piperidines and Head-and-Neck-Neoplasms

The purpose of this systematic review and meta-analysis was to evaluate the diagnostic value of salivary biological markers in the diagnosis of head and neck carcinoma. Studies were gathered by searching Cochrane, EMBASE, LILACS, MEDLINE, and PubMed. The references were also crosschecked and a partial grey literature search was undertaken using Google Scholar. The methodology of selected studies was evaluated using the 14-item Quality Assessment Tool for Diagnostic Accuracy Studies. After a two-step selection process, 15 articles were identified and subjected to qualitative and quantitative analyses. The studies were homogeneous, and all had high methodological quality. Combined biomarkers demonstrated better accuracy with higher sensitivity and specificity than those tested individually. Furthermore, the salivary biomarkers reviewed predicted the early stages of head and neck carcinoma better than the advanced stages. A restricted set of five single biomarkers (interleukin-8, choline, pipecolinic acid, l-phenylalanine, and S-carboxymethyl-l-cysteine) as well as combined biomarkers demonstrated excellent diagnostic test accuracy. The present systematic review confirms the potential value of a selected set of salivary biomarkers as diagnostic tools for head and neck carcinoma.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers; Carbocysteine; Choline; Head and Neck Neoplasms; Humans; Interleukin-8; Middle Aged; Phenylalanine; Piperidines; Saliva; Sensitivity and Specificity; Young Adult

Survivors of childhood cancer frequently experience cancer-related cognitive dysfunction, commonly months to years after treatment for pediatric brain tumors, acute lymphoblastic leukemia (ALL), or tumors involving the head and neck. Risk factors for cancer-related cognitive dysfunction include young age at diagnosis, treatment with cranial irradiation, use of parenteral or intrathecal methotrexate, female sex, and pre-existing comorbidities. Limiting use and reducing doses and volume of cranial irradiation while intensifying chemotherapy have improved survival and reduced the severity of cognitive dysfunction, especially in leukemia. Nonetheless, problems in core functional domains of attention, processing speed, working memory and visual-motor integration continue to compromise quality of life and performance. We review the epidemiology, pathophysiology and assessment of cancer-related cognitive dysfunction, the impact of treatment changes for prevention, and the broad strategies for educational and pharmacological interventions to remediate established cognitive dysfunction following childhood cancer. The increased years of life saved after childhood cancer warrants continued study toward the prevention and remediation of cancer-related cognitive dysfunction, using uniform assessments anchored in functional outcomes.

Topics: Adolescent; Adult; Age Factors; Antimetabolites, Antineoplastic; Attention; Benzhydryl Compounds; Brain Neoplasms; Central Nervous System Stimulants; Child; Child, Preschool; Cognitive Dysfunction; Comorbidity; Cranial Irradiation; Donepezil; Early Intervention, Educational; Education, Special; Head and Neck Neoplasms; Human Growth Hormone; Humans; Indans; Infant; Injections, Spinal; Memory, Short-Term; Methotrexate; Methylphenidate; Modafinil; Neoplasms; Neurosurgical Procedures; Nootropic Agents; Patient Education as Topic; Piperidines; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Psychomotor Performance; Quality of Life; Radiotherapy Dosage; Risk Factors; Severity of Illness Index; Sex Factors; Survivors; Thinking; Wakefulness-Promoting Agents; Young Adult

Cancer of the head and neck is an important medical problem, with approximately 46,500 cases predicted in the United States alone in 2003. Worldwide, more than 600,000 cases are anticipated. While several different histologic subtypes of head and neck cancer are seen in different parts of the world, more than 90% of tumors diagnosed in the United States are squamous cell carcinomas. Major strides in the management of this disease have been made in the last decade. These include, but are not limited to, the evolution of organ preservation, the increasingly well recognized role of concurrent chemoradiation therapy as either definitive therapy for unresectable disease or adjuvant therapy for high-risk surgical disease, and significant improvements in cytotoxic chemotherapy. The role of chemotherapy in this disease has been a subject of debate. Chemotherapy is now routinely included in the multimodality treatment of unresectable disease of the oral pharynx, larynx, and oral cavity. There is now increasing evidence supporting the role of induction chemotherapy in head and neck cancer. As intensified chemotherapy and radiation therapy have improved local control, the increasing incidence of distant metastases has necessitated the need for enhanced systemic control. These approaches are the topics of extensive investigations.

Topics: Adenoviridae; Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Anticarcinogenic Agents; Antineoplastic Agents; Carcinoma, Squamous Cell; Cetuximab; Clinical Trials as Topic; Combined Modality Therapy; ErbB Receptors; Genes, p53; Head and Neck Neoplasms; Humans; Piperidines; Pyridines; ras Proteins; Viral Vaccines

Vandetanib, added to cisplatin and radiation therapy (RT) overcomes chemoradiation therapy (CRT) and epidermal growth factor receptor (EGFR) inhibitor resistance in head and neck squamous cell carcinoma (HNSCC) lines and models.. Patients with previously untreated HNSCC received vandetanib daily for 14 days (starting dose 100 mg) and then vandetanib + RT (2.2 Gy/day, 5 days/week) for 6 weeks (regimen 1) or vandetanib + RT (2 Gy/day, 5 days/week) + cisplatin (30 mg/m(2) weekly) for 7 weeks (regimen 2). The primary objective was the maximum tolerated dose (MTD) of vandetanib with RT +/- cisplatin.. Of 33 treated patients, 30 completed therapy (regimen 1, n = 12; regimen 2, n = 18). MTD in regimen 2 was 100 mg (3 dose limiting toxicities [DLTs] at 200 mg), whereas regimen 1 was stopped because of poor recruitment (1 DLT at 200 mg). Most common grade ≥3 adverse events (AEs) were dysphagia (30%), stomatitis (33%), and mucosal inflammation (27%). Five patients discontinued vandetanib because of AEs.. Vandetanib with CRT was feasible.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Chemoradiotherapy; Cisplatin; Female; Head and Neck Neoplasms; Humans; Male; Maximum Tolerated Dose; Middle Aged; Piperidines; Protein-Tyrosine Kinases; Quinazolines; Squamous Cell Carcinoma of Head and Neck

There are limited chemotherapeutic options for advanced recurrent or metastatic SCCHN. The efficacy and toxicity of docetaxel with or without vandetanib was investigated in these patients.. Patients with pathologically confirmed, recurrent or metastatic SCCHN who had progressed on platinum based therapy given as definitive or palliative treatment, were randomized in this open label, multicenter phase II study of docetaxel (75 mg/m2 IV Q3 weeks) with or without vandetanib (100 mg PO daily). The primary objective was response rate (RR) and secondary objectives were progression free survival (PFS), overall survival (OS), disease control rate (DCR) and duration of response (DOR).. 29 analyzable patients were enrolled, 14 in docetaxel arm and 15 in combined arm. PR was achieved in 1 patient in the docetaxel arm and 2 patients in the combined arm. The objective RR was 7% (1/14) (95% CI 0.2-33.8%) in the single and 13% (2/15) (95% CI 1.6-40.4%) combined arm. The median PFS was 3.21 (95% CI 3.0-22.0) and 9 (95% CI (5.86-18.1) weeks; median OS was 26.8(95% CI 17.7-100.7+) and 24.1 (95% CI, 16.4-171.1+) weeks. Most common adverse events were fatigue, dysphagia, diarrhea or constipation, cytopenias and alopecia.. Although an initial benefit in response was noted and statistical criteria met there was only a minor trend towards improved PFS for the combined arm. The study was designed with low threshold for activity in each arm and results were deemed not to be of enough clinical significance in this group of patients to continue accrual.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Docetaxel; Female; Head and Neck Neoplasms; Humans; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Piperidines; Quinazolines; Taxoids

Treatment options for recurrent squamous cell carcinoma of the head and neck (SCCHN) following platinum-based therapy are limited. Lonafarnib is a potent, specific inhibitor of farnesyl transferase that demonstrated marked antitumor activity as monotherapy in treatment-naive SCCHN in a phase Ib study. A phase II study of lonafarnib was conducted to determine its efficacy and safety in patients with recurrent, platinum-refractory SCCHN.. This was an open-label, phase II, single-center study in patients with recurrent SCCHN after platinum-based therapy. A Simon 2-stage design was used, with a plan to close the study to further accrual if <2 of the first 15 patients had objective responses. Patients were treated with lonafarnib 200 mg twice daily (b.i.d.) by mouth continuously in 4-week cycles.. Fifteen patients with baseline Eastern Cooperative Oncology Group PS 0-1 and median age 57 years were enrolled. Twelve patients had received at least 2 previous chemotherapy regimens. Median duration of treatment with lonafarnib was 61 days. No objective response was observed. Seven (47%) patients maintained stable disease through >or=3 cycles of therapy. Median time to progression and survival time were 2.04 and 9.17 months, respectively. Most treatment-related toxicities were grade 1-2, and there were no treatment-related deaths.. Lonafarnib at a dose of 200 mg b.i.d. was well-tolerated. However, there were no objective responses observed in the first 15 patients enrolled in this study, and the study was closed to further accrual, as per predefined criteria. Further evaluation of lonafarnib in platinum-refractory SCCHN is not planned.

Topics: Adult; Aged; Carcinoma, Squamous Cell; Drug Resistance, Neoplasm; Female; Head and Neck Neoplasms; Humans; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Recurrence, Local; Neoplasm Staging; Piperidines; Prognosis; Pyridines; Survival Rate; Treatment Outcome

Farnesyl transferase inhibitors (FTI) exhibit anticancer activity as a single agent in preclinical studies and show promise in combination with other therapeutics in clinical trials. Previous studies show that FTIs arrest cancer cells in mitosis; however, the mechanism by which this occurs is unclear. Here, we observed that treatment of various cancer cell lines with the FTI lonafarnib caused mitotic chromosomal alignment defects, leaving cells in a pseudometaphase state, whereby both aligned chromosomes and chromosomes juxtaposed to the spindle poles (termed "lagging chromosomes") were observed in the same cell. To determine how this occurs, we investigated the functionality of two farnesylated mitotic proteins, CENP-E and CENP-F, which mediate chromosomal capture and alignment. The data show that lonafarnib in proliferating cancer cells depletes CENP-E and CENP-F from metaphase but not prometaphase kinetochores. Loss of CENP-E and CENP-F metaphase localization triggered aberrant chromosomal maintenance, causing aligned chromosomes to be prematurely released from the spindle equator and become lagging chromosomes, resulting in a mitotic delay. Furthermore, lonafarnib treatment reduces sister kinetochore tension and activates the BubR1 spindle checkpoint, suggesting that farnesylation of CENP-E and CENP-F is critical for their functionality in maintaining kinetochore-microtubule interactions. Importantly, apparently similar chromosomal alignment defects were observed in head and neck tumors samples from a phase I trial with lonafarnib, providing support that lonafarnib disrupts chromosomal maintenance in human cancers. Lastly, to examine how farnesylation could regulate CENP-E in mediating kinetochore-microtubule attachments, we examined possible docking motifs of a farnesyl group on the outer surface of the microtubule. This analysis revealed three hydrophobic patches on the tubulin dimer for insertion of a farnesyl group, alluding to the possibility of an association between a farnesyl group and the microtubule.

Topics: Binding Sites; Cell Line, Tumor; Cell Proliferation; Chromosomal Proteins, Non-Histone; Chromosomes, Human; Enzyme Activation; Enzyme Inhibitors; Farnesyltranstransferase; Head and Neck Neoplasms; Humans; Kinetochores; Metaphase; Microfilament Proteins; Microtubules; Piperidines; Prometaphase; Protein Kinases; Protein Serine-Threonine Kinases; Pyridines; Spindle Apparatus

Anorexia is a common problem in cancer patients who receive radiotherapy. In this current study, we attempt to determine the effect of megestrol acetate and prepulsid on appetite and nutritional improvement in patients with head and neck cancers undergoing radiotherapy.. One hundred twenty-nine consecutive patients with head and neck cancers treated between July 1993 and June 1994 were prospectively randomized to receive either megestrol acetate, 40 mg qid (megace group), prepulsid, 5 mg tid (cisapride group), or a placebo treatment (control group) during radiotherapy. Before radiotherapy, body weight (kg), appetite score, performance status, biochemical parameters and hematological parameters were evaluated, and the above-noted clinical and biochemical parameters were assessed and recorded every other week. All patients received 6- 10 MV X-rays or Co-60 gamma-ray to head and neck region for a full course of radiotherapy, 61.2-75.6 Gy/7-9 weeks.. Forty-eight patients were enrolled in the megace group, 41 patients in the cisapride group, and 40 patients in the control group. At the 2nd, 4th, 6th and 8th week, as the radiation dose escalated, the megace group had significantly less body weight loss than did the cisapride and control groups (P = 0.045, 0.024, 0.006, 0.003, respectively). The appetite scores of the megace group were significantly higher than those of the cisapride and control groups (P = 0.0001). However, there were no statistically significant differences in the change of albumin level among these three groups at the 2nd, 4th, 6th and 8th week (P > 0.05, respectively).. Megestrol acetate can significantly decrease the degree of body weight loss, and can prevent the deterioration of appetite in patients with head and neck cancers receiving radiotherapy. However, prepulsid lacks the above-mentioned clinical benefits.

Topics: Adult; Aged; Appetite Stimulants; Cisapride; Female; Head and Neck Neoplasms; Humans; Male; Megestrol Acetate; Middle Aged; Nutritional Physiological Phenomena; Piperidines; Prospective Studies; Weight Loss

This study evaluated the utility of the histamine H2-receptor antagonist lafutidine in patients taking oral fluorouracil (S-1) for head and neck squamous cell carcinoma (HNSCC), by comparing patients with and without concomitant lafutidine.. Study subjects comprised 63 patients who received adjuvant S-1 following curative resection of HNSCC at our institutions between August 1, 2013 and December 31, 2019. The primary endpoint was the completion rate of S-1 therapy.. For the lafutidine-treated group, the median completion rate was significantly greater (94.4% vs. 24.6%, p=0.01), and progression-free and overall survival were both significantly prolonged compared to the non-lafutidine group. In terms of adverse events, the incidence of diarrhoea was significantly reduced (p<0.00189) in the lafutidine-treated group.. Taking lafutidine during S-1 treatment appeared to reduce gastrointestinal disturbance and increased the S-1 completion rate, improving both progression-free and overall survival as a result.

Topics: Acetamides; Adult; Aged; Antimetabolites, Antineoplastic; Drug Combinations; Female; Head and Neck Neoplasms; Histamine H2 Antagonists; Humans; Male; Middle Aged; Oxonic Acid; Piperidines; Pyridines; Retrospective Studies; Tegafur

Head and neck cancers (HNSCC) are routinely treated with radiotherapy; however, normal tissue toxicity remains a concern. Therefore, it is important to validate treatment modalities combining molecularly targeted agents with radiotherapy to improve the therapeutic ratio. The aim of this study was to assess the ability of the PARP inhibitor niraparib (MK-4827) alone, or in combination with cell cycle checkpoint abrogating drugs targeting Chk1 (MK-8776) or Wee1 (MK-1775), to radiosensitize HNSCCs in the context of HPV status.. PARP1, PARP2, Chk1 or Wee1 shRNA constructs were analyzed from an in vivo shRNA screen of HNSCC xenografts comparing radiosensitization differences between HPV(+) and HPV(-) tumors. Radiosensitization by niraparib alone or in combination with MK-8776 or MK-1775 was assessed by clonogenic survival in HPV(-) and HPV(+) cells; and the role of p16 in determining response was explored. Relative expressions of DNA repair genes were compared by PCR array in HPV(+) and HPV(-) cells, and following siRNA-mediated knockdown of TRIP12 in HPV(-) cells.. In vivo shRNA screening showed a modest preferential radiosensitization by Wee1 and PARP2 in HPV(-) and Chk1 in HPV(+) tumor models. Niraparib alone enhanced the radiosensitivity of all HNSCC cell lines tested. However, HPV(-) cells were sensitized to a greater degree, as suggested by the shRNA screen. When combined with MK-8776 or MK-1775, radiosensitization was further enhanced in an HPV dependent manner with HPV(+) cells enhanced by MK-8776 and HPV(-) cells enhanced by MK-1775. A PCR array for DNA repair genes showed PARP and HR proteins BRCA1 and RAD51 were much lower in HPV(+) cells than in HPV(-). Similarly, directly knocking down p16-dependent TRIP12 decreased expression of these same genes. Overexpressing p16 decreased TRIP12 expression and increased radiosensitivity in HPV(-) HN5. However, while PARP inhibition led to significant radiosensitization in the control, it led to no further significant radiosensitization in p16 overexpressing cells. Forced p16 expression in HPV(-) HN5 increased accumulation in G1 and subG1 and limited progression to S phase, thus reducing effectiveness of PARP inhibition.. Niraparib effectively radiosensitizes HNSCCs with a greater benefit seen in HPV(-). HPV status also plays a role in response to MK-8776 or MK-1775 when combined with niraparib due to differences in DNA repair mechanisms. This study suggests that using cell cycle abrogators in combination with PARP inhibitors may be a beneficial treatment option in HNSCC, but also emphasizes the importance of HPV status when considering effective treatment strategies.

Topics: Cell Cycle Checkpoints; Cell Line, Tumor; DNA Damage; Head and Neck Neoplasms; Humans; Indazoles; Piperidines; Poly(ADP-ribose) Polymerase Inhibitors; Pyrazoles; Pyrimidinones; Radiation Tolerance

Multiple mechanisms of immunosuppression have been identified in the tumor microenvironment including regulatory B cells (B. Blood (n = 42) and tumor tissue (n = 39) of head and neck cancer patients and healthy donors (n = 60) were analyzed by FACS. The effect of ADO on phenotype, intracellular signaling pathways, Ca. ADO-producing B. Our data demonstrate the presence of a novel ADO-producing B

Topics: Adenine; Adenosine; Agammaglobulinaemia Tyrosine Kinase; Animals; Apoptosis; B-Lymphocytes, Regulatory; Case-Control Studies; Cell Proliferation; Head and Neck Neoplasms; Humans; Male; Mice; Piperidines; Prognosis; Pyrazoles; Pyrimidines; Squamous Cell Carcinoma of Head and Neck; Tumor Cells, Cultured; Tumor Microenvironment; Xenograft Model Antitumor Assays

Combining photon or proton radiotherapy with targeted therapy shows promise for head and neck cancer (HNSCC). The poly (adenosine diphosphate [ADP]-ribose) polymerase-1/2 inhibitor niraparib targets DNA damage repair (DDR). We evaluated the effects of niraparib in combination with photons or protons, and its effects on the relative biological effectiveness (RBE) of protons, in human HNSCC cell lines.. Radiosensitivity was assessed and RBE was calculated with clonogenic survival assays; unrepaired DNA double-strand breaks were evaluated using immunocytochemical analysis of 53BP1 foci.. Niraparib reduced colony formation in two of the four cell lines tested (P < .05), enhanced radiosensitivity in all four cell lines, delayed DDR (P < .05), and increased proton vs photon RBE.. Niraparib enhanced the sensitivity of four HNSCC cell lines to both photons and protons and increased the RBE of protons, possibly by inhibiting DDR. Niraparib may enhance the effectiveness of both photon and proton radiotherapy for patients with HNSCC.

Topics: Cell Line, Tumor; Head and Neck Neoplasms; Humans; Indazoles; Photons; Piperidines; Poly(ADP-ribose) Polymerase Inhibitors; Protons; Radiation-Sensitizing Agents

An inflammatory myofibroblastic tumor (IMT) is a rare mesenchymal neoplasm that typically develops in the lungs and seldom in the head and neck region. It is often related to the anaplastic lymphoma kinase (ALK) fusion gene. Crizotinib, a first-generation ALK inhibitor, has been shown to have a notable response in patients with ALK-positive IMT. Here, we report the first case of a 46-year-old man with IMT harboring a novel SQSTM1-ALK fusion gene who demonstrated marked response to alectinib. The patient presented a right neck mass (5-cm diameter) that progressively enlarged and expanded to the upper mediastinum. ALK-rearranged IMT was diagnosed after complete tumor resection. Spindle cells displayed diffuse cytoplasmic staining for ALK on immunohistochemistry. A fluorescence in situ hybridization analysis revealed the translocation of a part of the ALK gene locus at chromosome 2p23. FoundationOne CDx™ assay identified an SQSTM1-ALK gene fusion. After a year, right cervical, subclavian, and mediastinal lymph node metastases, considered unresectable, developed. Notably, the patient exhibited a marked response to alectinib treatment and has sustained for 17 months following systemic therapy initiation without significant adverse events. This report highlights the possibility of alectinib being a reasonable option for advanced IMT with the SQSTM1-ALK fusion.

Topics: Anaplastic Lymphoma Kinase; Antineoplastic Agents; Carbazoles; Head and Neck Neoplasms; Humans; Male; Middle Aged; Myofibroblasts; Piperidines; Protein Kinase Inhibitors; Tomography, X-Ray Computed; Treatment Outcome

Epidermal growth factor receptor (EGFR) overexpression is characteristic in head and neck cancers and is associated with tumour regrowth following photodynamic therapy (PDT).. We investigated vandetanib, which selectively blocks EGFR and vascular endothelial growth factor receptor-2 (VEGFR-2), to enhance the efficacy of PDT.. We assessed the in vitro therapeutic efficacy of: 1) vandetanib; 2) PDT with the photosensitizer Chlorin e6 (Fotolon®); and 3) combined PDT + vadetanib treatment in CAL-27 oral squamous cell carcinoma (OSCC) cell line by cell viability, γH2AX foci immunostaining, cell cycle arrest and western blot. We also performed in vivo tumour regression study and immunohistochemical staining of formalin-fixed paraffin-embedded (FFPE) regressed and regrown tumour tissues.. First, we observed significantly higher cytotoxicity and residual DNA damage in vandetanib + PDT-treated CAL-27 OSCC cells than tumour cells treated with PDT alone. This is due to impaired DNA DSB repair caused by downregulation of EGFR-mediated DNA-dependent protein kinase catalytic subunit (DNA-PKcs) activation. Next, combined vandetanib and PDT resulted in significant tumour growth delay in vivo that is linked to reduction of PDT-induced EGFR phosphorylation and cellular proliferation, along with loss of tumour vasculature. In particular, we observed significant revascularisation of the microenvironment that is associated with upregulated ERK1/2 phosphorylation in regrown tumours post-vandetanib + PDT, thereby corroborating the importance of microenvironmental modification for the observed drug-PDT synergistic interaction.. Taken together, our data suggests that vandetanib enhances the efficacy of PDT through both direct and indirect effects on the cellular DNA repair machinery and tumour microenvironment, respectively.

Topics: Animals; Cell Line, Tumor; Cell Proliferation; Cell Survival; Chlorophyllides; DNA Damage; DNA-Activated Protein Kinase; Down-Regulation; Drug Therapy, Combination; ErbB Receptors; Head and Neck Neoplasms; Humans; Mice; Mice, Nude; Photochemotherapy; Photosensitizing Agents; Piperidines; Porphyrins; Quinazolines; Squamous Cell Carcinoma of Head and Neck; Tumor Microenvironment; Vascular Endothelial Growth Factor Receptor-2

Endocannabinoids have recently drawn attention as promising anti-cancer agents. We previously observed that anandamide (AEA), one of the representative endocannabinoids, effectively inhibited the proliferation of head and neck squamous cell carcinoma (HNSCC) cell lines in a receptor-independent manner. In this study, using HNSCC cell lines, we examined the anti-cancer effects and the mechanisms of action of docosahexaenoyl ethanolamide (DHEA) and N-arachidonoyl-L-alanine (NALA), which are polyunsaturated fatty acid (PUFA)-based ethanolamides like AEA.. DHEA and NALA were found to effectively inhibit HNSCC cell proliferation. These anti-proliferative effects seemed to be mediated in a cannabinoid receptor-independent manner, since the antagonist of cannabinoid receptor-1 (CB1) and vanilloid receptor-1 (VR1), two endocannabinoid receptors, did not reverse the ability of DHEA and NALA to induce cell death. Instead, we observed an increase in reactive oxygen species (ROS) production and a decrease of phosphorylated Akt as a result of DHEA and NALA treatment. Antioxidants efficiently reversed the inhibition of cell proliferation and the decrease of phosphorylated Akt induced by DHEA and NALA; inhibition of 5-lipoxygenase (5-LO), which is expected to be involved in DHEA- and NALA-degradation pathway, also partially blocked the ability of DHEA and NALA to inhibit cell proliferation and phosphorylated Akt. Interestingly, ROS production as a result of DHEA and NALA treatment was decreased by inhibition of 5-LO.. From these findings, we suggest that ROS production induced by the 5-LO pathway mediates the anti-cancer effects of DHEA and NALA on HNSCC cells. Finally, our findings suggest the possibility of a new cancer-specific therapeutic strategy, which utilizes 5-LO activity rather than inhibiting it.

Topics: Alanine; Antineoplastic Agents; Apoptosis; Arachidonate 5-Lipoxygenase; Arachidonic Acids; Azoles; Benzoquinones; Carcinogenesis; Carcinoma, Squamous Cell; Cell Line, Tumor; Cell Proliferation; Endocannabinoids; Head and Neck Neoplasms; Humans; Hydroxyurea; Isoindoles; Lipoxygenase Inhibitors; Organoselenium Compounds; Phosphorylation; Piperidines; Proto-Oncogene Proteins c-akt; Pyrazoles; Reactive Oxygen Species; Receptor, Cannabinoid, CB1; Signal Transduction; Squamous Cell Carcinoma of Head and Neck; TRPV Cation Channels

The NUT midline carcinoma (NMC) is a rare but fatal cancer for which systematic testing of therapy options has never been performed.. On the basis of disease biology, we compared the efficacy of the CDK9 inhibitor flavopiridol (FP) with a panel of anticancer agents in NMC cell lines and mouse xenografts.. In vitro anthracyclines, topoisomerase inhibitors, and microtubule poisons were among the most cytotoxic drug classes for NMC cells, while efficacy of the bromodomain inhibitor JQ1 varied considerably between lines carrying different BRD4 (bromodomain-containing protein 4)-NUT (nuclear protein in testis) translocations. Efficacy of FP was comparable to vincristine and doxorubicin, drugs that have been previously used in NMC patients. All three compounds showed significantly better activity than etoposide and vorinostat, agents that have also been used in NMC patients. Statins and antimetabolites demonstrated intermediate single-agent efficacy. In vivo, vincristine significantly inhibited tumour growth in two different NMC xenografts. Flavopiridol in vivo was significantly effective in one of the two NMC xenograft lines, demonstrating the biological heterogeneity of this disease.. These results demonstrate that FP may be of benefit to a subset of patients with NMC, and warrant a continued emphasis on microtubule inhibitors, anthracyclines, and topoisomerase inhibitors as effective drug classes in this disease.

Topics: Animals; Anthracyclines; Antineoplastic Agents; Carcinoma, Squamous Cell; Cell Line, Tumor; Doxorubicin; Drug Screening Assays, Antitumor; Female; Flavonoids; Head and Neck Neoplasms; Humans; Mice; Mice, Inbred BALB C; Mice, Nude; Oncogene Proteins; Piperidines; Topoisomerase Inhibitors; Tubulin Modulators; Vincristine; Xenograft Model Antitumor Assays

Anesthetic management with airway stenosis is challenging. Techniques for maintaining spontaneous respiration are required under sedative and analgesic conditions.. A 35-year-old Chinese woman presented to our hospital with difficulty breathing. Computerized tomography showed a tumor in the frontal area of her neck, which was causing extreme narrowing of her trachea. She was immediately scheduled for emergency surgery to remove the tumor. Fiberscopic intubation was carefully performed with dexmedetomidine sedation and remifentanil analgesia. Spontaneous respiration was successfully maintained.. In cases of extreme airway stenosis, intubation can be safely achieved with dexmedetomidine sedation and remifentanil analgesia.

Topics: Adult; Airway Obstruction; Constriction, Pathologic; Dexmedetomidine; Female; Head and Neck Neoplasms; Humans; Hypnotics and Sedatives; Intubation, Intratracheal; Piperidines; Remifentanil; Tomography, X-Ray Computed

Cancer stem-like cells (CSC) thought to contribute to head and neck squamous carcinomas (HNSCC) may offer attractive therapeutic targets if a tractable approach can be developed. In this study, we report that silencing c-Met is sufficient to suppress sphere formation, tumor initiation, and metastatic properties of HN-CSC. Pharmacologic inhibition of c-Met with the selective inhibitor PF-2341066 preferentially targeted CSC and synergized with conventional chemotherapy to improve efficacy in a mouse xenograft model of HNSCC, impeding tumor growth and reducing metastasis. Mechanistic investigations showed that CSC elimination was due to downregulation of Wnt/β-catenin signaling in HN-CSC and that the Wnt pathway receptor FZD8 was essential for interactions of c-Met and Wnt/β-catenin signaling in HN-CSC. Notably, ectopic expression of FZD8 rescued the impaired phenotype of HN-CSC where c-Met was inhibited. Furthermore, c-Met upregulated FZD8 through the ERK/c-Fos cascade in HN-CSC. Taken together, our results offer a preclinical proof-of-concept for targeting the c-Met/FZD8 signaling axis as a CSC-directed therapy to improve HNSCC treatment.

Topics: Animals; Carcinoma, Squamous Cell; Crizotinib; Gene Expression Regulation, Neoplastic; Head and Neck Neoplasms; Humans; Mice; Neoplastic Stem Cells; Piperidines; Primary Cell Culture; Proto-Oncogene Proteins c-met; Pyrazoles; Pyridines; Receptors, Cell Surface; Signal Transduction; Xenograft Model Antitumor Assays

Metastasis is a critical event in the progression of head and neck squamous cell carcinoma (HNSCC) and closely correlates with clinical outcome. We previously showed that the farnesyl transferase inhibitor SCH66336 has antitumor activities in HNSCC by inducing the secretion of insulin-like growth factor binding protein 3 (IGFBP-3), which in turn inhibits tumor growth and angiogenesis. In our study, we found that SCH66336 at a sublethal dose for HNSCC inhibited the migration and invasion of HNSCC cells. The inhibitory effect of SCH66336 was associated with the blockade of the IGF-1 receptor (IGF-1R) pathway via suppressing IGF-1R itself and Akt expression. Consistent with previous work, induction of IGFBP-3 by SCH66336 also contributed in part to the anti-invasive effect. SCH66336 treatment also reduced the expression and activity of the urokinase-type plasminogen activator (uPA) and matrix metalloproteinase 2 (MMP-2), both important regulators of tumor metastasis. The effect of SCH66336 on uPA activity was inhibited partly by knockdown of IGFBP-3 using small interfering RNA. The inhibitory effect of SCH66336 on migration or invasion was attenuated partly or completely by knockdown of IGFBP-3, Akt or IGF-1R expression, respectively. Our results demonstrate that the IGF-1R pathway plays a major role in the proliferation, migration and invasion of HNSCC cells, suggesting that therapeutic obstruction of the IGF-1R pathway would be a useful approach to treating patients with HNSCC.

Topics: Animals; Carcinoma, Squamous Cell; Cell Line, Tumor; Cell Movement; Farnesyltranstransferase; Female; Head and Neck Neoplasms; Humans; Insulin-Like Growth Factor Binding Protein 3; Matrix Metalloproteinase 2; Mice; Mice, Nude; Neoplasm Invasiveness; Neoplasm Metastasis; Piperidines; Proto-Oncogene Proteins c-akt; Pyridines; Receptor, IGF Type 1; RNA Interference; RNA, Small Interfering; Squamous Cell Carcinoma of Head and Neck; Urokinase-Type Plasminogen Activator

The epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor (VEGFR) have been implicated as therapeutic targets for head and neck squamous cell carcinoma (HNSCC). Vandetanib is a small-molecule tyrosine kinase inhibitor (TKI) with dual specificity for EGFR and VEGFR. Here we characterize the phenotypic and biochemical effects of vandetanib on various HNSCC cell lines.. In vitro models were used for studying tumor cell viability, invasion, and signaling as well as in vivo xenograft models.. Treatment with vandetanib reduced viability, invasion, and tumor growth of HNSCC cell lines. Phosphorylation levels of mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription 3 (STAT3) were reduced in vandetanib-treated HNSCC cells. Additionally, vandetanib abrogates EGF-induced STAT3 activity and STAT3 target gene expression.. We demonstrated that vandetanib inhibits the growth of head and neck cancer cell lines. The antitumor effects of vandetanib appear to be exerted via the EGFR inhibitory effect of the compound.

Topics: Animals; Antineoplastic Agents; Blotting, Western; Carcinoma, Squamous Cell; Enzyme-Linked Immunosorbent Assay; ErbB Receptors; Head and Neck Neoplasms; Humans; Immunoprecipitation; In Vitro Techniques; Mice; Molecular Targeted Therapy; Piperidines; Quinazolines; Signal Transduction; Tumor Cells, Cultured

We investigated the effects of vandetanib, an inhibitor of vascular endothelial growth factor receptor 2 (VEGFR-2) and epidermal growth factor receptor (EGFR), alone and in combination with paclitaxel in an orthotopic mouse model of human head and neck squamous cell carcinoma (HNSCC).. The in vitro effects of vandetanib (ZACTIMA) were assessed in 2 HNSCC cell lines on cell growth, apoptosis, receptor and downstream signaling molecule expression, and phosphorylation levels. We assessed in vivo effects of vandetanib and/or paclitaxel by measuring tumor cell apoptosis, endothelial cell apoptosis, microvessel density, tumor size, and animal survival.. In vitro, vandetanib inhibited the phosphorylation of EGFR and its downstream targets in HNSCC cells and inhibited proliferation and induced apoptosis of HNSCC cells and extended survival and inhibited tumor growth in nude mice orthotopically injected with human HNSCC.. Vandetanib has the potential to be a novel molecular targeted therapy for HNSCC.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Blotting, Western; Carcinoma, Squamous Cell; Disease Models, Animal; ErbB Receptors; Flow Cytometry; Head and Neck Neoplasms; Humans; Male; Mice; Mice, Nude; Molecular Targeted Therapy; Paclitaxel; Piperidines; Protein-Tyrosine Kinases; Quinazolines; Random Allocation; Sensitivity and Specificity; Survival Rate; Tumor Cells, Cultured; Vascular Endothelial Growth Factor Receptor-2; Xenograft Model Antitumor Assays

We investigated whether vandetanib, an inhibitor of the tyrosine kinase activities of vascular endothelial growth factor receptor-2 (VEGFR-2), epidermal growth factor receptor (EGFR), and rearranged during transfection (RET), could augment the antitumor activity of radiation with or without cisplatin in preclinical in vitro and in vivo models of human head and neck squamous cell carcinoma (HNSCC).. OSC-19 and HN5 HNSCC cells that were cisplatin and radioresistant were treated with vandetanib, cisplatin, and radiation alone or in combination in vitro and in vivo using an orthotopic nude mouse model. Treatment effects were assessed using clonogenic survival assay, tumor volume, bioluminescence imaging, tumor growth delay, survival, microvessel density, tumor and endothelial cell apoptosis, and EGFR and Akt phosphorylation data.. Vandetanib plus cisplatin radiosensitized HNSCC cells in vitro and in vivo. The combination treatment with vandetanib, cisplatin, and radiation was superior to the rest of treatments (including the double combinations) in antitumoral effects, prolonging survival, decreasing cervical lymph node metastases in vivo. It also increased both tumor and tumor-associated endothelial cell apoptosis and decreased microvessel density in vivo. An analysis of tumor growth delay data revealed that vandetanib plus cisplatin enhanced radioresponse in vivo. All vandetanib-containing treatments inhibited EGFR and Akt phosphorylation in vitro and in vivo.. The addition of vandetanib to combination therapy with cisplatin and radiation was able to effectively overcome cisplatin and radioresistance in in vitro and in vivo models of HNSCC. Further study of this regimen in clinical trials may be warranted.

Topics: Animals; Antineoplastic Agents; Carcinoma, Squamous Cell; Cell Line, Tumor; Cell Survival; Cisplatin; Combined Modality Therapy; Drug Resistance, Neoplasm; Head and Neck Neoplasms; Humans; Lymphatic Metastasis; Male; Mice; Mice, Nude; Neovascularization, Pathologic; Piperidines; Quinazolines; Radiation Tolerance; Radiation-Sensitizing Agents; Tumor Burden; Xenograft Model Antitumor Assays

We determined hepatocyte growth factor (HGF) and c-Met expression and signaling in human head and neck squamous cell carcinoma (HNSCC) cells and primary tissues and tested the ability of c-Met tyrosine kinase inhibitors (TKI) to block HGF-induced biological signaling.. Expression and signaling were determined using immunoblotting, ELISA, and immunohistochemistry. Biological end points included wound healing, cell proliferation, and invasion. c-Met TKIs were tested for their ability to block HGF-induced signaling and biological effects in vitro and in xenografts established in nude mice.. c-Met was expressed and functional in HNSCC cells. HGF was secreted by HNSCC tumor-derived fibroblasts, but not by HNSCC cells. Activation of c-Met promoted phosphorylation of AKT and mitogen-activated protein kinase as well as release of the inflammatory cytokine interleukin-8. Cell growth and wound healing were also stimulated by HGF. c-Met TKIs blocked HGF-induced signaling, interleukin-8 release, and wound healing. Enhanced invasion of HNSCC cells induced by the presence of tumor-derived fibroblasts was completely blocked with a HGF-neutralizing antibody. PF-2341066, a c-Met TKI, caused a 50% inhibition of HNSCC tumor growth in vivo with decreased proliferation and increased apoptosis within the tumors. In HNSCC tumor tissues, both HGF and c-Met protein were increased compared with expression in normal mucosa.. These results show that HGF acts mainly as a paracrine factor in HNSCC cells, the HGF/c-Met pathway is frequently up-regulated and functional in HNSCC, and a clinically relevant c-Met TKI shows antitumor activity in vivo. Blocking the HGF/c-Met pathway may be clinically useful for the treatment of HNSCC.

Topics: Animals; Blotting, Western; Carcinoma, Squamous Cell; Cell Line, Tumor; Cell Movement; Cell Proliferation; Crizotinib; Dose-Response Relationship, Drug; Head and Neck Neoplasms; Hepatocyte Growth Factor; Humans; Immunohistochemistry; Indoles; Mice; Mice, Nude; Neoplasm Transplantation; Paracrine Communication; Piperazines; Piperidines; Proto-Oncogene Proteins c-met; Pyrazoles; Pyridines; Signal Transduction; Stress, Mechanical; Sulfonamides; Transplantation, Heterologous; Tumor Burden

Vandetanib (ZD6474, Zactima) is a novel, orally available inhibitor of vascular endothelial growth factor receptor-2 (VEGFR2) tyrosine kinase activity with additional activity against epidermal growth factor receptor (EGFR) tyrosine kinase. Vandetanib has demonstrated enhanced efficacy in combination with radiation therapy (RT) in human tumor models. This study aimed to evaluate the schedule-dependent interaction of clinically relevant dosing of vandetanib with RT in human head and neck cancer models that had been characterized as EGFR positive (EGFR+) or negative (EGFR-) in order to begin differentiating vandetanib and RT interactions at the level of antitumor (EGFR) or antivascular (VEGFR2) activities.. The human head and neck squamous cell carcinoma (HNSCC) cell lines UMSCC2 (EGFR+) and UMSCC10 (EGFR(-)) are sensitive and resistant to EGFR inhibitors, respectively, while having similar sensitivity to ionizing radiation. Nude mice with UMSCC2 or UMSCC10 tumor xenografts were treated with vandetanib or RT alone, or with combinations of concomitant and sequential therapy. Vandetanib was dosed at 30 mg kg(-1) day(-1) based on pharmacokinetic studies in nude mice showing that this dose results in drug exposure similar to that seen in humans at clinical doses. RT was dosed at 3 Gy twice a week for two consecutive weeks for a total dose of 12 Gy.. Vandetanib alone caused regression in EGFR+ but not EGFR- tumors and RT therapy alone was similar in both tumor types. Combinations of vandetanib and RT showed concomitant use of vandetanib and RT was superior to RT followed by vandetanib or visa versa in EGFR- tumors. Therapeutic response of EGFR+ tumors was similar regardless of treatment sequencing.. The combination of vandetanib and RT is active in both EGFR+ and EGFR- HNSCC tumor xenografts, however, vandetanib alone is only active in EGFR+ xenografts. EGFR+ tumor response to vandetanib and RT was independent of treatment sequencing, but concomitant treatment was superior to sequencing in EGFR- tumors. These results suggest that the anti-VEGFR2 antitumor activity of vandetanib is enhanced by RT as presumably the activity seen in EGFR- tumors is due to antiangiogenic activity, whereas the anti-EGFR antitumor activity dominates in EGFR+ tumors such that RT enhancement is not observed.

Topics: Animals; Blotting, Western; Cell Line, Tumor; Cell Proliferation; Combined Modality Therapy; ErbB Receptors; Gefitinib; Head and Neck Neoplasms; Humans; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Transplantation; Piperidines; Quinazolines; Receptors, Vascular Endothelial Growth Factor; Signal Transduction; Vascular Endothelial Growth Factor Receptor-2; Xenograft Model Antitumor Assays

Although preclinical studies have suggested that farnesyltransferase inhibitors (FTI) have promising antitumor activity, clinical trials have shown that FTI activity in patients is actually limited. The mechanism that induces resistance to FTI treatment is still not fully understood. The FTI SCH66336 has been shown to induce apoptotic and antiangiogenic activities in a subset of head and neck squamous cell carcinoma (HNSCC) and non-small cell lung cancer (NSCLC) cell lines. We therefore investigated the mechanisms mediating resistance to the therapeutic activities of SCH66336 in HNSCC and NSCLC. Our various analyses showed that insulin-like growth factor-I receptor (IGF-IR) activation interferes with the antitumor activity of SCH66336 in HNSCC and NSCLC cells. Treatment with SCH66336 activated the IGF-IR/phosphatidylinositol 3-kinase/Akt pathway, leading to increased mammalian target of rapamycin (mTOR)-mediated protein synthesis of survivin in a subset of HNSCC and NSCLC cell lines that were insensitive to the apoptotic activities of the drug. Inhibition of IGF-IR, Akt, or mTOR or the knockdown of survivin expression abolished resistance to SCH66336 and induced apoptosis in the cells. Overexpression of survivin by the use of adenoviral vector protected SCH66336-sensitive HNSCC cells from the apoptotic activities of the drug. Our results suggest that expression of phosphorylated IGF-IR, phosphorylated Akt, phosphorylated mTOR, and survivin serves as biological markers of SCH66336 responsiveness in HNSCC and NSCLC cells and that SCH66336 induces survivin expression through an IGF-IR/Akt/mTOR-dependent pathway. Thus, combining inhibitors of IGF-IR, phosphatidylinositol 3-kinase/Akt, mTOR, or survivin with SCH66336 may be an effective anticancer therapeutic strategy for patients with HNSCC or NSCLC.

Topics: Apoptosis; Blotting, Western; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Cell Cycle; Drug Resistance, Neoplasm; Head and Neck Neoplasms; Humans; Inhibitor of Apoptosis Proteins; Lung Neoplasms; Microtubule-Associated Proteins; Neoplasm Proteins; Phosphatidylinositol 3-Kinases; Phosphorylation; Piperidines; Protein Kinases; Proto-Oncogene Proteins c-akt; Pyridines; Receptor, IGF Type 1; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Signal Transduction; Survivin; TOR Serine-Threonine Kinases; Tumor Cells, Cultured

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.

Topics: Animals; Antineoplastic Agents; Apoptosis; Carcinoma, Squamous Cell; Cell Line, Tumor; Cell Proliferation; Head and Neck Neoplasms; Humans; Inhibitory Concentration 50; Mice; Mice, Nude; Models, Chemical; Neoplasm Transplantation; Neovascularization, Pathologic; Piperidines; Quinazolines

The farnesyl transferase inhibitor (FTI) SCH66336 has been shown to have antitumor activities in head and neck squamous cell carcinoma (HNSCC) in vitro and in vivo. However, its mechanism of action has not been well defined. Here, we report that the insulin-like growth factor (IGF) binding protein (IGFBP)-3 mediates antitumor activities of SCH66336 in HNSCC by inhibiting angiogenesis. SCH66336 significantly suppressed HNSCC tumor growth and angiogenesis via mechanisms that are independent of H-Ras and RhoB. By inducing IGFBP-3 secretion from HNSCC cells, this compound suppresses angiogenic activities of endothelial cells, including vessel formation in chorioallantoic membranes of chick, endothelial cell sprouting from chick aorta, and capillary tube formation of human umbilical vascular endothelial cells (HUVEC). Knockdown of IGFBP-3 expression in HNSCC cells by RNA interference or depletion of IGFBP-3 in HUVECs by neutralizing antibody effectively blocked the effects of IGFBP-3 secreted from SCH66336-treated HNSCC cells on HUVECs. These findings suggest that IGFBP-3 could be a primary target for antitumor activities of FTIs and that IGFBP-3 is an effective therapeutic approach against angiogenesis in HNSCC.

Topics: Animals; Aorta; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Cell Proliferation; Chickens; Chorioallantoic Membrane; Endothelium, Vascular; Enzyme Inhibitors; Farnesyltranstransferase; Female; Gene Expression Regulation, Neoplastic; Genes, ras; Head and Neck Neoplasms; Humans; Insulin-Like Growth Factor Binding Protein 3; Mice; Mice, Nude; Neovascularization, Pathologic; Piperidines; Pyridines; rhoB GTP-Binding Protein; Tumor Cells, Cultured; Umbilical Veins; Vascular Endothelial Growth Factor A

Farnesyltransferase inhibitors (FTI) are a class of therapeutic agents designed to target tumors with mutations of the ras oncogene. However, the biological effect of FTIs is often independent of ras mutation status, which suggests the existence of additional mechanisms. In this study, we investigated the molecular effects of SCH66336, an FTI, in head and neck squamous cell carcinoma cells using proteomic approaches. We showed that SCH66336 induced phosphorylation (inactivation) of eukaryotic translation elongation factor 2 (eEF2), an important molecule for protein synthesis, as early as 3 hours after SCH66336 administration. Protein synthesis was subsequently reduced in the cells. Paradoxically, activation of eEF2 kinase (eEF2K), the only known kinase that regulates eEF2, was observed only at 12 hours after SCH66336 treatment. Consistent with this observation, the inhibition of phosphorylated-MEK and phosphorylated-p70S6K, the two key signaling molecules responsible for activation of eEF2K, also occurred at least 12 hours after SCH66336 administration. Our data suggest that inhibition of protein synthesis through inactivation of eEF2 is a novel mechanism of SCH66336-mediated growth inhibition and that this effect is independent of ras-MEK/p70S6K-eEF2K signaling cascades.

Topics: Alkyl and Aryl Transferases; Amino Acid Sequence; Carcinoma, Squamous Cell; Cell Cycle; Cell Growth Processes; Cell Line, Tumor; Farnesyltranstransferase; Head and Neck Neoplasms; Humans; MAP Kinase Signaling System; Molecular Sequence Data; Neoplasm Proteins; Peptide Elongation Factor 2; Phosphorylation; Piperidines; Protein Synthesis Inhibitors; Pyridines

Tumor hypoxia modifies the efficacy of conventional anticancer therapy and promotes malignant tumor progression. Human chorionic gonadotropin (hCG) is a glycoprotein secreted during pregnancy that has been used to monitor tumor burden in xenografts engineered to express this marker. We adapted this approach to use urinary beta-hCG as a secreted reporter protein for tumor hypoxia. We used a hypoxia-inducible promoter containing five tandem repeats of the hypoxia-response element (HRE) ligated upstream of the beta-hCG gene. This construct was stably integrated into two different cancer cell lines, FaDu, a human head and neck squamous cell carcinoma, and RKO, a human colorectal cancer cell line. In vitro studies showed that tumor cells stably transfected with this plasmid construct secrete beta-hCG in response to hypoxia or hypoxia-inducible factor 1alpha (HIF-1alpha) stabilizing agents. The hypoxia responsiveness of this construct can be blocked by treatment with agents that affect the HIF-1alpha pathways, including topotecan, 1-benzyl-3-(5'-hydroxymethyl-2'-furyl)indazole (YC-1), and flavopiridol. Immunofluorescent analysis of tumor sections and quantitative assessment with flow cytometry indicate colocalization between beta-hCG and 2-(2-nitro-1H-imidazol-1-yl)-N-(2,2,3,3,3-pentafluoropropyl)acetamide (EF5) and beta-hCG and pimonidazole, two extrinsic markers for tumor hypoxia. Secretion of beta-hCG from xenografts that contain these stable constructs is directly responsive to changes in tumor oxygenation, including exposure of the animals to 10% O2 and tumor bed irradiation. Similarly, urinary beta-hCG levels decline after treatment with flavopiridol, an inhibitor of HIF-1 transactivation. This effect was observed only in tumor cells expressing a HRE-regulated reporter gene and not in tumor cells expressing a cytomegalovirus-regulated reporter gene. The 5HRE beta-hCG reporter system described here enables serial, noninvasive monitoring of tumor hypoxia in a mouse model by measuring a urinary reporter protein.

Topics: Animals; Carcinoma, Squamous Cell; Cell Hypoxia; Cell Line, Tumor; Chorionic Gonadotropin, beta Subunit, Human; Colorectal Neoplasms; DNA-Binding Proteins; Flavonoids; Genes, Reporter; Genetic Vectors; Head and Neck Neoplasms; Humans; Hypoxia-Inducible Factor 1; Hypoxia-Inducible Factor 1, alpha Subunit; Mice; Mice, Inbred BALB C; Mice, Inbred SENCAR; Neoplasm Transplantation; Nuclear Proteins; Piperidines; Topotecan; Transcription Factors; Transfection; Transplantation, Heterologous

The farnesyltransferase inhibitor SCH66336, in combination with other receptor tyrosine kinase inhibitors, inhibits the growth of non-small-cell lung cancer (NSCLC) cells. We examined whether SCH66336 inhibits angiogenesis of aerodigestive tract cancer cells.. Antiangiogenic activities of SCH66336 against NSCLC, head and neck squamous cell carcinoma (HNSCC), and endothelial cells were examined with cell proliferation, capillary tube formation, and chick aorta (under hypoxic, normoxic, insulin-like growth factor I (IGF)-stimulated, and unstimulated conditions); reverse transcription-polymerase chain reaction; and western blot analyses. The specific roles of the ubiquitin-mediated proteasome machinery, mitogen-activated protein kinase (MAPK) and Akt pathways, and heat shock protein 90 (Hsp90) in the SCH66336-mediated degradation of hypoxia-inducible factor 1alpha (HIF-1alpha) were assessed with ubiquitin inhibitors and adenoviral vectors that express constitutively active MAP kinase kinase (MEK)1, constitutively active Akt, or Hsp90.. SCH66336 showed antiangiogenic activities and decreased the expression of vascular endothelial cell growth factor (VEGF) and HIF-1alpha in hypoxic, IGF-stimulated, and unstimulated aerodigestive tract cancer and endothelial cells. SCH66336 reduced the half-life of the HIF-1alpha protein, and ubiquitin inhibitors protected the hypoxia- or IGF-stimulated HIF-1alpha protein from SCH66336-mediated degradation. SCH66336 inhibited the interaction between HIF-1alpha and Hsp90. The overexpression of Hsp90, but not constitutive Akt or constitutive MEK, restored HIF-1alpha expression in IGF-stimulated or hypoxic cells but not in unstimulated cells.. SCH66336 appears to inhibit angiogenic activities of NSCLC and HNSCC cells by decreasing hypoxia- or IGF-stimulated HIF-1alpha expression and to inhibit VEGF production by inhibiting the interaction between HIF-1alpha and Hsp90, resulting in the proteasomal degradation of HIF-1alpha.

Topics: Alkyl and Aryl Transferases; Angiogenesis Inhibitors; Animals; Blotting, Western; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Cell Hypoxia; Cell Line, Tumor; Cell Proliferation; Enzyme Inhibitors; Farnesyltranstransferase; Female; Gene Expression Regulation, Neoplastic; Head and Neck Neoplasms; HSP90 Heat-Shock Proteins; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Immunohistochemistry; Immunoprecipitation; Lung Neoplasms; Mice; Mice, Nude; Mitogen-Activated Protein Kinase Kinases; Neovascularization, Pathologic; Phosphatidylinositol 3-Kinases; Piperidines; Proteasome Endopeptidase Complex; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-akt; Pyridines; Reverse Transcriptase Polymerase Chain Reaction; Transcription Factors; Ubiquitin; Up-Regulation; Vascular Endothelial Growth Factor A

Remifentanil is an ultra-short-acting opioid that is frequently used in adults for surgical anesthesia or conscious sedation, but its use in children is much less common. We report the case of a 7-year-old boy with lateral cervical tumors displacing all cervical and facial structures. An emergency tracheostomy was performed when he developed respiratory difficulty due to partial airway obstruction. Because of the size and location of the intraoral tumors and a history of bleeding, orotracheal intubation and other airway management techniques were ruled out. The tracheostomy was performed under local anesthesia and sedation with a perfusion of 0.05 x microgKg(-1) x min(-1) provided the necessary relaxation and immobility for surgery. Sedation under observation with monitoring is among the indications of remifentanil. Spontaneous breathing is maintained with infusions less than 0.05 to 0.1 microg x Kg(-1) x min(-1). In the case we report, the patient's risk of complete airway obstruction due to bleeding upon manipulation had to be assessed and compared with the respiratory depression that might possibly have been caused by remifentanil perfusion. We judged that the option of sedation would cause less morbidity and offered greater safety for the patient. The outcome of this case is consistent with reports that remifentanil is a good option for adequately sedating children who are breathing spontaneously.

Topics: Airway Obstruction; Child; Conscious Sedation; Head and Neck Neoplasms; Humans; Hypnotics and Sedatives; Male; Piperidines; Remifentanil; Risk Factors; Tracheostomy

The farnesyltransferase inhibitor SCH66336 exhibits antitumor activity in vitro and in vivo; however, its mechanism of action is still unresolved. We found that SCH66336 suppressed growth and induced apoptosis of human head and neck squamous carcinoma cells (HNSCC). SCH66336 suppressed protein kinase B/Akt activity as well as the phosphorylation of the Akt substrates glycogen synthase kinase (GSK)-3 beta, forkhead transcription factor, and BAD. Infection of SqCC/Y1 cells with an adenovirus that contained a constitutively active form of Akt rescued cells from SCH66336-induced apoptosis. These results suggest that SCH66336 is a potent apoptosis inducer in HNSCC cells and that it may act by suppressing the Akt pathway.

Topics: Alkyl and Aryl Transferases; Apoptosis; bcl-X Protein; Carcinoma, Squamous Cell; Enzyme Inhibitors; Farnesyltranstransferase; Head and Neck Neoplasms; Humans; Piperidines; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-bcl-2; Pyridines; Tumor Cells, Cultured

Flavopiridol (HMR 1275) has been identified recently as a novel antineoplastic agent in the primary screen conducted by the Developmental Therapeutics Program, National Cancer Institute. Flavopiridol inhibits most cyclin-dependent kinases (cdks) and displays unique anticancer properties. Here, we investigated whether this compound was effective against head and neck squamous cell carcinomas (HNSCC). Exposure of HNSCC cells to flavopiridol diminished cdc2 and cdk2 activity and potently inhibited cell proliferation (IC50 43-83 nM), which was concomitant with the appearance of cells with a sub-G1 DNA content. Moreover, DNA fragmentation and TUNEL (terminal deoxynucleotidyl transferase-mediated nick end labeling) reaction confirmed that flavopiridol induces apoptosis in all cell lines, even on certain HNSCC cells that are insensitive to apoptosis to DNA-damaging agents (gamma-irradiation and bleomycin). A tumorigenic HNSCC cell line was used to assess the effect of flavopiridol in vivo. Treatment (5 mg/kg per day, intraperitoneally) for 5 d led to the appearance of apoptotic cells in the tumor xenografts and caused a 60-70% reduction in tumor size, which was sustained over a period of 10 wk. Flavopiridol treatment also resulted in a remarkable reduction of cyclin D1 expression in HNSCC cells and tumor xenografts. Our data indicate that flavopiridol exerts antitumor activity in HNSCC, and thus it can be considered a suitable candidate drug for testing in the treatment of refractory carcinomas of the head and neck.

Topics: Animals; Antineoplastic Agents; Apoptosis; Carcinoma, Squamous Cell; CDC2 Protein Kinase; CDC2-CDC28 Kinases; Cell Cycle; Cell Division; Cyclin D1; Cyclin D3; Cyclin E; Cyclin-Dependent Kinase 2; Cyclin-Dependent Kinases; Cyclins; Enzyme Inhibitors; Female; Flavonoids; Gene Expression; Growth Inhibitors; Head and Neck Neoplasms; Mice; Mice, Nude; Piperidines; Protein Serine-Threonine Kinases; Transplantation, Heterologous; Tumor Cells, Cultured

The risk of aspiration during tube feedings has been reduced but not abolished by percutaneous endoscopic gastrostomy (PEG). This open study was planned to evaluate whether cisapride may play some role in preventing aspiration in long-term enteral feeding via PEG. A group of 29 patients, unable to swallow because of head and neck cancer (14 cases) or neurological disorders (15 cases) entered the study; 7 neurological patients, fed via nasogastric tube before PEG placement, had suffered from aspiration pneumonia during nasogastric feeding. All patients underwent PEG, and 10 mg cisapride was routinely given via PEG before each administration of enteral feeding and 6 h after its initiation when the feeding was continued for 12 h or more. Only 1 minor complication was observed during the acute hospital setting (ileus, spontaneously resolving after 36 h). After hospital discharge, the patients were followed for a total of 4935 days of feeding (range 47-508 days, mean time per patient: 170 days) and assessed weekly for the development of complications. No episode of probable/possible aspiration pneumonia was observed during the follow-up. Two neurological patients with involuntary movements had rupture of the feeding tube, which was replaced without complications. These results support the hypothesis that cisapride might play some role in the prevention of aspiration in patients fed via PEG, and justify the planning of some controlled, double-blind trials to verify such a hypothesis.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Cisapride; Deglutition Disorders; Enteral Nutrition; Female; Follow-Up Studies; Gastroscopy; Gastrostomy; Head and Neck Neoplasms; Humans; Intubation, Gastrointestinal; Male; Middle Aged; Nervous System Diseases; Pilot Projects; Piperidines; Pneumonia, Aspiration; Serotonin Antagonists; Survival Rate

Topics: Adhesiveness; Animals; Antineoplastic Agents; Blood Cell Count; Blood Platelets; Capillaries; Carcinoma 256, Walker; Dipyridamole; Embolism; Endothelium; Head; Head and Neck Neoplasms; Humans; Lung Neoplasms; Morpholines; Neoplasm Metastasis; Neoplasm Transplantation; Neoplastic Cells, Circulating; Piperidines; Platelet Adhesiveness; Pulmonary Embolism; Pyrimidines; Rats; Sarcoma; Thiophenes; Transplantation, Homologous; Vasodilator Agents