PMID: 9180151May 29, 1997Paper

Decreased drug accumulation in a mitoxantrone-resistant gastric carcinoma cell line in the absence of P-glycoprotein

International Journal of Cancer. Journal International Du Cancer
U KellnerS H Kaufmann

Abstract

An established gastric-carcinoma cell line, EPG85-257P, is extremely sensitive to mitoxantrone (IC50, 0.12 ng/ml). Stepwise selection with mitoxantrone for 3 years resulted in a cell line (EPG85-257RN) that is 7,056-fold resistant to mitoxantrone (IC50, 846 ng/ml) and displays cross-resistance to the topoisomerase(topo)-II poisons ametantrone (411x), etoposide (112x) and teniposide (60x) as well as the topo-I poisons 7-ethyl-10-hydroxycamptothecin (331x) and topotecan (58x). We now show that this resistance is multifactorial. Western blotting revealed a 5-fold decrease in topo-IIalpha polypeptide in the mitoxantrone-resistant cells. Immunohistochemistry and Western blotting failed to demonstrate P-glycoprotein overexpression. Formation of trapped topo-II-DNA complexes in the resistant cells required higher mitoxantrone concentrations than in parental cells, even though nuclei isolated from the EPG85-257RN cells formed cleavage complexes normally. In agreement with these observations, which suggest the possibility of a defect in mitoxantrone accumulation, examination of mitoxantrone accumulation in both cell lines by confocal laser microscopy revealed that the EPG85-257RN cells accumulate less mitoxantrone at steady state. From ...Continue Reading

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Citations

Jul 31, 1998·Leukemia & Lymphoma·S H KaufmannJ E Karp
Oct 20, 2007·Expert Review of Anticancer Therapy·Dexin Zhang, Daiming Fan
Aug 28, 2009·Expert Opinion on Drug Metabolism & Toxicology·Yi An, Weg M Ongkeko
Aug 20, 2015·Medicinal Research Reviews·Benny J EvisonSuzanne M Cutts
Jan 8, 2003·International Journal of Cancer. Journal International Du Cancer·Holger TönniesHermann Lage
Feb 2, 2006·International Journal of Cancer. Journal International Du Cancer·Hermann LageIsmail Yalcin
Aug 10, 2000·Biochemical Pharmacology·C H YangY C Chen
Feb 22, 2002·International Journal of Cancer. Journal International Du Cancer·Ulrike SteinManfred Dietel
May 6, 2016·Integrative Cancer Therapies·Sridaran DhivyaKumpati Premkumar
Feb 27, 2007·Cancer Metastasis Reviews·Robert W RobeySusan E Bates
Jun 21, 2015·Pharmacological Reviews·Dustin R WalshPeter A Friedman
Aug 19, 2000·International Journal of Hyperthermia : the Official Journal of European Society for Hyperthermic Oncology, North American Hyperthermia Group·H LageM Dietel
Feb 14, 2007·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Sophie VibetIgor Chourpa
Feb 24, 2001·Annals of the New York Academy of Sciences·C H Takimoto, R Thomas
Aug 3, 2019·International Journal of Molecular Sciences·Sabino RussiVitalba Ruggieri

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