Abstract:
:The intensive use of chemotherapeutic agents for the treatment of cancer has resulted in the cure or improved survival of many patients. But unfortunately, many cancers including human hepatocellular carcinoma (HCC) don't respond to chemotherapy. One of the major mechanisms for the drug resistance in the HCC is an elevated MDR1 RNA expression which makes cells become multidrug resistant. To overcome the multidrug resistance (MDR) phenotype, a high dose of verapamil is required both clinically and experimentally. Accordingly we have examined the MDR modulating effects with combinations of tamoxifen, cyclosporin A, and verapamil in vitro with the physiologically achievable concentrations of each agent, i.e., 2.0 microM/L for tamoxifen, 1.6 microM/L for cyclosporin A, and 2.5 microM/L for verapamil respectively in HCC lines. As expected, verapamil alone with the physiologically achievable concentration at which we tested didn't enhance the doxorubicin cytotoxicity in the HCC lines. Furthermore, any verapamil combination with cyclosporin A or tamoxifen was not effective in overcoming the doxorubicin resistance in the high MDR1 expressor (Hep-G2) line. However tamoxifen reduced the IC50 of doxorubicin by a factor of 1.9 in the low MDR1 expressor (SK-Hep1) and 1.1 in the high MDR1 expressor line (p < 10(-5) respectively). Of interest, combinations of tamoxifen and cyclosporin A showed a significant reduction in the IC50 of doxorubicin in both HCC lines. The IC50 of doxorubicin was reduced by a factor of 3.9 and 1.3, i.e., from 0.023943 micrograms/ml to 0.006157 micrograms/ml (p < 10(-5)) in the SK-Hep1 cell line, and 0.068819 micrograms/ml to 0.052442 micrograms/ml (p < 10(-5)) in Hep-G2 respectively when tamoxifen and cyclosporin A were administered together. Both the estrogen and progesterone receptors in the SK-Hep1 and Hep-G2 lines were less than 0.01 fmol/mg of cytosol protein, respectively. It is therefore suggested that the reversal of doxorubicin resistance is unrelated to their anti-estrogenic activity in the HCC lines. Three modulator combinations of tamoxifen, cyclosporin A, and verapamil were not more effective than the combination of tamoxifen and cyclosporin A on the sensitivity to doxorubicin. MDR modulators of tamoxifen, cyclosporin A, and verapamil didn't reduce the IC50 of cisplatin to the clinically achievable concentration range in HCC lines. In summary, the combination of tamoxifen and cyclosporin A at the concentrations normally seen after clinical administration of these modulators showed significant synergism on the sensitivity to doxorubicin in both low and high MDR1 expressor HCC lines. These data indicate the need for in vivo trials.
journal_name
Yonsei Med Jjournal_title
Yonsei medical journalauthors
Kim JH,Chung JB,Park IS,Kim BS,Yoo NC,Choi JH,Roh JK,Kim HS,Kwon OH,Lee KSdoi
10.3349/ymj.1993.34.1.35subject
Has Abstract,Author List Incompletepub_date
1993-03-01 00:00:00pages
35-44issue
1eissn
0513-5796issn
1976-2437journal_volume
34pub_type
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journal_title:Yonsei medical journal
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doi:10.3349/ymj.2009.50.5.667
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journal_title:Yonsei medical journal
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更新日期:2020-02-01 00:00:00
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journal_title:Yonsei medical journal
pub_type: 杂志文章,随机对照试验
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更新日期:2018-07-01 00:00:00
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journal_title:Yonsei medical journal
pub_type: 杂志文章
doi:10.3349/ymj.2018.59.4.480
更新日期:2018-06-01 00:00:00
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journal_title:Yonsei medical journal
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更新日期:2004-04-30 00:00:00
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journal_title:Yonsei medical journal
pub_type: 杂志文章
doi:10.3349/ymj.1999.40.2.159
更新日期:1999-04-01 00:00:00
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journal_title:Yonsei medical journal
pub_type: 杂志文章
doi:10.3349/ymj.2004.45.5.885
更新日期:2004-10-31 00:00:00
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pub_type: 杂志文章
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更新日期:1992-03-01 00:00:00
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journal_title:Yonsei medical journal
pub_type: 杂志文章
doi:10.3349/ymj.2007.48.4.665
更新日期:2007-08-31 00:00:00
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pub_type: 杂志文章
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更新日期:2016-01-01 00:00:00
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journal_title:Yonsei medical journal
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doi:10.3349/ymj.2011.52.3.535
更新日期:2011-05-01 00:00:00
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pub_type: 杂志文章
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journal_title:Yonsei medical journal
pub_type: 杂志文章
doi:10.3349/ymj.2012.53.4.742
更新日期:2012-07-01 00:00:00
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journal_title:Yonsei medical journal
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doi:10.3349/ymj.2001.42.1.120
更新日期:2001-02-01 00:00:00
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更新日期:2012-09-01 00:00:00
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journal_title:Yonsei medical journal
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更新日期:1995-05-01 00:00:00
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journal_title:Yonsei medical journal
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doi:10.3349/ymj.2013.54.1.139
更新日期:2013-01-01 00:00:00
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journal_title:Yonsei medical journal
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更新日期:2015-07-01 00:00:00
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pub_type: 杂志文章
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journal_title:Yonsei medical journal
pub_type: 杂志文章
doi:10.3349/ymj.2014.55.3.644
更新日期:2014-05-01 00:00:00
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