title: Increased efficacy of CDDP in a xenograft model of hepatoblastoma using             the apoptosis sensitizer ABT-737.
abstract: The response of standard-risk hepatoblastoma (HB) to neoadjuvant cisplatin (CDDP) chemotherapy is excellent; however, in high-risk HB, drug resistance remains a major challenge. Alternative therapeutic strategies may consider combining cytotoxic drugs with apoptosis sensitizers as this has shown additive effects in various types of malignancies. Analysis of published expression databases have revealed an anti-apoptosis state in HB samples. Herein, we evaluated the synergistic effects of ABT-737 as a modulator of apoptosis in combination with CDDP in HB. To this end, clonogenic assays were performed with HepT1 and HUH6 HB cells to evaluate the synergistic effects of CDDP and ABT-737. Combination treatment with CDDP and ABT-737 reduced the clonogenicity of HB cells more than 5-fold compared to treatment with CDDP alone. Furthermore, the HUH6 mixed-type HB cells showed higher sensitivity to CDDP and combination treatment compared to the HepT1 embryonal-type cells. Subcutaneous HUH6 tumors in NOD/LtSz-scid IL2Rγnull mice were treated with CDDP (1.25 and 3 mg/kg body weight, n=6), ABT-737 (100 mg/kg, n=5) and the combination of both agents (n=5). Combined treatment led to a significantly reduced tumor growth compared to CDDP treatment alone (p<0.02). When using higher doses of CDDP (3 mg/kg) alone or in combination with ABT-737, dose-dependent toxicity was observed in this mouse strain. In conclusion, our results demonstrated the enhancement of chemotherapy efficacy by using modulators of apoptosis together with cytotoxic agents. Additive effects of ABT-737 may allow reduction in CDDP dosages with maintenance of antitumor activity. Sensitizing HB to apoptosis may also render resistant HB susceptible to established chemotherapy regimens.
authors.affiliation: Department of Paediatric Surgery and Paediatric Urology, University Children's Hospital, 72076 Tübingen, Germany. justus.lieber@med.uni-tuebingen.de
authors.forename: Justus
authors.initials: J
authors.lastname: Lieber
authors.forename: Alexander
authors.initials: A
authors.lastname: Dewerth
authors.forename: Julia
authors.initials: J
authors.lastname: Wenz
authors.forename: Bettina
authors.initials: B
authors.lastname: Kirchner
authors.forename: Carmen
authors.initials: C
authors.lastname: Eicher
authors.forename: Steven W
authors.initials: SW
authors.lastname: Warmann
authors.forename: Jörg
authors.initials: J
authors.lastname: Fuchs
authors.forename: Sorin
authors.initials: S
authors.lastname: Armeanu-Ebinger
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001713:Biphenyl Compounds / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000008:administration & dosage / Q000009:adverse effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D020869:Gene Expression Profiling; D018197:Hepatoblastoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009596:Nitrophenols / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D010879:Piperazines / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D013449:Sulfonamides / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D015431:Weight Loss / Q000187:drug effects
chemical_list: C501332:ABT-737; D001713:Biphenyl Compounds; D009596:Nitrophenols; D010879:Piperazines; D013449:Sulfonamides; D002945:Cisplatin