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KMID : 0360319930250020225
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Journal of Korean Cancer Research Association
1993 Volume.25 No. 2 p.225 ~ p.235
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Effects of Verapamil, Tamoxifen and Cyclosporin A for the Modulation of Multidrug Resistance in Human Lung Cancer Cell Lines
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김주항
김병수/최정주/김경미/유내춘/최진혁/임호영/노재경/이경식
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Abstract
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The cellular mechanisms underlying the development of drug resistance are poorly understood. So far it has been shown that cells accumulate less drug due to an increase in drug efflux in cell lines expressing the classical multidrug
resistance(MDR)
phenotype. Verapamil, a calcium channel blocker, partially reverse the resistance of numerous MDR cell lines by decreasing drug efflux and increasing intracellular drug accumulation.
However some clinical trials for modulating the MDR, a particular difficulty lies in achieving plasma levels of the verapamil which might have the desired effect on tumor cell drug transport. The dosage of verapamil required to test these in
vitro
experimental data resulted in an unacceptable level of cardiac toxicities in clinical studies.
Nevertheless, a range of other membrane active compounds such as tamoxifen and cyclosporin A have been identified as possessing similar MDR modulating capacities. Accordingly we have examined the MDR modulating effects of verapamil, tamoxifen and
cyclosporin A in viro with the physiologically achievable concentrations of each agent, i.e., 2.5μM/S for verapamil, 2.0μM/L for tamoxifen and 1.6μM/L for cyclosporin A, respectively in human lung cancer cell lines. The cytotoxicity test was
determined by the semiautomated MTT assay.
@ES T he results are summarized as follows:
@EN 1) There was close relationship between the expression level of MDR1 RNA and level resistance to adriamycin.
2) Any MDR modulator of verapoamil, tamoxifen and cycloporin A shows the similar synergisitic interaction on adriamycin cytotoxicity in cell line of NCI-H810 which expresses the high MDR1 RNA but variable interactions in NCI-H209 which expresses
low
MDR1 RNA.
3) Administration of two modulator combination, especially the combination of tamoxifen and cyclosporin A, shows the more pronounced cell killing effect of the adriamycin compare to that of one modulator in NCI-H810.
4) Three modulator combination was not more effective on adriamycin cytotoxicity compare to that of two modulator combinations.
In summary, two modulator combinations, especially the tamoxifen and cyclosporin A, at concentrations of normally seen after the clinical administration of these modulators showed significant synergism on the sensitivity to adriamycin in high
MDR1
RNA
expressor of NCI-H810. These data indicate the need for in vivo trials.
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KEYWORD
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