Phase II trial of gemcitabine concurrent with radiation for locally advanced squamous cell carcinoma of the head and neck

Aguilar-Ponce, José Luis; Granados-García, Martín; Villavicencio, Victor Corona; Poitevin-Chacón, Adela; Green, D.; Dueñas‐González, Alfonso; Herrera‐Gómez, Ángel; Ortíz, Kuauhyama Luna; Alvarado, A.; Saíd, Héctor Martínez; Castillo-Henkel, Carlos; Segura-Pacheco, Blanca; Garza, Jaime de la

doi:10.1093/annonc/mdh071

Cited by 34 publications

(30 citation statements)

References 28 publications

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“…In our study, the results of both univariate and multivariate analyses provided a rational for using postoperative radiotherapy to improve survival after surgery. Based on experience with other head and neck tumors, some investigators believe that concomitant chemoradiotherapy represents an alternative for patients with advanced disease (Aguilar-Ponce et al, 2004); however, according to other data, chemotherapy is relatively inefficacious in the treatment of ACC which grows slowly, and the agents such as 5-fluorouracil appear to have low rates of response (Haddad et al, 2006). We used postoperative chemotherapy in 15 cases, and found it could significantly improve the survival rate.…”

Section: Discussionmentioning

confidence: 99%

Nerve Growth Factor and Vascular Endothelial Growth Factor: Retrospective Analysis of 63 Patients with Salivary Adenoid Cystic Carcinoma

Nong

Chen

et al. 2010

Int J Oral Sci

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Section: Discussionmentioning

confidence: 99%

Nerve Growth Factor and Vascular Endothelial Growth Factor: Retrospective Analysis of 63 Patients with Salivary Adenoid Cystic Carcinoma

Nong

Chen

et al. 2010

Int J Oral Sci

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“…The use of GMZ for the treatment of HNSCC in combination with CP, imatinib, or vinca alkaloids has been reported previously (Kroep et al, 1999;Airoldi et al, 2003;Bruce et al, 2005;Jiang et al, 2005). In addition, GMZ was known to sensitize HNSCC cells to radiation (Aguilar-Ponce et al, 2004). However, these studies reported some toxicity, which limit their therapeutic significance.…”

Section: Pyr-ceramide/gemcitabine Inhibits Hnscc Tumor Growth 1197mentioning

confidence: 96%

“…Recent studies have evaluated the combination of gemcitabine with a variety of anticancer agents such as vinorelbine, imatinib, or cisplatinum with limited pharmacokinetic or synergistic interaction (Airoldi et al, 2003;Bruce et al, 2005;Jiang et al, 2005). Radiosensitization property of GMZ was also examined in patients with advanced HNSCC, and the data showed that the concurrent use of radiotherapy and gemcitabine was effective but caused severe mucositis in the majority of patients (Aguilar-Ponce et al, 2004). Combination therapy involving anthracyclines against these cancers has also been analyzed previously, with strict adherence to the dose limitations of these cardiotoxic compounds (Harrington et al, 2001).…”

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confidence: 99%

Potent Antitumor Activity of a Novel Cationic Pyridinium-Ceramide Alone or in Combination with Gemcitabine against Human Head and Neck Squamous Cell Carcinomas in Vitro and in Vivo

Senkal¹,

Ponnusamy²,

Rossi³

et al. 2006

J Pharmacol Exp Ther

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In this study, a cationic water-soluble ceramide analog L-threo-C 6 -pyridinium-ceramide-bromide (L-t-C 6 -Pyr-Cer), which exhibits high solubility and bioavailability, inhibited the growth of various human head and neck squamous cell carcinoma (HNSCC) cell lines at low IC 50 concentrations, independent of their p53 status. Consistent with its design to target negatively charged intracellular compartments, L-t-C 6 -Pyr-Cer accumulated mainly in mitochondria-, and nuclei-enriched fractions upon treatment of human UM-SCC-22A cells [human squamous cell carcinoma (SCC) of the hypopharynx] at 1 to 6 h. In addition to its growth-inhibitory function as a single agent, the supra-additive interaction of L-t-C 6 -Pyr-Cer with gemcitabine (GMZ), a chemotherapeutic agent used in HNSCC, was determined using isobologram studies. Then, the effects of this ceramide, alone or in combination with GMZ, on the growth of UM-SCC-22A xenografts in SCID mice was assessed following the determination of preclinical parameters, such as maximum tolerated dose, clearance from the blood, and bioaccumulation. Results demonstrated that treatment with L-t-C 6 -PyrCer in combination with GMZ significantly prevented the growth of HNSCC tumors in vivo. The therapeutic efficacy of L-t-C 6 -Pyr-Cer/ GMZ combination against HNSCC tumors was approximately 2.5-fold better than that of the combination of 5-fluorouracil/cisplatin. In addition, liquid chromatography/mass spectroscopy analysis showed that the levels of L-t-C 6 -Pyr-Cer in HNSCC tumors weresignificantly higher than its levels in the liver and intestines; interestingly, the combination with GMZ increased the sustained accumulation of this ceramide by approximately 40%. Moreover, treatment with L-t-C 6 -Pyr-Cer/GMZ combination resulted in a significant inhibition of telomerase activity and decrease in telomere length in vivo, which are among downstream targets of ceramide.Human head and neck squamous cell carcinomas (HNSCCs) are among the five most common cancers in the world. Global occurrence of HNSCC is high, and it is estimated that approximately 780,000 new patients are diagnosed with HNSCC each year in the adult population. There are approximately 41,000 new HNSCC cases diagnosed annually in the United States in 2004, and the overall 5-year survival of patients with stage III and IV disease remains less than 50% (Her, 2001;Jemal et al., 2004).Historically, chemotherapy did not play a curative role in the treatment of HNSCC but was reserved for palliative therapy. Surgery and radiation therapy remained the primary curative options; however, complications of these ther-

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“…The mortality from head and neck squamous cell carcinoma (HNSCC) has not changed significantly in the last 30 years (1). Thus, HNSCC is considered to be a very aggressive cancer because it is often diagnosed at a very late stage.…”

Section: Introductionmentioning

confidence: 99%

Disruption of Transforming Growth Factor-β Signaling by Five Frequently Methylated Genes Leads to Head and Neck Squamous Cell Carcinoma Pathogenesis

2009

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Head and neck squamous cell carcinoma (HNSCC) is an aggressive cancer with low survival rates in advanced stages. To facilitate timely diagnosis and improve outcome, early detection markers (e.g., DNA methylation) are crucial for timely cancer diagnosis. In a recent publication, an epigenomewide screen revealed a set of genes that are commonly methylated and downregulated in head and neck cancers (SEPT9, SLC5A8, FUSSEL18, EBF3, and IRX1). Interestingly, these candidates are potentially involved in the transforming growth factor-β (TGF-β) signaling pathway, which is often disrupted in HNSCC. Therefore, we sought to determine coordinated epigenetic silencing of these candidate genes in HNSCC as potential key disruptors of TGF-β signaling, which could ultimately result in HNSCC progression. Through immunoprecipitation studies, all five of the investigated candidate genes were found to interact with components of the TGF-β pathway. Overexpression of SLC5A8, EBF3, and IRX1 resulted in decreased mitotic activity and increased apoptosis. In addition, EBF3 was found to increase p21 promoter activity, and SMAD2 significantly increased IRX1 promoter activity. These findings are significant because they reveal a set of genes that interact with components of the TGF-β pathway, and their silencing via methylation in HNSCC results in coordinated decrease in apoptosis, increased proliferation, and decreased differentiation. [Cancer Res 2009;69(24):9301-5]

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Phase II trial of gemcitabine concurrent with radiation for locally advanced squamous cell carcinoma of the head and neck

Abstract: The concurrent use of radiotherapy and gemcitabine is effective but produces manageable severe mucositis in a high percentage of patients.

Cited by 34 publications

References 28 publications

Nerve Growth Factor and Vascular Endothelial Growth Factor: Retrospective Analysis of 63 Patients with Salivary Adenoid Cystic Carcinoma

Nerve Growth Factor and Vascular Endothelial Growth Factor: Retrospective Analysis of 63 Patients with Salivary Adenoid Cystic Carcinoma

Potent Antitumor Activity of a Novel Cationic Pyridinium-Ceramide Alone or in Combination with Gemcitabine against Human Head and Neck Squamous Cell Carcinomas in Vitro and in Vivo

Disruption of Transforming Growth Factor-β Signaling by Five Frequently Methylated Genes Leads to Head and Neck Squamous Cell Carcinoma Pathogenesis

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