Antitumor effects of ZD6474 on head and neck squamous cell carcinoma

Angiogenesis is required for tumor growth and metastasis and, therefore, represents a target for cancer treatment. While many factors have been implicated in promoting angiogenesis, vascular endothelial growth factor (VEGF) plays a key role in tumor angiogenesis. ZD6474 is a potent VEGF receptor-2 (VEGFR-2) tyrosine kinase inhibitor which also has activity against the epidermal growth factor receptor (EGFR) tyrosine kinase. The purpose of this study was to investigate the sensitivity of head and neck squamous cell carcinoma (HNSCC) cell lines to ZD6474, and to evaluate its antitumor efficacy on HNSCC xenografts. This is the first demonstration of antitumor effects of ZD6474 on HNSCC. In vitro ZD6474 displayed antiproliferative effects on HNSCC cells and inhibition of VEGFR-2 and EGFR pathways. In vivo ZD6474 displayed antitumor activity, induced apoptosis and antiangiogenic activity on nude mice bearing an established xenograft of YCU-H891 cells. These results suggest that ZD6474 has the potential to inhibit two key pathways in tumor growth via inhibition of VEGF-dependent tumor angiogenesis and via inhibition of EGFR-dependent tumor cell proliferation.     

Antitumor effects of IDN5109 on head and neck squamous cell carcinoma

Taxanes, a new class of antitumor drugs, are effective against a large number of human tumors, although there are problems with drug resistance. The novel taxane, IDN5109, is characterized by its high tolerability, antitumor efficacy, ability to overcome multidrug resistance, and oral bioavailabilty. We investigated the cellular response of IDN5109 to head and neck squamous cell carcinoma (HNSCC), and compared the antitumor activity of IDN5109 with that of paclitaxel. This is the first demonstration of antitumor effects of IDN5109 on HNSCC. In in vitro experiments, IDN5109 showed antiproliferative effects against HNSCC cell lines. After treatment with IDN5109, Bcl-2 and Bcl-XL were down-regulated, Bax was up-regulated, and caspase-3 was activated. After treatment with IDN5109, concentrations of both VEGF and IL-8 in the culture supernatant of HNSCC cells decreased. In in vivo experiments, the oral administration of IDN5109 showed antitumor effects against HNSCC tumor xenografts. Immunohistochemistry showed that IDN5109 inhibited tumor angiogenesis and induced apoptosis in HNSCC cells, producing a decreased blood vessel density and increased apoptosis index. On the basis of these results, IDN5109 is useful as a chemotherapeutic agent against HNSCC.     

Antitumor effect of gefitinib ('Iressa') on esophageal squamous cell carcinoma cell lines in vitro and in vivo

High expression of epidermal growth factor receptor (EGFR) is thought to be correlated with cell proliferation, invasion, metastasis, resistance to chemoradiotherapy, and poor prognosis in various kinds of human cancers. Blockade of EGFR signal transduction can be a promising strategy for cancer therapy. Approximately 40-70% of esophageal squamous cell carcinomas (ESCCs) show high expression of EGFR. In this study, we examined the antitumor effect of gefitinib, an EGFR tyrosine kinase inhibitor, against ESCC cells in vitro and in vivo. In three ESCC cell lines (TE8, T.T and T.Tn), cell proliferation had been inhibited in a dose-dependent manner and IC(50) values (respectively, 8.49, 18.9 and 17.3muM). Gefitinib inhibited EGF-induced autophosphorylation of EGFR and its downstream signaling pathways, Ras/Raf/MAPK and PI3K/Akt, and caused G(1) arrest of cell cycle and apoptosis confirmed with flow cytometry. We examined the effect of gefitinib on nude mice bearing established TE8 and T.T xenografts. Gefitinib (100 or 200mg/kg once-daily, p.o.) showed antitumor activity in a dose-dependent manner, resulting in a significantly improved survival of treated mice as compared with untreated mice. Immunohistochemical examination of the harvested tumor was performed to examine the status of phosphorylated EGFR, PCNA, Factor VIII and apoptosis. We found inhibition of EGFR phosphorylation, cell cycle arrest (by PCNA staining), decrease of microvessel density (Factor VIII) and induction of apoptosis by TUNEL staining. In conclusion, our findings demonstrate that gefitinib is effective for growth inhibition of ESCC cell lines in vitro and in vivo and suggest that gefitinib may be one of the new therapeutic options for ESSC.     

经颞浅动脉灌注PDD-Fudr/5Fu治疗头颈部鳞状细胞癌

 目的　观察经颞浅动脉灌注PDD +Fudr/ 5 Fu治疗头颈部鳞状细胞癌的疗效。方法　从 1996年 1月～ 2 0 0 0年 12月有 89例头颈部鳞状细胞癌给予动脉化疗 ,A组 4 9例予PDD +Fudr方案 ,B组 4 0例予PDD + 5Fu方案 ,方法与剂量两组相同。结果　A组的总有效率为 83.7% (41/ 4 9) ,其中CR10 .2 % ,PR73.5 % ,SD16 .3% ;B组的总有效率为 75 .0 % (30 / 4 0 ) ,其中CR2 .5 % ,PR72 .5 % ,SD2 5 % ,统计学上两组有效率无明显差异 (P >0 .0 5 )。而口腔溃疡在A组的发生率明显低于B组 ,经 χ2 检验 ,两组有显著差异。结论Fudr在头颈部鳞状细胞癌的辅助化疗中是安全、低毒、高效的 ,值得推荐。     

Re-irradiation for head and neck squamous cell carcinoma

Introduction

Local recurrences after curative treatment have a potential for cure with salvage surgery or with re-irradiation.

Involvement of EGFR in the response of squamous cell carcinoma of the head and neck cell lines to gefitinib

Epidermal growth factor receptor (EGFR) gene mutations are associated with the sensitivity of non-small cell lung carcinomas (NSCLCs) to gefitinib, but such findings have not been reported in squamous cell carcinomas of the head and heck (SCCHNs). Accordingly, we determined whether EGFR gene expression and mutations correlate with the in vitro efficacy of gefitinib in SCCHN cell lines. EGFR status was analyzed in 16 different SCCHN cell lines by polymerase chain reaction (PCR) and direct sequencing for activating mutations, by real-time quantitative RT-PCR, and by Western blot analysis for RNA and protein expression. Using direct sequencing of PCR products from exons 18-23 of 9 SCCHN cell lines, we found a heterozygous EGFR mutation (EGFRmut) with a 2607Gright curved arrow A transition in exon 20 (G/A genotype). The 9 different cell lines that showed this mutation also showed higher sensitivity (lower IC50 values) to gefitinib than cell lines with wild-type EGFR (EGFRwt: G/G genotype) (p=0.016). EGFR protein levels correlated robustly (r=0.76) and significantly (p=0.0007) with EGFR mRNA levels and with IC50 values for gefitinib (r=0.65, p=0.0067). EGFR mRNA correlated with IC50 values (r=0.67, p=0.0046). Our conclusion was that the heterozygous and synonymous transition of the EGFR gene and low EGFR expression levels of mRNA and protein in SCCHN may be reliable predictors of high sensitivity in SCCHN patients to gefitinib.     

抗血管生成治疗头颈部鳞状细胞癌的研究进展

目前对于复发或转移头颈部鳞状细胞癌（HNSCC）以姑息性化疗及 EGFR 靶向治疗为主,肿瘤血管的形成是肿瘤生长和远处转移的关键因素,因此,促进血管生成的因子及其受体成为靶向治疗的靶点,目前抗血管生成药物主要通过阻断 VEGF-VEGF 受体（VEGFR）通路,其在治疗 HNSCC 的临床试验中取得一定效果,为治疗 HNSCC 提供更多选择。     

Functional surgery for head and neck squamous cell carcinoma

Surgery for head and neck squamous cell carcinoma can alter speech, swallowing, and cosmoses. Recent tendency is to avoid mutilating surgery unless the tumour is aggressive or resistant to chemotherapy and or radiotherapy. Functional surgery is being widely employed, and for example it may vary between conventional partial surgery and endoscopic laser surgery for small sized vocal cord cancers. Various new reconstructive procedures have been developed to help early functional restoration. Loco-regional flaps can be used to replace gums and avoid dental extractions. Free flaps with micro-vascular anastomosis can be employed for immediate reconstruction of extensive surgical defects involving pharyngeal wall, tongue, mandible and mid-face to restore better function and cosmoses. Few recently developed techniques can be also employed in selected cases of laryngo-pharyngeal cancers to avoid permanent laryngeal mutilation. Another goal of functional surgery is to decrease the postoperative radiotherapy or chemo-radiotherapy sequelae, and obtain successful postoperative functional rehabilitation.     

Docetaxel and squamous cell carcinoma of the head and neck

Chemotherapy in head and neck carcinoma is used as palliative treatment but also as induction treatment or combined treatment with concurrent radiation therapy. Platinum and 5-fluorouracil are the most commonly used cytotoxic agents. Docetaxel is an active drug for treating head and neck carcinoma. For patients with recurrent or metastatic disease, docetaxel could be used either as a second line chemotherapy or a first line for patients who received previously platinum or 5FU. In combination with platinum and 5FU, used as induction chemotherapy the TPF regimen is a very active treatment with an overall response rate of 85 to 90% with a manageable acute toxicity rate. This approach is under investigation in terms of ability to obtain more larynx preservation compared to the standard approach with platinum and 5FU. Docetaxel is a radiosensitizer. Concurrent radiochemotherapy using docetaxel alone is feasible, Trials are needed to define the optimal regimen for combining radiation, platinum and docetaxel.     

Satraplatin提高头颈部鳞癌放射治疗疗效的动物实验研究

目的:观察satraplatin是否能提高移植性FaDu头颈部鳞癌的放射治疗疗效。方法:建立裸鼠肿瘤模型70只,当位于每只裸鼠右大腿的肿瘤直径达到8．0 mm(7．6～8．3 mm)时开始实验。实验共分成7组(每组10只),分别是对照组、satra- platin组、放疗(radiotherapy,RT)组、satraplatin+RT(6 h后)组、satraplatin+RT(24 h后)组、RT+satraplatin(6 h后)组和RT+satraplatin(24 h后)组。观察指标为肿瘤生长延迟时间(肿瘤直径从8．0 mm生长至12．0 mm所需时间)和肿瘤治愈的情况。结果:3只荷瘤鼠在治疗过程中死亡,其余67只无治愈。观察肿瘤生长情况发现satraplatin组和放疗组的绝对延迟时间分别为(0．7±0．4)d和(5．5±1．1)d,而satraplatin+RT(6 h后)组、satraplatln+RT(24 h后)组、RT+satraplatin(6 h后)组和RT+satraplatin(24 h后)组的绝对延迟时间则分别为(8．1±1．3)、(7．8±1．1)、(6．6±1．1)和(4．3±0．6)d,其标准化的延迟时间分别为(7．4±1．3)、(7．1±1．1)、(5．9±0．6)和(3．6±0．6)d,增益因子分别为1．30、1．25、1．04和0．63。结论:实验结果显示在放疗前6或24 h应用satraplatin能提高移植性FaDu头颈部鳞癌的放射治疗疗效。     

Chemoprevention of squamous cell carcinoma of the head and neck

PURPOSE OF REVIEW: The aim of this article is to summarize progress in understanding of the biology of squamous cell carcinoma of the head and neck and of trials to prevent malignant conversion of oral premalignant lesions and the development of second primary tumors in those already treated for squamous cell carcinoma of the head and neck. RECENT FINDINGS: The understanding of squamous cell carcinoma of the head and neck biology is rapidly evolving. Clinical trials for chemoprevention are involving more diverse regimens, following disappointing results of retinoid monotherapy. In-vitro and animal studies form the rationale for the next generation of studies, employing combination, synergistic treatments. SUMMARY: Based on trial data to date, no recommendation for intervention with a chemopreventive agent can be made. It is clear, however, that smoking cessation is an effective intervention for preventing oral premalignant lesions and second primary tumors. Promising trials are being conducted and designed currently. The future of this area of study will involve rational choice of multidrug regimens based on current understanding of the biology of squamous cell carcinoma of the head and neck.     

Nivolumab in squamous cell carcinoma of the head and neck

Introduction: The prognosis of recurrent/metastatic (R/M) squamous cell carcinoma of the head and neck (HNSCC) after failure of first line chemotherapy is dismal. Until the publication of the results of CheckMate 141, not a single agent provided any survival benefit as a second line treatment for R/M HNSCC.

Areas covered: A comprehensive review of the literature was conducted on the role of nivolumab in HNSCC.

Expert commentary: Nivolumab is approved by the Food and Drug Administration for the treatment of patients based on the results of CheckMate 141 showing an overall survival benefit as compared to standard care (single agent docetaxel, methotrexate, or cetuximab). Of particular interest are immune-related adverse events which should be managed according to published guidelines.     

Cetuximab in squamous cell carcinoma of the head and neck

Surgery and radiotherapy are the standard treatment options for patients with squamous cell carcinoma of the head and neck (SCCHN). Chemotherapy and chemoradiotherapy are new alternatives for locally advanced disease, particularly induction chemotherapy for patients with unresectable tumors. In recurrent/metastatic disease and after progression to platin-based regimens, no treatments other than best supportive care are currently available. Most SCCHN tumors overexpress the epidermal growth factor receptor (EGFR). This is a tyrosine kinase membrane receptor and has a clear implication in angiogenesis, tumor progression and resistance to different cancer treatments. Cetuximab is a monoclonal antibody that binds to EGFR and alters the tyrosine kinase-mediated signal transduction pathway. The drug is active in colon cancer and is currently being tested in SCCHN patients. For locally advanced disease, cetuximab/radiotherapy combination has demonstrated a benefit in survival when compared with radiotherapy alone as radical treatment. Cetuximab is an active treatment in platin-refractory patients with recurrent/metastatic disease.