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Query: UNIPROT:P06889 (Mol)
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Head and neck squamous cell carcinoma (HNSCC) is characterized by epidermal growth factor receptor (EGFR) overexpression, where EGFR levels correlate with survival. To date, EGFR targeting has shown limited antitumor effects in head and neck cancer when administrated as monotherapy. We previously identified a gastrin-releasing peptide/gastrin-releasing peptide receptor (GRP/GRPR) aurocrine regulatory pathway in HNSCC, where GRP stimulates Src-dependent cleavage of EGFR proligands with subsequent EGFR phosphorylation and mitogen-activated protein kinase (MAPK) activation. To determine whether GRPR targeting can enhance the antitumor efficacy of EGFR inhibition, we investigated the effects of a GRPR antagonist (PD176252) in conjunction with an EGFR tyrosine kinase inhibitor (erlotinib). Combined blockade of GRPR and EGFR pathways significantly inhibited HNSCC, but not immortalized mucosal epithelial cell, proliferation, invasion, and colony formation. In addition, the percentage of apoptotic cells increased upon combined inhibition. The enhanced antitumor efficacy was accompanied by increased expression of cleaved poly(ADP-ribose) polymerase (PARP) and decreased phospho-EGFR, phospho-MAPK, and proliferating cell nuclear antigen (PCNA). Using reverse-phase protein microarray (RPPA), we further detected decreased expression of phospho-c-Jun, phospho-p70S6K, and phospho-p38 with combined targeting. Cumulatively, these results suggest that GRPR targeting can enhance the antitumor effects of EGFR inhibitors in head and neck cancer.
Mol Cancer Ther 2007 Apr
PMID:Antitumor mechanisms of combined gastrin-releasing peptide receptor and epidermal growth factor receptor targeting in head and neck cancer. 1743 Nov 20

The epidermal growth factor receptor (EGF-R) is an important growth regulator of epithelial cancer cells, overexpressed by several human tumors and scantly detectable in most normal tissues. The introduction of monoclonal antibodies (Mabs) and more recently engineered humanized Mabs have greatly expanded the therapeutic potential of this modality of cancer treatment. The present study was designed to compare the specificity of the murine and humanized anti-EGF-R Mabs. Biotinylated Mabs were tested in samples of fetal and adult normal and neoplastic tissues by ABC peroxidase method. All fetal tissues studied were positive for both Mabs, showing 2 different staining patterns, one homogeneous and finely granular in cytoplasm and another grosser with intense labeling in both membrane and cytoplasm. A similar recognition pattern was exhibited in adult normal tissues, where an intense reactivity was also evidenced in skin, tongue, gastrointestinal tract, renal tubules, and breast gland epithelium. In tissues from genitourinary and central nervous system, a faint staining was demonstrate, whereas those from cardiovascular and lymphoid tissues proved to be negative. These Mabs exhibited a heterogeneous and strong membrane and cytoplasm staining in neoplastic cells from lung, breast, and head and neck cancer. On the basis of these results, we conclude that the humanized (h-R3) and murine (egf/r3) anti-EGF-R Mabs show a very similar immunohistochemical pattern of recognition of fetal, adult, and neoplastic tissues. Also h-R3 Mab is a novel candidate for the development of an immunotherapeutic approach suitable for the treatment of tumors with EGF-R overexpression.
Appl Immunohistochem Mol Morphol 2007 Jun
PMID:Immunohistochemical evaluation of H-R3 a novel humanized monoclonal antibody that neutralizes the EGF-receptor. 1752 37

This study aimed to characterize the antitumor activity of 5-Chloro-N-[2-[2-(4-chloro-phenyl)-3-methyl-butoxy]-5-trifluoromethyl-phenyl]-2-hydroxy-benzamide (CTFB), a novel anticancer agent, in head and neck cancer cell lines, FaDu, SCC-25 and cisplatin-resistant CAL-27. CTFB was generated as a result of an extensive medicinal chemistry effort on a lead compound series discovered in a high-throughput screen for inducers of apoptosis. All cell lines showed significant growth delay in response to CTFB treatment at a concentration of 1 micromol/L with 17.16 +/- 2.08%, 10.92 +/- 1.22%, and 27.03 +/- 1.86% of cells surviving at 120 h in FaDu, CAL-27, and SCC-25, respectively. To define proteins involved in the mechanism of action of CTFB, we determined differences in the proteome profile of cell lines before and after treatment with CTFB using two-dimensional difference gel electrophoresis followed by computational image analysis and mass spectrometry. Eight proteins were found to be regulated by CTFB in all cell lines. All these proteins are involved in cytoskeleton formation and function and/or in cell cycle regulation. We showed that CTFB-induced cell growth delay was accompanied by cell cycle arrest at the G(0)-G(1) phase that was associated with the up-regulation of p21/WAF1 and p27/Kip1 expression and the down-regulation of cyclin D1. Furthermore, we showed that activity of CTFB depended on the down-regulation of nuclear factor-kappaB (NF-kappaB) and NF-kappaB p65 phosphorylated at Ser(536). The level of proteasome activity correlated with the response to CTFB treatment, and the down-regulation of NF-kappaB is accompanied by enhanced proteasome activity in all investigated head and neck cancer cell lines. In this report, we show that CTFB reveals multiple effects that lead to delayed cell growth. Our data suggest that this compound should be studied further in the treatment of head and neck cancer.
Mol Cancer Ther 2007 Jun
PMID:Antitumor activity of CTFB, a novel anticancer agent, is associated with the down-regulation of nuclear factor-kappaB expression and proteasome activation in head and neck squamous carcinoma cell lines. 1757 18

Oxidative DNA damage and DNA repair mediate the development of several human pathologies, including cancer. The major pathway for oxidative DNA damage repair is base excision repair (BER). Functional assays performed in blood leukocytes of cancer patients and matched controls show that specific BER pathways are decreased in cancer patients, and may be risk factors. These include 8-oxoguanine (8-oxoG) repair in lung and head and neck cancer patients and repair of lipid peroxidation (LPO) induced 1,N(6)-ethenoadenine (epsilonA) in lung cancer patients. Decrease of excision of LPO-induced DNA damage, epsilonA and 3,N(4)-ethenocytosine (epsilonC) was observed in blood leukocytes of patients developing lung adenocarcinoma, specific histological type of cancer related to inflammation and healing of scars. BER proteins activity depends on gene polymorphism, interactions between BER system partners and post-translational modifications. Polymorphisms of DNA glycosylases may change their enzymatic activities, and some polymorphisms increase the risk of inflammation-related cancers, colorectal, lung and other types. Polymorphisms of BER platform protein, XRCC1 are connected with increased risk of tobacco-related cancers. BER efficiency may also be changed by reactive oxygen species and some diet components, which induce transcription of several glycosylases as well as a major human AP-endonuclease, APE1. BER is also changed in tumors in comparison to unaffected surrounding tissues, and this change may be due to transcription stimulation, post-translational modification of BER enzymes as well as protein-protein interactions. Modulation of BER enzymes activities may be, then, an important factor determining the risk of cancer and also may participate in cancer development.
Mol Aspects Med
PMID:Base excision repair modulation as a risk factor for human cancers. 1762 57

Human papillomavirus (HPV) is a causal agent for approximately 5.3% of cancers worldwide, including cervical cancer, and subsets of genital and head and neck cancer. Persistent HPV infection is a necessary, but not sufficient, cause of cervical cancer. Of the >100 HPV genotypes, only about a dozen, termed "high-risk", are associated with cancer. HPV-16 is present in approximately 50% of all cervical cancers and HPV-16, HPV-18, HPV-31 and HPV-45 together account for approximately 80%. Most high-risk HPV infections are subclinical, and are cleared by the host's immune system. The remainder produces low or high-grade squamous intraepithelial lesions (SILs), also called cervical intraepithelial neoplasia (CIN), which also may regress spontaneously. However persistent high grade SIL represents the precursor lesion of cervical cancer and carcinogenic progression is associated with integration of the viral DNA, loss of E2 and upregulation of viral oncogene expression, and chromosomal rearrangements like 3q gain. Cytologic screening of the cervix for SIL and intervention has reduced the incidence of cervical cancer in the US by an estimated 80% and HPV viral DNA and other molecular tests may improve screening further. The licensure of a preventive HPV vaccine ushers in a new era, but issues remain, including: protection restricted to a few oncogenic HPV types, access in low resource settings and impact on current cytologic screening protocols. Importantly, preventive HPV vaccination does not help with current HPV infection or disease. Here we examine the potential of second-generation preventive HPV vaccines and therapeutic HPV vaccination to address these outstanding issues.
Curr Mol Med 2007 Aug
PMID:Opportunities to improve the prevention and treatment of cervical cancer. 1769 64

Treatment of most head and neck cancers includes radiotherapy. Salivary glands (SGs) in the irradiation (IR) field are irreversibly damaged resulting in severe hyposalivation. We evaluated the importance of SG endothelial cells to this IR-induced injury, and whether serotype 5 adenoviral (Ad5) vector-mediated transfer of basic fibroblast growth factor (AdbFGF) or vascular endothelial growth factor (AdVEGF) complementary DNAs would afford radioprotection. Four hours after IR, microvessel density (MVD) in SGs decreased by approximately 45%. However, if mice were pre-treated with either AdVEGF or AdbFGF 48 hours before IR the loss in MVD was significantly reduced. An irrelevant vector, AdLacZ, encoding Escherichia coli beta-galactosidase, was without effect. After 8 weeks, IR reduced salivary flow by approximately 65% in untreated mice. Mice pre-treated (using 5 x 10(9) particles/gland 48 hours prior to IR) with AdLacZ exhibited a reduction in salivary flow similar to untreated mice receiving IR. However, irradiated mice pre-treated with AdbFGF or AdVEGF showed a significant improvement in their salivary flow, to approximately 70% (P < 0.01) and 80% (P < 0.01), respectively, compared to non-irradiated control mice. These results are consistent with the notion that injury to the adjacent microvasculature may play an important role in SG radiation damage. Furthermore, our results suggest that a local transient treatment directed at protecting SG endothelial cells may be beneficial for patients undergoing IR for head and neck cancer.
Mol Ther 2007 Dec
PMID:Prevention of irradiation-induced salivary hypofunction by microvessel protection in mouse salivary glands. 1772 56

Natural killer (NK) cells play a dominant role in the network of innate immunity. Via Toll-like receptor 3 (TLR3), NK cells can be efficiently stimulated by double-stranded (ds)RNA. In head and neck squamous cell carcinoma (HNSCC), NK cells seem to be strongly impaired, but the true mechanisms of immune escape are not sufficiently known to date. It is obvious that the microenvironment of head and neck cancer results in strongly affected immune functions. NK cells play a major role in the local immune response of HNSCC. In this study we showed that TLR3 is predominantly expressed on the cell surface of native NK cells and becomes rapidly internalized in response to the HNSCC microenvironment. These findings represent a novel potential immune escape mechanism of head and neck cancer. The internalization of TLR3 in response to HNSCC was also observed in fibroblasts expressing heterologous TLR3 protein. Specific stimulation of NK cell TLR3 with its ligand polyinosinic-polycytidylic acid (Poly I:C) impairs the internalization of this Toll-like receptor and leads to activated NK cells within the HNSCC microenvironment.
Int J Mol Med 2007 Oct
PMID:Head and neck cancer triggers the internalization of TLR3 in natural killer cells. 1778 79

Cyclophosphamide (CPA) is a chemotherapeutic agent that is primarily activated in the liver by cytochrome P4502B6 (CYP2B6) and then transported to the tumor via blood flow. To prevent deleterious secondary effects, P450-based gene-directed enzyme prodrug therapy (GDEPT) consists of expressing CYP2B6 in tumor cells before CPA treatment. Given the relatively low affinity of CYP2B6 for CPA, the aim of our work was to modify CYP2B6 to increase its catalytic efficiency (V(max)/K(m)) to metabolize CPA into 4'-OH CPA. A molecular model of CYP2B6 was built, and four residues in close contact with the substrate were subjected to mutagenesis. Canine CYP2B11 exhibiting a particularly low K(m) to CPA, the amino acids exclusively present in the CYP2B11 substrate recognition sequences were substituted in human CYP2B6. All mutants (n = 26) were expressed in Saccharomyces cerevisiae and their enzymatic constants (K(m), V(max)) evaluated using CPA as substrate. Five mutants exhibited a 2- to 3-fold higher catalytic efficiency than wild-type CYP2B6. A double mutant, comprising the two most effective mutations, showed a 4-fold increase in K(m)/V(max). Molecular dynamic simulations of several mutants were found to be consistent with the observed modifications in catalytic efficiency. Finally, expression of the CYP2B6 114V/477W double mutant, contrary to wt CYP2B6, allowed switching of a resistant human head and neck cancer cell line (A-253) into a sensitive cell line toward CPA. Thus, we were able to obtain a new efficient CYP2B6 mutant able to metabolize CPA, an important step in the GDEPT strategy for human cancer treatment.
Mol Pharmacol 2008 Apr
PMID:Improvement of cyclophosphamide activation by CYP2B6 mutants: from in silico to ex vivo. 1821 49

Class IA phosphoinositide 3-kinases (PI 3-kinases) are key signaling components downstream of tyrosine kinases and Ras, regulating many different cellular functions and contributing to tumorigenesis. Class IA PI 3-kinases are heterodimers comprised of a p85 regulatory and a p110 catalytic subunit. Nijmegen breakage syndrome (NBS) is a chromosomal instability syndrome associated with cancer predisposition, radiosensitivity, microcephaly, and growth retardation. The NBS gene product p95 (also known as NBS1) is part of the Mre11-Rad50-Nbs1 complex, a central player associated with double-strand break repair. We previously demonstrated that NBS1 overexpression induces transformation through activation of PI 3-kinase/Akt. In this study, we show that NBS1 directly interacts, through a highly conserved C-terminal motif (aa 653-669) of NBS1, with the N-terminal domain (aa 1-108) of the p110alpha catalytic subunit of PI 3-kinase, and stimulates PI 3-kinase activity. Mutations of different regions of the conserved motif abolish the ability of NBS1 to activate PI 3-kinase in vitro and in vivo. Co-expression of NBS1/p110alpha/p-Akt is observed in certain percentage of head and neck cancer patient samples. These results demonstrate that NBS1 can function as an adaptor/activator of p110alpha PI 3-kinase through a novel activation motif, consistent with its possible role in cell transformation and tumorigenesis.
J Mol Med (Berl) 2008 Apr
PMID:Activation of phosphoinositide 3-kinase by the NBS1 DNA repair protein through a novel activation motif. 1827 Jun 79

Viventia Biotech Inc, under license from the University of Zurich, is developing VB4-845, comprising a Pseudomonas exotoxin fused to an anti-epithelial cell adhesion molecule single-chain antibody fragment, for the potential treatment of head and neck cancer (intratumoral) and bladder cancer (intravesical). VB4-845 is currently undergoing phase II and III clinical trials in patients with head and neck squamous cell carcinomas, as well as phase II clinical trials for the treatment of superficial transitional cell carcinoma of the bladder.
Curr Opin Mol Ther 2008 Apr
PMID:VB4-845, a conjugated recombinant antibody and immunotoxin for head and neck cancer and bladder cancer. 1838 30


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