P-glycoprotein modulation improves in vitro chemosensitivity in malignant pediatric liver tumors.
BACKGROUND
Multidrug resistance (MDR) is a major reason for the poor outcome of advanced pediatric liver malignancies. The P-glycoprotein (P-gP), which contributes to this phenomenon, has been potently antagonized in other tumors. Our aim was to investigate the influence of P-gP antagonizers on the chemotherapy of pediatric liver malignancies in vitro.


METHODS
One hepatocellular carcinoma (HCC) and three hepatoblastoma (HB) cell lines were incubated with doxorubicin or cisplatin. Additional effects of three P-gP-modulators were determined in a cytotoxicity assay. Expression levels of the MDR1 gene were determined using rT-PCR.


RESULTS
Modulation of P-gP improved chemotherapy results in all HB cell lines, more effectively in the more highly differentiated tumors. Combined treatment of the HCC cell line was only more efficient using doxorubicin and PSC 833.


CONCLUSIONS
Modulation of P-gP can overcome MDR in HCC and HB in vitro. Our data encourage further studies analyzing this effect under in vivo conditions.
Department of Pediatric Surgery, University of Tübingen, Hoppe-Seyler-Str. 3, 72076 Tübingen, Germany. Steven.Warmann@med.uni-tuebingen.de
Steven
S
Warmann
Gudrun
G
Göhring
Birgit
B
Teichmann
Heinz
H
Geerlings
Torsten
T
Pietsch
Jörg
J
Fuchs
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000502:physiology; D000166:Acridines / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects; D002648:Child; D002945:Cisplatin / Q000627:therapeutic use; D003524:Cyclosporins / Q000627:therapeutic use*; D004317:Doxorubicin / Q000627:therapeutic use; D018432:Drug Resistance, Multiple / Q000187:drug effects; D018197:Hepatoblastoma / Q000188:drug therapy / Q000473:pathology; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000473:pathology; D044005:Tetrahydroisoquinolines / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000166:Acridines; D000970:Antineoplastic Agents; D003524:Cyclosporins; D044005:Tetrahydroisoquinolines; D004317:Doxorubicin; C083501:Elacridar; D002945:Cisplatin; C070272:valspodar