sdz-psc-833 and Hepatoblastoma

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.. 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.. 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.. 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.

Topics: Animals; Antineoplastic Agents; ATP Binding Cassette Transporter, Subfamily B; Cisplatin; Cyclosporins; Drug Resistance, Multiple; Gene Expression Regulation, Neoplastic; Genes, MDR; Hepatoblastoma; Humans; Infant; Liver Neoplasms; Male; Mice; Neoplasms, Experimental; Transplantation, Heterologous; Up-Regulation

P-glycoprotein, a membrane efflux pump encoded by the MDR1 gene, plays an important role in the development of multidrug resistance in human hepatoblastoma (HB). Chemosensitizers antagonize the efflux action of P-glycoprotein. This study investigates the effects of 3 chemosensitizers (the cyclosporin analogue SDZ PSC 833 (PSC 833), the acridone carboxamide derivative GG 918, and verapamil) on the chemotherapy of HB in vitro.. The doxorubicin (DOXO) concentration that produces 50% growth inhibition (IC50) in a HB cell line was determined and additional effects of PSC 833, GG 918, and verapamil were investigated in a cytotoxicity assay. The MDR1 gene expression after treatment was determined in a semiquantitative reverse transcription polymerase chain reaction approach.. The IC50 of DOXO is 2.5 microg/mL, 0.61 microg/mL for DOXO + PSC 833, 1.17 microg/mL for DOXO + verapamil, and 1.47 microg/mL for DOXO + GG 918. In combination with DOXO, cell growth was inhibited 4.1-fold by PSC 833, 2.1-fold by verapamil, and 1.9-fold by GG 918. The MDR1 gene expression was enhanced significantly in all treated cells, with and without modulator.. MDR1 modulators significantly improve the response of HB to DOXO in vitro. The combination of anticancer agents and MDR1 modulators might be a possible contribution to overcome multidrug resistance in HB.

Topics: Acridines; Antibiotics, Antineoplastic; ATP Binding Cassette Transporter, Subfamily B, Member 1; Cyclosporins; Doxorubicin; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Gene Expression; Genes, MDR; Hepatoblastoma; Humans; Inhibitory Concentration 50; Isoquinolines; Liver Neoplasms; Tetrahydroisoquinolines; Tumor Cells, Cultured; Verapamil