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The role of the MDR1 gene in the development of multidrug resistance in human hepatoblastoma
Author(s) -
Warmann Steven,
Hunger Mona,
Teichmann Birgit,
Flemming Peer,
Gratz Klaus Friedrich,
Fuchs Jörg
Publication year - 2002
Publication title -
cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.052
H-Index - 304
eISSN - 1097-0142
pISSN - 0008-543X
DOI - 10.1002/cncr.10858
Subject(s) - hepatoblastoma , chemosensitizer , chemotherapy , cisplatin , medicine , multiple drug resistance , in vivo , cancer research , gene expression , drug resistance , transplantation , gene , pathology , biology , biochemistry , microbiology and biotechnology
BACKGROUND The P‐glyprotein (P‐gp), which is a membrane channel encoded by the MDR1 gene, represents a possible explanation for multidrug resistance in human hepatoblastoma (HB). P‐gp shows up‐regulation in tumor cells after chemotherapy; however, to date, its exact role in HB has not been described. The authors investigated the role of the MDR1 gene in the clinical course of patients with HB and in an in vivo model of HB. They also studied the effects of the MDR1 antagonizer PSC 833 on chemotherapy in mice xenotransplanted with HB. METHODS Resected tumor specimens, including both primary tumors and recurrent tumors, from a child suffering from HB were investigated histologically. Cell suspensions from the originally removed tumor were incorporated subcutaneously into nude mice. Animals were treated with cisplatin (CDDP) plus PSC 833. MDR1 gene expression levels in the different resected tumors from the patient and in the xenotransplants after treatment were determined with polymerase chain reaction analysis. RESULTS MDR1 gene expression was increased in the patient's tumors after every course of chemotherapy from 30% to > 190%. In the xenotransplants, MDR1 gene expression was enhanced significantly after chemotherapy ( P CDDP = 0.008; P CDDP+PSC = 0.002). Tumor volumes ( P < 0.001) and serum α‐fetoprotein levels ( P = 0.0002) were significantly lower in the animals that were treated with CDDP + PSC compared with the animals that were treated with CDDP alone. CONCLUSIONS The current results suggest that MDR1 gene expression and P‐gp are a potential mechanism of drug resistance in HB. The chemosensitizer PSC 833 significantly improved the effects of chemotherapy in animals xenotransplanted with HB. These data encourage further studies concerning the role of chemosensitizers in overcoming multidrug resistance in patients with HB. Cancer 2002;95:1795–801. © 2002 American Cancer Society. DOI 10.1002/cncr.10858