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The BH3 mimetic ABT-737 increases treatment efficiency of paclitaxel against hepatoblastoma
© Lieber et al; licensee BioMed Central Ltd. 2011
Received: 25 February 2011
Accepted: 19 August 2011
Published: 19 August 2011
The primary goal of current chemotherapy in hepatoblastoma (HB) is reduction of tumour volume and vitality to enable complete surgical resection and reduce risk of recurrence or metastatic disease. Drug resistance remains a major challenge for HB treatment. In some malignancies inhibition of anti-apoptotic pathways using small BH3 mimetic molecules like ABT-737 shows synergistic effects in combination with cystotoxic agents in vitro. Now we analysed toxicology and synergistic effects of this approach in HB cells and HB xenografts.
Viability was monitored in HB cells (HUH6 and HepT1) and fibroblasts treated with paclitaxel, ABT-737 and a combination of both in a MTT assay. HUH6 xenotransplants in NOD/LtSz-scid IL2Rγnull mice (NSG) were treated accordingly. Tumour volume and body weight were monitored. Xenografted tumours were analysed by histology and immunohistochemistry (Ki-67 and TUNEL assay).
ABT-737 reduced viability in HUH6 and HepT1 cells cultures at concentrations above 1 μM and also enhanced the cytotoxic effect of paclitaxel when used in combination. Thereby paclitaxel could be reduced tenfold to achieve similar reduction of viability of tumour cells. In contrast no toxicity in fibroblasts was observed at the same regiments. Subcutaneous HB (HUH6) treated with paclitaxel (12 mg/kg body weight, n = 7) led to delayed tumour growth in the beginning of the experiment. However, tumour volume was similar to controls (n = 5) at day 25. Combination treatment with paclitaxel and ABT-737 (100 mg/kg, n = 8) revealed significantly 10 fold lower relative tumour volumes compared to control and paclitaxel groups. Paclitaxel dependent toxicity was observed in this mice strain.
Our results demonstrate enhancement of chemotherapy by using modulators of apoptosis. Further analyses should include improved pharmacological formulations of paclitaxel and BH3 mimetics in order to reduce toxicological effects. Sensitising HB to apoptosis may also render resistant HB susceptible to established chemotherapy regimens.
Treatment results of children suffering from hepatoblastoma (HB) have been improved impressively during recent years. Current treatment strategies include neoadjuvant chemotherapy regimens and surgery in standard risk HB, achieving a 3-year overall survival probability of 96% [1–4]. However, the outcome of patients with high risk HB and relapsed HB (3-year survival: 69%) is still poor.
To improve outcome, therapy has been intensified using second-line cystostatic drugs in the standard treatment protocol for high risk HB . Paclitaxel is mainly used in treatment regimes for ovarian, breast and non-small cell lung cancer. It has also been applied in paediatric patients with refractory malignancies and has been proposed as potential agent against high risk HB [5–9]. Paclitaxel stabilizes microtubules and as a result, interferes with the normal breakdown of microtubules during cell division . This mitotic inhibitor promotes apoptosis as a secondary effect.
Apoptosis is an important factor in anticancer treatment and targeting this cell death mechanism has been constituted a promising alternative treatment option. HB cells express high amounts of anti-apoptotic molecules encoded by genes of the Bcl family [11, 12]. Bcl-2, an important member of this family, blocks cytochrome C release by sequestering pro-apoptotic BH3-only proteins such as tBid, Bad, Bax, and Bim. Bcl-2 overexpression plays a central role in resistance to chemotherapy in multiple malignancies including HB . Small BH3 mimetic molecules facilitate the activation of pro-apoptotic Bcl proteins by binding to the hydrophobic groove in Bcl-2 and Bcl-XL thus sensitizing tumour cells for apoptosis . One of these molecules, ABT-737, was developed as an anti-tumour agent, induces apoptosis by selectively inhibiting the anti-apoptotic proteins Bcl-2, Bcl-XL, and Bcl-W. ABT-737 as a single agent has shown activity against several hematopoietic cell lines (leucaemias, multiple myeloma and cultured lymphoma) and some solid tumour cell lines, whereas efficiency was high in small cell lung carcinoma only [15–19]. Because ABT-737 does not block Mcl-1, it is anticipated that this drug will be most effective as a single agent against tumours that express low levels of these pro-survival protein . Thus, ABT-737 may be active also in HB tumours, as gene expression analysis revealed a 2-fold lower expression of Mcl-1 in native HB tissue than in normal liver tissue . Highly synergistic in vivo effects have been described when combining ABT-737 with established chemotherapeutic drugs [15, 22]. In HB cells ABT-737 also induces apoptosis and enhances the effect of cytotoxic drugs (DOXO (doxorubicin), CDDP (cisplatin), paclitaxel and etoposide) commonly used in treatment protocols of HB .
In this study we describe the effects of ABT-737 in combination with paclitaxel in HB xenografts.
ABT-737 and its enantiomer were kindly provided by Abbott (Abbott GmbH & Co. KG, Wiesbaden, Germany). For in vitro studies ABT-737 and its enantiomer were dissolved in DMSO at 1 mM and diluted with medium to a final concentration in the cell culture of 0.01, 0.1, 0.3, and 1 μM. For animal studies ABT-737 was slowly dissolved in a mixture consisting of 30% propylene glycol, 5% Tween80 and 65% dextrose in water. The vehicle was brought to a pH of 1.0 by adding 5 mol HCL to enable the compound to go into solution supported by sonication. After the compound was in solution, the pH was slowly raised to 3-4 by addition of aqueous NaOH. Paclitaxel was provided by Neocorp AG (Weilheim, Germany).
Cells and culture conditions
The HB cell lines HepT1  and HUH6  were used for all experiments. The cells were transduced with a plasmid encoding gaussia luciferase (GLuc, pCMV-GLuc, NEB, Frankfurt am Main, Germany). Stable clones were isolated and maintained in DMEM (GIBCO BRL, Carlsbad, CA) supplemented with 10% FCS and G418. Tumour cells were grown as monolayer in Dulbecco's MEM medium (Biochrom, Berlin, Germany) supplemented with 10% fetal calf serum, 1% glutamine, and 2,5% HEPES buffer (Gibco, Eggenstein, Germany). The cells were grown at 37°C in a humidified atmosphere containing 5% carbon dioxide. All used cells were mycoplasma negative.
Fibroblasts were derived from human skin samples by tissue culture and grown as monolayer in the first three passages as described for tumour cells.
Cell viability assay
HB cells (10,000 cells/100 μl) were seeded out in 96-well plates (Becton Dickinson GmbH, Heidelberg, Germany) and cultured as described above. At day two, paclitaxel was added to the cells at 7 different concentrations around IC50 . ABT-737 was added to a final concentration in the cell culture of 0.01, 0.1, 1, and 3 μM. Experiments were repeated with fibroblasts and ABT-737 alone, as well as with ABT-737 combined with paclitaxel. Drug diluents were prepared shortly before administration. All assays were performed 3 times in quadruplicates.
Cell viability was assessed by MTT [3-(4.5-dimethylthiazol-2-yl)-2.5-diphenyl-tetrazoliumbromide]-assay (Sigma-Aldrich, Munich, Germany). 25 μl MTT (5 mg/ml) dissolved in PBS was added to each well. After incubation for 3 hours 100 μl/well lysis solution (10% SDS in acid water; Merck, Darmstadt, Germany) was added and further incubated over night in the dark at room temperature. Cell viability was assessed by measuring absorption at 570 nm using a Milena Kinetic Analyzer (DPC Bierman, Bad Nauheim, Germany). Percentages of cell viability were calculated by normalization of culture background without cells against untreated cultures as control. Dose dependent viability curves were computed by sigmoidal curves with variable slope to determine IC50.
For detecting apoptosis, the active caspase 3 assay was performed using Caspase-Glo™ 3/7 Assay according to the manufactory instructions (Promega, Mannheim, Germany). Briefly, 104 cells were seeded into a 96-well plate. After 24 h, the cells were treated with paclitaxel (0.1 and 0.3 μg/ml) and ABT-737 (0.3 μM). After treatment, the cells were harvested in Caspase substrate and luminescence was recorded for 10 seconds.
Animals and Xenotransplantation
Xenotransplantation was performed as previously described . All animal studies were approved by the local Government's ethical authority for animal experiments. (Regierungspräsidium Tübingen, Fachgebiet Tierschutz, Number K3/10). HUH6 cells were injected into the flank of 6-8 weeks old NOD/LtSz-scid IL2Rγnull mice (NSG). Animals were held under pathogen free conditions and were fed ad libitum with autoclaved food and sterilized water. For each tumour 0.2 ml of tumour cell suspension (2 × 106 cells) was injected subcutaneously into paravertebral areas. The observation time was 4 weeks, each group consisted of 6-8 animals. Treatment was initiated when tumours had reached a length of 5 mm. Paclitaxel in 200 μl saline solution was administered i.p. once per day on days 1-4 and 15-18 with a dosage of 12 mg/kg bodyweight. ABT-737 was administed i.p. with a dosage of 100 mg/kg bodyweight alone or in combination with paclitaxel using the same schedule. Drugs were prepared immediately prior to administration. Control animals were left untreated till day 25 unless tumour volume exceeded 1.5 cm3. Tumour volumes (V = 4/3π × a/2 × b/2 × c/2) and body weight of all animals were determined every 5 days. Relative tumour growth was calculated as a proportion of tumour volumes at each time point compared to day 0. Blood samples were taken from the retrobulbar plexus on days 0, 14, and 25. Serum GLuc activity was quantified in fresh serum. Therefore, 5 μl serum was added to 50 μl Gaussia GlowJuice (J.P.K. Instruments AG, Berlin, Germany) and GLuc activity was measured using a luminometer (Magic® Lite Analysator, Ciba Corning) after adding 1 μl coelenterazine 100 μM to acquire photon counts for 10 sec. Activity was expressed as relative light units per second (RLU/s). Tumours were explanted on day 25 and prepared for histological analysis.
Histology and Immunohistochemistry
Paraffin embedded sections obtained from xenografted tumours and liver were used for immunohistochemical staining against Ki-67. For each group 3 sections were cut (10 μm) from 4-5 different paraffined tumour blocks and mounted onto SuperFrost® Plus microscope slides (R. Langenbrinck, Emmendingen, Germany). Sections were fixed and dehydrated using graded alcohol. The endogenous peroxidase activity was blocked by adding 0.03% Peroxidase (Merck, Darmstadt, Germany) for 10 min. Unspecific binding sites were blocked by incubation with phosphate buffered saline (PBS) containing 0.1% Tween 20 (PBST) (Sigma Aldrich, Munich, Germany) and 1% goat serum (Dako, Carpinteria, CA, USA) for 30 min. Sections were incubated with monoclonal mouse anti-human Ki-67 antibody (1:400; Dako) over night. Polyclonal rabbit anti-rat IgG antibody (1:100 biotin-labeled; Biozol, Eching, Germany) was used as secondary antibody. Avidin-biotin-peroxidase-complex (ABC) and DAB staining was applied using ABC-Kit PK-6100 standard (Linaris, Wertheim, Germany) according to manufacturer's protocol. Positively dividing cells were stained brown. For nuclear staining sections were counterstained in Mayer's Haemalaun solution for 30 sec. The proliferation index (PI) was calculated through division of the number of Ki-67 positive cell nuclei by the number of all tumour cells per high power field (20×). PI was given as mean of 3 randomly evaluated regions for all tumour samples. Sections were also stained using standard Mayer's Haemalaun as well as Eosin G-dilution and were analyzed by microscopy (Axioscope 40; Carl Zeiss, Oberkochen, Germany).
Apotosis in explanted tumour tissue was assessed using TUNEL assay (Roche, Mannheim, Germany) according to the manufacturer's guidelines. Cells positive for apoptosis showed a green fluorescent signal and were visualized by fluorescence microscopy using a Zeiss Axio Scope epifluorescence microscope (Carl Zeiss GmbH, Oberkochen, Germany) and AxioVision software 3.1 (Carl Zeiss Vision, Aalen, Germany).
Statistical analysis of relative tumour growth and body weights at distinct time points was carried out by one way ANOVA followed by Dunns' multiple test using GraphPad Prism 4.00 (GraphPad Software, San Diego, Califonia, USA, http://www.graphpad.com). Viability curves and tumour growth were fitted with a sigmoidal dose response function with variable slope. F-Test was used to compare curve parameters of treatment with and without ABT-737. All numeric data were expressed as means. Data plotted on graphs represent means and SD. Significance was assumed for all p < 0.05.
Synergistic effect of paclitaxel and ABT-737 on HB cells
Treatment of HB-xenografts with a combination of paclitaxel and ABT-737
Apoptosis was detected by TUNEL assay. Thereby green fluorescent cells showed DNA fragmentation. The highest amount of apoptotic cells was seen in tumours after combined paclitaxel/ABT-737 treatment. Only in this group large areas of disintegrated tumours were detected. In summary, additive effects after paclitaxel and ABT-737 treatment were demonstrated in HB xenografts assessing tumour growth and histological appearance.
Toxicity of paclitaxel in NSG mice
Survival for children with HB is linked to complete resection of the primary tumour, which is possible in fewer than 50% of cases [1–3, 26]. Chemotherapy plays an essential role in the treatment of HB by reducing extension of primarily unresectable tumours [1, 2]. However, multi drug resistance develops in 80% of initially CDDP and DOXO sensitive patients after 4-5 courses of chemotherapy and remains a challenge in the optimization of treatment strategies. For high-risk and relapsed HB-characterized by complex drug resistance-various cytotoxic agents are used that have shown encouraging preclinical results as second line treatment in some interventional trials. Paclitaxel has proven efficiency in the treatment of HB cells in vitro and in xenotransplanted HB and has been proposed for the treatment of pediatric refractory malignancies [5, 6, 12]. In our study an initial tumour response to paclitaxel mono therapy was observed in xenografts. However, at the end of the observation time, tumours began to re-grow. Several mechanisms are currently under investigation in order to improve efficiency of chemotherapeutic agents .
One of them is modulation of apoptosis using small BH3 mimetic molecules, such as ABT-737, obatoclax, TW-37 and HA14 . ABT-737 induces apoptosis as a single drug when treating various cell lines including HB in vitro and has previously shown additive effects when combined with various cytotoxic drugs including paclitaxel [12, 15, 17, 22, 28]. We observed additive effects of the combined therapy using paclitaxel and ABT-737 in a xenograft HB model, resulting in inhibition of tumour growth. Similar to our findings, CDDP reduced tumour growth when used alone but was more effective in some HB xenografts when combined with inhibitors of multi drug resistant proteins [25, 29]. However, in this case the inhibitor targeted a putative induced expression of a particular drug resistant protein, which is also expressed in various normal tissues. In this study we used an inhibitor of an apoptosis modulating protein, thereby enhancing the tumour sensitivity to other drugs without compromising normal cells.
Paclitaxel is well tolerated in adults and children with some refractory or progressive solid tumours showing acceptable minor toxicity [30, 31]. However, dose-dependent neurotoxicity and some local toxic effects such as abdominal pain after treatment with paclitaxel, which is rapidly cleared by the liver, have also been described [32, 33]. In this study, toxicity of paclitaxel in NSG mice was observed. Other authors described no discernable increased toxicity, but used athymic NCr-nu ⁄ nu nude mice rather than NSG mice in their xenograft experiments [34, 35]. The more resistant strains such as NMRI mice were omitted from these experiments because of a lower HB incidence after xenotransplantation .
Some pharmacological properties of paclitaxel were changed in previous studies by chemical derivation and liposomal formulation in order to reduce liver toxicity. Docetaxel, a semi-synthetic analogue of paclitaxel also leading to tumour regression, was described without significant toxicity in athymic NMRI mice . The concept of reducing toxic effects by combining chemotherapeutics with natural compounds, such as beta-1,3-D-glucan, is very compelling, since some hepatotoxic side effects have finally been reported, even though higher paclitaxel dosage were used than in our study . In addition, lyophilized paclitaxel magnetoliposomes demonstrated to be effectively delivered to the tumour and exert significant anticancer activity with fewer side effects when administrated parenterally in a xenograft mouse model for breast carcinoma . However, we used paclitaxel in our study for a better comparability, since this agent had been used in previous studies of HB as well. Nevertheless, formulations with improved pharmacological properties might be more suitable for testing cytotoxic agents in NSG mice.
In contrast to paclitaxel, ABT-737 alone (100 mg/kg bodyweight) was not associated with toxic effects in this and other studies [15, 22]. But when combining paclitaxel and ABT-737, toxicity was even higher than after treatment with paclitaxel alone. Treatment with paclitaxel led to toxicity related death in 1 of 7 mice, but in the group treated with combined paclitaxel/ABT-737 3 of 8 animals died in the first treatment cycle and the remaining 5 during the second. Histological analysis of liver tissue after combination treatment revealed multiple piknotic cell nuclei as a sign of induction of apoptosis also in healthy tissues instead of direct hepatic toxicity . However, these local changes were unlikely to cause death exclusively. We assume that other tissues such as bowel and brain might have been affected, and will be assessed in further optimization studies. As the animals showed regeneration of body weight between the two cycles, elongation of the treatment free interval might reduce adverse side effects. Toxicity due to combination treatment may also be reduced by using second generation orally bioavailable BH3 mimetics, such as ABT-263 . ABT-263 might further increase additive effects of combination treatment in HB cells in vivo compared to ABT-737. In this coherency, reduction of paclitaxel dosages might become usable with maintainance of anti-tumour activity and synchronous lowering of side effects.
The primary goal of current chemotherapy in HB is reduction of tumour volume to enable complete surgical resection. Our results have proven optimization of chemotherapy by using modulators of apoptosis. However, improvement of pharmacological properties of both, paclitaxel and ABT-737, seems essential to reduce toxic side effects. Sensitising HB cells to apoptosis may restore sensitivity of resistant HB to established therapeutic regimens.
The authors wish to acknowledge ABBOTT Laboratories for providing ABT-737.
- Fuchs J, Rydzynski J, Von Schweinitz D, Bode U, Hecker H, Weinel P, Burger D, Harms D, Erttmann R, Oldhafer K, Mildenberger H: Pretreatment prognostic factors and treatment results in children with hepatoblastoma: a report from the German Cooperative Pediatric Liver Tumor Study HB 94. Cancer. 2002, 95 (1): 172-182. 10.1002/cncr.10632.View ArticlePubMedGoogle Scholar
- Perilongo G, Shafford E, Maibach R, Aronson D, Brugieres L, Brock P, Childs M, Czauderna P, MacKinlay G, Otte JB, Pritchard J, Rondelli R, Scopinaro M, Staalman C, Plaschkes J: Risk-adapted treatment for childhood hepatoblastoma. final report of the second study of the International Society of Paediatric Oncology--SIOPEL 2. Eur J Cancer. 2004, 40 (3): 411-421. 10.1016/j.ejca.2003.06.003.View ArticlePubMedGoogle Scholar
- Reynolds M: Conversion of unresectable to resectable hepatoblastoma and long-term follow-up study. World J Surg. 1995, 19 (6): 814-816. 10.1007/BF00299776.View ArticlePubMedGoogle Scholar
- Zsiros J, Maibach R, Shafford E, Brugieres L, Brock P, Czauderna P, Roebuck D, Childs M, Zimmermann A, Laithier V, Otte JB, de Camargo B, MacKinlay G, Scopinaro M, Aronson D, Plaschkes J, Perilongo G: Successful treatment of childhood high-risk hepatoblastoma with dose-intensive multiagent chemotherapy and surgery: final results of the SIOPEL-3HR study. J Clin Oncol. 2009, 28 (15): 2584-2590.View ArticleGoogle Scholar
- Andre N, Meille C: Taxanes in paediatric oncology: and now?. Cancer Treat Rev. 2006, 32 (2): 65-73. 10.1016/j.ctrv.2005.12.010.View ArticlePubMedGoogle Scholar
- Fuchs J, Habild G, Leuschner I, Schweinitz DV, Haindl J, Knop E: Paclitaxel: an effective antineoplastic agent in the treatment of xenotransplanted hepatoblastoma. Med Pediatr Oncol. 1999, 32 (3): 209-215. 10.1002/(SICI)1096-911X(199903)32:3<209::AID-MPO8>3.0.CO;2-0.View ArticlePubMedGoogle Scholar
- Heney M, Alipour M, Vergidis D, Omri A, Mugabe C, Th'ng J, Suntres Z: Effectiveness of liposomal paclitaxel against MCF-7 breast cancer cells. Can J Physiol Pharmacol. 2010, 88 (12): 1172-1180. 10.1139/Y10-097.View ArticlePubMedGoogle Scholar
- Pisters KM, Vallieres E, Crowley JJ, Franklin WA, Bunn PA, Ginsberg RJ, Putnam JB, Chansky K, Gandara D: Surgery with or without preoperative paclitaxel and carboplatin in early-stage non-small-cell lung cancer: Southwest Oncology Group Trial S9900, an intergroup, randomized, phase III trial. J Clin Oncol. 2010, 28 (11): 1843-1849. 10.1200/JCO.2009.26.1685.View ArticlePubMedPubMed CentralGoogle Scholar
- Sehouli J, Oskay-Ozcelik G: Use of paclitaxel for advanced ovarian cancer in clinical practice: analysis of 541 patients. Results from a German multi-centre observational study. Anticancer Res. 2010, 30 (10): 4245-4250.PubMedGoogle Scholar
- Ganguly A, Yang H, Cabral F: Paclitaxel-dependent cell lines reveal a novel drug activity. Mol Cancer Ther. 2010, 9 (11): 2914-2923. 10.1158/1535-7163.MCT-10-0552.View ArticlePubMedPubMed CentralGoogle Scholar
- Adesina AM, Lopez-Terrada D, Wong KK, Gunaratne P, Nguyen Y, Pulliam J, Margolin J, Finegold MJ: Gene expression profiling reveals signatures characterizing histologic subtypes of hepatoblastoma and global deregulation in cell growth and survival pathways. Hum Pathol. 2009, 40 (6): 843-853. 10.1016/j.humpath.2008.10.022.View ArticlePubMedPubMed CentralGoogle Scholar
- Lieber J, Kirchner B, Eicher C, Warmann SW, Seitz G, Fuchs J, Armeanu-Ebinger S: Inhibition of Bcl-2 and Bcl-X enhances chemotherapy sensitivity in hepatoblastoma cells. Pediatr Blood Cancer. 2010, 55 (6): 1089-1095. 10.1002/pbc.22740.View ArticlePubMedGoogle Scholar
- Warmann SW, Frank H, Heitmann H, Ruck P, Herberts T, Seitz G, Fuchs J: Bcl-2 gene silencing in pediatric epithelial liver tumors. J Surg Res. 2008, 144 (1): 43-48. 10.1016/j.jss.2007.03.054.View ArticlePubMedGoogle Scholar
- Chonghaile TN, Letai A: Mimicking the BH3 domain to kill cancer cells. Oncogene. 2008, 27 (Suppl 1): S149-157.View ArticlePubMed CentralGoogle Scholar
- High LM, Szymanska B, Wilczynska-Kalak U, Barber N, O'Brien R, Khaw SL, Vikstrom IB, Roberts AW, Lock RB: The Bcl-2 homology domain 3 mimetic ABT-737 targets the apoptotic machinery in acute lymphoblastic leukemia resulting in synergistic in vitro and in vivo interactions with established drugs. Mol Pharmacol. 2010, 77 (3): 483-494. 10.1124/mol.109.060780.View ArticlePubMedGoogle Scholar
- Konopleva M, Contractor R, Tsao T, Samudio I, Ruvolo PP, Kitada S, Deng X, Zhai D, Shi YX, Sneed T, Verhaegen M, Soengas M, Ruvolo VR, McQueen T, Schober WD, Watt JC, Jiffar T, Ling X, Marini FC, Harris D, Dietrich M, Estrov Z, McCubrey J, May WS, Reed JC, Andreeff M: Mechanisms of apoptosis sensitivity and resistance to the BH3 mimetic ABT-737 in acute myeloid leukemia. Cancer Cell. 2006, 10 (5): 375-388. 10.1016/j.ccr.2006.10.006.View ArticlePubMedGoogle Scholar
- Oltersdorf T, Elmore SW, Shoemaker AR, Armstrong RC, Augeri DJ, Belli BA, Bruncko M, Deckwerth TL, Dinges J, Hajduk PJ, Joseph MK, Kitada S, Korsmeyer SJ, Kunzer AR, Letai A, Li C, Mitten MJ, Nettesheim DG, Ng S, Nimmer PM, O'Connor JM, Oleksijew A, Petros AM, Reed JC, Shen W, Tahir SK, Thompson CB, Tomaselli KJ, Wang B, Wendt MD, et al: An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature. 2005, 435 (7042): 677-681. 10.1038/nature03579.View ArticlePubMedGoogle Scholar
- Trudel S, Stewart AK, Li Z, Shu Y, Liang SB, Trieu Y, Reece D, Paterson J, Wang D, Wen XY: The Bcl-2 family protein inhibitor, ABT-737, has substantial antimyeloma activity and shows synergistic effect with dexamethasone and melphalan. Clin Cancer Res. 2007, 13 (2 Pt 1): 621-629.View ArticlePubMedGoogle Scholar
- van Delft MF, Wei AH, Mason KD, Vandenberg CJ, Chen L, Czabotar PE, Willis SN, Scott CL, Day CL, Cory S, Adams JM, Roberts AW, Huang DC: The BH3 mimetic ABT-737 targets selective Bcl-2 proteins and efficiently induces apoptosis via Bak/Bax if Mcl-1 is neutralized. Cancer Cell. 2006, 10 (5): 389-399. 10.1016/j.ccr.2006.08.027.View ArticlePubMedPubMed CentralGoogle Scholar
- van Delft MF, Huang DC: How the Bcl-2 family of proteins interact to regulate apoptosis. Cell Res. 2006, 16 (2): 203-213. 10.1038/sj.cr.7310028.View ArticlePubMedGoogle Scholar
- E-MEXP-1851 D: [http://www.ebi.ac.uk/arrayexress/]
- Mason KD, Khaw SL, Rayeroux KC, Chew E, Lee EF, Fairlie WD, Grigg AP, Seymour JF, Szer J, Huang DC, Roberts AW: The BH3 mimetic compound, ABT-737, synergizes with a range of cytotoxic chemotherapy agents in chronic lymphocytic leukemia. Leukemia. 2009, 23 (11): 2034-2041. 10.1038/leu.2009.151.View ArticlePubMedGoogle Scholar
- Pietsch T, Fonatsch C, Albrecht S, Maschek H, Wolf HK, von Schweinitz D: Characterization of the continuous cell line HepT1 derived from a human hepatoblastoma. Lab Invest. 1996, 74 (4): 809-818.PubMedGoogle Scholar
- Doi I: Establishment of a cell line and its clonal sublines from a patient with hepatoblastoma. Gann. 1976, 67 (1): 1-10.PubMedGoogle Scholar
- Warmann SW, Heitmann H, Teichmann B, Gratz KF, Ruck P, Hunger M, Fuchs J: Effects of P-glycoprotein modulation on the chemotherapy of xenotransplanted human hepatoblastoma. Pediatr Hematol Oncol. 2005, 22 (5): 373-386. 10.1080/08880010590964192.View ArticlePubMedGoogle Scholar
- Exelby PR, Filler RM, Grosfeld JL: Liver tumors in children in the particular reference to hepatoblastoma and hepatocellular carcinoma: American Academy of Pediatrics Surgical Section Survey--1974. J Pediatr Surg. 1975, 10 (3): 329-337. 10.1016/0022-3468(75)90096-2.View ArticlePubMedGoogle Scholar
- Warmann SW, Fuchs J, Bitzer M, Lauer UM: Emerging gene-directed anti-tumor strategies against human hepatoblastoma. Expert Opin Biol Ther. 2009, 9 (9): 1155-1161. 10.1517/14712590903136696.View ArticlePubMedGoogle Scholar
- Chauhan D, Velankar M, Brahmandam M, Hideshima T, Podar K, Richardson P, Schlossman R, Ghobrial I, Raje N, Munshi N, Anderson KC: A novel Bcl-2/Bcl-X(L)/Bcl-w inhibitor ABT-737 as therapy in multiple myeloma. Oncogene. 2007, 26 (16): 2374-2380. 10.1038/sj.onc.1210028.View ArticlePubMedGoogle Scholar
- Warmann S, Gohring G, Teichmann B, Geerlings H, Fuchs J: MDR1 modulators improve the chemotherapy response of human hepatoblastoma to doxorubicin in vitro. J Pediatr Surg. 2002, 37 (11): 1579-1584. 10.1053/jpsu.2002.36188.View ArticlePubMedGoogle Scholar
- Biesma B, Wymenga AN, Vincent A, Dalesio O, Smit HJ, Stigt JA, Smit EF, van Felius CL, van Putten JW, Slaets JP, Groen HJ: Quality of life, geriatric assessment and survival in elderly patients with non-small-cell lung cancer treated with carboplatin-gemcitabine or carboplatin-paclitaxel: NVALT-3 a phase III study. Ann Oncol. 2011Google Scholar
- Hayashi RJ, Blaney S, Sullivan J, Weitman S, Vietti T, Bernstein ML: Phase 1 study of Paclitaxel administered twice weekly to children with refractory solid tumors: a pediatric oncology group study. J Pediatr Hematol Oncol. 2003, 25 (7): 539-542. 10.1097/00043426-200307000-00008.View ArticlePubMedGoogle Scholar
- Bouquet W, Ceelen W, Adriaens E, Almeida A, Quinten T, De Vos F, Pattyn P, Peeters M, Remon JP, Vervaet C: In vivo toxicity and bioavailability of Taxol and a paclitaxel/beta-cyclodextrin formulation in a rat model during HIPEC. Ann Surg Oncol. 2010, 17 (9): 2510-2517. 10.1245/s10434-010-1028-x.View ArticlePubMedGoogle Scholar
- Green H, Soderkvist P, Rosenberg P, Mirghani RA, Rymark P, Lundqvist EA, Peterson C: Pharmacogenetic studies of Paclitaxel in the treatment of ovarian cancer. Basic Clin Pharmacol Toxicol. 2009, 104 (2): 130-137. 10.1111/j.1742-7843.2008.00351.x.View ArticlePubMedGoogle Scholar
- Dorsey JF, Mintz A, Tian X, Dowling ML, Plastaras JP, Dicker DT, Kao GD, El-Deiry WS: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and paclitaxel have cooperative in vivo effects against glioblastoma multiforme cells. Mol Cancer Ther. 2009, 8 (12): 3285-3295. 10.1158/1535-7163.MCT-09-0415.View ArticlePubMedGoogle Scholar
- Kang HJ, Lee SH, Price JE, Kim LS: Curcumin suppresses the paclitaxel-induced nuclear factor-kappaB in breast cancer cells and potentiates the growth inhibitory effect of paclitaxel in a breast cancer nude mice model. Breast J. 2009, 15 (3): 223-229. 10.1111/j.1524-4741.2009.00709.x.View ArticlePubMedGoogle Scholar
- Schnater JM, Bruder E, Bertschin S, Woodtli T, de Theije C, Pietsch T, Aronson DC, von Schweinitz D, Lamers WH, Kohler ES: Subcutaneous and intrahepatic growth of human hepatoblastoma in immunodeficient mice. J Hepatol. 2006, 45 (3): 377-386. 10.1016/j.jhep.2006.03.018.View ArticlePubMedGoogle Scholar
- Sommer K, Peters SO, Robins IH, Raap M, Wiedemann GJ, Remmert S, Sieg P, Bittner C, Feyerabend T: A preclinical model for experimental chemotherapy of human head and neck cancer. Int J Oncol. 2001, 18 (6): 1145-1149.PubMedGoogle Scholar
- Karaduman D, Eren B, Keles ON: The protective effect of beta-1,3-D-glucan on taxol-induced hepatotoxicity: a histopathological and stereological study. Drug Chem Toxicol. 2010, 33 (1): 8-16. 10.3109/01480540903380472.View ArticlePubMedGoogle Scholar
- Zhang JQ, Zhang ZR, Yang H, Tan QY, Qin SR, Qiu XL: Lyophilized paclitaxel magnetoliposomes as a potential drug delivery system for breast carcinoma via parenteral administration: in vitro and in vivo studies. Pharm Res. 2005, 22 (4): 573-583. 10.1007/s11095-005-2496-8.View ArticlePubMedGoogle Scholar
- Elmore S: Apoptosis: a review of programmed cell death. Toxicol Pathol. 2007, 35 (4): 495-516. 10.1080/01926230701320337.View ArticlePubMedPubMed CentralGoogle Scholar
- Tse C, Shoemaker AR, Adickes J, Anderson MG, Chen J, Jin S, Johnson EF, Marsh KC, Mitten MJ, Nimmer P, Roberts L, Tahir SK, Xiao Y, Yang X, Zhang H, Fesik S, Rosenberg SH, Elmore SW: ABT-263: a potent and orally bioavailable Bcl-2 family inhibitor. Cancer Res. 2008, 68 (9): 3421-3428. 10.1158/0008-5472.CAN-07-5836.View ArticlePubMedGoogle Scholar
- The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2407/11/362/prepub
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