A preclinical model for experimental chemotherapy of human head and neck cancer

Sommer, K.; Peters, Stefan O.; Robins, Ian H.; Raap, M.; Wiedemann, G. J.; Remmert, S.; Sieg, Peter; Bittner, Cordula; Feyerabend, Thomas

doi:10.3892/ijo.18.6.1145

Cited by 10 publications

(10 citation statements)

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“…Docetaxel, a semi-synthetic analogue of paclitaxel also leading to tumour regression, was described without significant toxicity in athymic NMRI mice [37]. 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 [38].…”

Section: Discussionmentioning

confidence: 75%

The BH3 mimetic ABT-737 increases treatment efficiency of paclitaxel against hepatoblastoma

et al. 2011

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BackgroundThe 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.MethodsViability 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).ResultsABT-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.ConclusionsOur 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.

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Section: Discussionmentioning

confidence: 75%

The BH3 mimetic ABT-737 increases treatment efficiency of paclitaxel against hepatoblastoma

et al. 2011

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“…In fact, docetaxel was more effective than cisplatin in inhibiting the growth of two SCCHN xenograft models (HNX-14C and HNX-22B) (Braakhuis et al, 1994). Further preclinical evidence for docetaxel efficacy has been derived from studies employing a murine model, representative of human head and neck cancer (Sommer et al, 2001). From the drugs investigated (cisplatin, carboplatin, docetaxel, methotrexate, 5-FU), as single agents or in combination, an ifosfamide -docetaxel combination produced the best tumourfree survival.…”

Section: Potential Of Docetaxel In Scchnmentioning

confidence: 99%

Docetaxel induction therapy in locally advanced squamous cell carcinoma of the head and neck

Posner

Lefèbvre

2003

Br J Cancer

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Patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN) are often treated with induction chemotherapy or chemoradiotherapy, but to date without major impact on survival. The combination of cisplatin -5-fluorouracil (5-FU) (PF) has been used as standard induction therapy; however, poor patient survival has stimulated investigation into new agents with potential activity in SCCHN. Docetaxel has significant single-agent activity in SCCHN and has been investigated in combination with PF regimens as induction therapy. The results of six phase II studies of docetaxel -PF regimens (TPF) as induction in locally advanced SCCHN patients are reviewed and reported. Consistently, high 2-year survival rates and overall response rates were demonstrated across the phase II trials in the range 42 -82 and 71 -100%, respectively. The toxicity profile seen with TPF-based regimens was acceptable. The primary toxicity was neutropenia, which together with gastrointestinal complaints accounted for the majority of adverse events. Given the encouraging phase II experience with TPF-based regimens, two large-scale phase III studies comparing TPF-based regimens with standard PF regimens are underway. The results have significant potential for validating the findings of the phase II studies, demonstrating improved survival and overall response of patients treated with docetaxel-based induction chemotherapy.

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“…as animal receiving gefitinib and were injected with equal volume of saline solution as animal receiving IFN-a. Tumor size were measured twice weekly by the modified ellipsoid formula: (k / 6) Â AB 2 , where A is the longest and B is the shortest perpendicular axis of an assumed ellipsoid corresponding to tumor mass (42). Body weight was measured twice weekly as control for treatment toxicity.…”

Section: Methodsmentioning

confidence: 99%

Synergistic Antitumor Activity of Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Gefitinib and IFN-α in Head and Neck Cancer Cells In vitro and In vivo

Bruzzese

Gennaro

Avallone³

et al. 2006

Clinical Cancer Research

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Purpose: Epidermal growth factor receptor (EGFR) overexpression has been implicated in the development of head and neck squamous cell carcinomas (HNSCC) and represents a potential therapeutic target for this disease.We have reported previously that growth inhibitory concentrations of IFN-a enhance the expression and activity of EGFR and that this effect could represent an escape mechanism to the growth inhibition and apoptotic cell death induced by IFN-a. In this study, we investigate whether the combination of IFN-a and gefitinib (Iressa, AstraZeneca Pharmaceuticals, Macclesfield, United Kingdom), a selective EGFR tyrosine kinase inhibitor, might have a cooperative antitumor effect on HNSCC-derived cell lines. Experimental Design: The interaction of IFN-a and gefitinib was evaluated in vitro on HNSCCderived cell lines by median drug effect analysis calculating a combination index with CalcuSyn software and in vivo by using HNSCC xenografts in nude mice. The mechanism of gefitinib and IFN-a interactions was also studied by analysis of cell cycle kinetics, apoptosis assays, and Western blotting of EGFR signal transduction components. Results: Simultaneous exposure to gefitinib and IFN-a produced synergistic antiproliferative and proapoptotic effects compared with single drug treatment. Furthermore, daily treatment of gefitinib (50 mg/kg p.o.) in combination with an IFN-a regimen (50,000 units s.c. three times weekly) induced tumor growth delay and increased survival rate on established HNSCC xenografts in nude mice. Moreover, the concomitant treatment with gefitinib suppressed the stimulation of extracellular signal-regulated kinase phosphorylation/activity induced by IFN-a both in vitro and in vivo. Conclusion: The observed cooperative antitumor effects could be, at least in part, explained by the inhibition exerted by gefitinib of an IFN-a-induced EGF-dependent survival pathway, which involves extracellular signal-regulated kinase activation. These results provide a rationale for the clinical evaluation of gefitinib in combination with IFN-a in HNSCC.

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A preclinical model for experimental chemotherapy of human head and neck cancer

Cited by 10 publications

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The BH3 mimetic ABT-737 increases treatment efficiency of paclitaxel against hepatoblastoma

The BH3 mimetic ABT-737 increases treatment efficiency of paclitaxel against hepatoblastoma

Docetaxel induction therapy in locally advanced squamous cell carcinoma of the head and neck

Synergistic Antitumor Activity of Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Gefitinib and IFN-α in Head and Neck Cancer Cells In vitro and In vivo

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