The role of the MDR1 gene in the development of multidrug resistance in human hepatoblastoma: clinical course and in vivo model.
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 alpha-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.
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000096:biosynthesis* / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002945:Cisplatin / Q000494:pharmacology; D003524:Cyclosporins / Q000494:pharmacology; D018432:Drug Resistance, Multiple / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D019450:Genes, MDR / Q000235:genetics*; D018197:Hepatoblastoma / Q000188:drug therapy* / Q000235:genetics*; D006801:Humans; D007223:Infant; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D008297:Male; D051379:Mice; D009374:Neoplasms, Experimental; D014183:Transplantation, Heterologous; D015854:Up-Regulation
D018435:ATP Binding Cassette Transporter, Subfamily B; D000970:Antineoplastic Agents; D003524:Cyclosporins; D002945:Cisplatin; C070272:valspodar