract
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PURPOSE: 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.
MATERIALS AND METHODS
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.
RESULTS
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.
CONCLUSION
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.
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