Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Targeted Genetics is developing, tgDCC-E1A, a E1A tumor suppressor gene therapy formulated in a non-viral, lipid-based delivery system as a potential treatment for solid tumors which overexpress the her-2/neu oncogene [221611]. Fournier is the European development partner [244180]. Preclinical studies of E1A in mouse models for human breast and ovarian cancer demonstrated inhibition of expression of the her-2/neu oncogene, a significant reduction in tumors and increased survival rate in the treated animals [244180]. Results of a phase I study of intratumoral liposomal-E1A gene therapy in patients with recurrent/refractory breast cancer and head and neck cancer were presented at the 1998 American Society of Clinical Oncology (ASCO) meeting. Results demonstrated that intratumoral delivery of the E1A gene caused a subsequent downregulation of HER-2/neu expression and tumor response. The phase I dose-escalation study treated nine patients with recurrent breast cancer and nine patients with head and neck cancer. In 16 patients evaluable for response, nine had stable disease, five had progressive disease and two had minor responses despite tumor progression at other sites. In one of six patients who had repeat biopsies of treated tumors, no pathological evidence of tumor was found. In four of seven patients evaluated to date (May 1998), evidence of downregulation of HER-2/neu was reported [287387,290118]. The first phase I trial in patients with breast and ovarian cancer was completed by the end of 1997. The second phase I trial, enrolling 12 to 24 patients with solid tumors, was initiated in April 1997. Its aim was to determine dosing and safety of tgDCC-E1A and evaluate levels of gene transfer and tumor response. Patients were administered tgDCC-E1A by intratumoral injections. The company completed this trial by the end of 1997. In October 1998, Targeted Genetics initiated a multicenter, open-label phase II clinical trial of tgDCC-E1A in patients with recurrent head and neck squamous cell carcinoma who have exhibited disease progression despite standard therapies. The study to be conducted at six medical institutions in the US will enrole up to 60 patients with an interim analysis scheduled to be performed after the first 20 evaluable patients have been enrolled. Patients will be treated with ten direct intratumoral injections of the E1A gene over a period of 8 weeks, with follow-up performed at week 12. Patients who demonstrate a response will be eligible for continued treatment and will be monitored for 1 year [300424]. Targeted Genetics has issued three patents covering methods and compositions of use of the E1A and LTgenes (qv) to treat a variety of cancers. US-05651964 covers the use of the E1A gene, US-05643567 and US-05641484 cover the use of either the E1A gene or the LT gene as cancer therapies. These three patents provide the company with broad patent protection for tgDCC-E1A and all future products based on the use of the E1A or LT gene as tumor suppressors [259808].
Curr Opin Mol Ther 1999 Apr
PMID:Technology evaluation: tgDCC-E1A, targeted genetics/MD Anderson. 1171 50

We evaluated the efficiency of recombinant vaccinia virus expressing interleukin-2 (rvv-IL-2) as a tumor vaccine in an immunocompetent mouse model of head and neck squamous cell carcinoma (SCC VII/SF). Mice with five-day-old tumors in the floor of the mouth were treated with rvv-IL-2 by intratumoral injections. These treated mice survived longer (P <.03) than mice treated with control vaccines. Splenocytes, bone marrow, and lymph node cells from tumor-bearing mice responded poorly to concanavalin A stimulation, suggesting induction of immunosuppression. The rvv-IL-2 virus grew for 7 days in the tumor following intratumoral injection. We did not detect any virus particles in several normal organs following rvv-IL-2 injection. Comparison of expression levels of several potential immune inhibitory mediators between the tumors growing in mice and cultured tumor cells demonstrated higher expression of IL-10, GM-CSF, TGF-beta, and NO synthetase in tumors. These results suggested possible roles for these molecules in immunosuppression. We conclude that rvv-IL-2 has potential as a therapeutic vaccine for head and neck cancer and that it can be more effective provided the immunosuppression is reversed.
Mol Ther 2001 Dec
PMID:Gene therapy for head and neck cancer using vaccinia virus expressing IL-2 in a murine model, with evidence of immune suppression. 1173 39

Allovectin-7 is a gene transfer product consisting of the human leukocyte antigen HLA-B7 gene co-expressed with the beta2-microglobulin gene. Allovectin-7 is being developed as an immunotherapy approach for a variety of malignancies, with special focus on melanoma, and head and neck cancer. Efficacy results in the phase II setting appear to be promising; an 11% systemic response rate among the intent-to-treat population and 15% response rate in the evaluable population was observed in patients with refractory metastatic melanoma with disease limited to skin, lymph nodes and lung. Stable disease was seen in 19.2% of the intent-to-treat population and 25.9% of the evaluable population in the same group of patients. Treatment has been extremely well tolerated with the most common side effects including mild-to-moderate injection site reactions and flu-like symptoms, all of which resolved rapidly and decreased in incidence after the first injection. Current evaluation of the drug includes higher Allovectin-7 doses and injection of multiple tumors in metastatic melanoma patients. A phase III trial comparing Allovectin-7 plus dacarbazine versus dacarbazine in untreated patients with metastatic melanoma has been completed, and preliminary results are soon to be reported. Phase I/II data also indicate promising activity of Alovectin-7 in patients with advanced refractory head and neck squamous cell carcinoma, with 10% of 60 patients achieving partial response and 23% stable disease after one cycle of treatment. Trials of Allovectin-7 as an adjuvant treatment in earlier stages of disease evolution are planned.
Curr Opin Mol Ther 2002 Feb
PMID:Technology evaluation: Allovectin-7, Vical. 1188 99

Head and neck cancer is a frequent malignancy with a complex, and up to now not clear etiology. The reactivation of telomerase activity and losses or gains of specific chromosomal regions, which point to deletions of tumor suppressor genes or amplification of oncogenes are supposed to be the molecular processes during the development and progression of head and neck cancer. Therefore, we analyzed telomerase activity and microsatellite markers using a genome wide panel of 28 microsatellite markers in 38 head and neck squamous-cell carcinomas (HNSCC). Our microsatellite marker set included distinct chromosomal areas that all likely harbor genes contributing to the carcinogenesis of HNSCC. DNA or protein lysates were obtained from primary tumors and compared to peripheral lymphocytes or corresponding normal tissue. At least one genomic alteration [loss of heterozygosity (LOH), or microsatellite instability (MSI)] was found in 31 of the 38 cases (82%). Most frequently we detected an LOH in the chromosomal region 9p12-21 where at least the tumor suppressor genes (TSG) p16INK4A, p14ARF and p15INKB are localized. The comparison between grade two and grade three tumors showed a highly changed frequency of LOH in the chromosomal region 7q31, where a putative TSG is predicted. Telomerase activity was present in 31/37 (83.8%) tumor samples independent of the histopathological staging and grading of the tumors. These molecular characterizations of HNSCC may be a further hint for the involvement of additional, so far unknown, TSGs in the tumor progression and will elucidate the regulation of telomerase.
Int J Mol Med 2002 Apr
PMID:Molecular characterization of head and neck tumors by analysis of telomerase activity and a panel of microsatellite markers. 1189 39

While fluorine-18 2-fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET) is helpful in the pretherapeutic evaluation of head and neck cancer, it is only available in selected centres. Therefore, single-photon emission tomography (SPET) tracers would be desirable if they were to demonstrate tumour uptake reliably. This multitracer study was performed to evaluate the pretherapeutic uptake of the SPET tracers iodine-123 alpha-methyl-L-tyrosine (IMT) and technetium-99m hexakis-2-methoxyisobutylisonitrile (99mTc-MIBI) in primary carcinomas of the hypopharynx and larynx and to compare the results with those of FDG PET. We examined 22 fasted patients (20 male, 2 female, mean age 60.5+/-10.2 years) with histologically confirmed carcinoma of the hypopharynx (n=9) or larynx (n=13), within 1 week before therapy. In 20 patients a cervical PET scan was acquired after intravenous injection of 232+/-43 MBq 18F-FDG. Data analysis was semiquantitative, being based on standardised uptake values (SUVs) obtained at 60-90 min after injection. After injection of 570+/-44 MBq 99mTc-MIBI, cervical SPET scans (high-resolution collimator, 64x64 matrix, 64 steps, 40 s each) were obtained in 19 patients, 15 and 60 min after tracer injection. Finally, 15 min after injection of 327+/-93 MBq 123I-IMT (medium-energy collimator, 64x64 matrix, 64 steps, 40 s each) SPET scans were acquired in 15 patients. All images were analysed visually and by calculating the tumour to nuchal muscle ratio. Eighteen of 20 (90%) carcinomas showed an increased glucose metabolism, with a mean SUV of 8.7 and a mean carcinoma to muscle ratio of 7.3. The IMT uptake was increased in 13 of 15 (87%) patients, who had a mean carcinoma to muscle ratio of 2.9. Only 13 of 19 (68%) carcinomas revealed pathological MIBI uptake, with a mean tumour to muscle ratio of 2.2 and no significant difference between early and late MIBI SPET images (P=0.23). In conclusion, in the diagnosis of primary carcinomas of the hypopharynx and larynx, IMT SPET achieved a detection rate comparable to that of FDG PET. IMT SPET was clearly superior to MIBI SPET in this population. A further evaluation of the specificity of IMT in a larger number of patients appears justified.
Eur J Nucl Med Mol Imaging 2002 Mar
PMID:Pretreatment evaluation of carcinomas of the hypopharynx and larynx with 18F-fluorodeoxyglucose, 123I-alpha-methyl-L-tyrosine and 99mTc-hexakis-2-methoxyisobutylisonitrile. 1200 6

The aim of this study was to assess the safety and biodistribution of technetium-99m BRU 59-21, a novel radioactively labelled 2-nitro-imidazole hypoxic marker, in head and neck cancer patients and to correlate uptake with pimonidazole staining. (99m)Tc-BRU 59-21 was administered intravenously (mean dose 824 MBq, range 780-857 MBq) to ten head and neck cancer patients scheduled for primary surgery, and whole-body images and SPET scans were then obtained. Uptake of radioactivity in the regions of interest was determined and tumour to normal tissue ratios were calculated after correlative evaluation with MRI/CT. Twelve to 16 h before surgery (up to 2 weeks after the scan), patients received pimonidazole intravenously. Tumour sections were stained immunohistochemically for pimonidazole binding. No serious adverse events were reported. In five patients there were ten adverse events, which were mild in intensity and resolved completely without intervention. Uptake of (99m)Tc-BRU 59-21 was observed in eight of the ten primary tumours. Tumour to normal tissue ratios on the SPET scans for primary tumour and lymph nodes increased from 1.8 (range 0.9-2.7) to 2.1 (range 0.8-3.7) between 30 min and 3 h post injection. Tumour to normal tissue ratios in the primary tumour were significantly correlated with pimonidazole staining for SPET scans performed 30 min and 3 h post injection ( P=0.016 and P=0.037, respectively). When primary tumour and involved lymph nodes were considered in conjunction, correlation between the tumour to normal tissue ratio and pimonidazole staining was observed for early ( P<0.001) but not for late SPET scans ( P=0.076). However, late scans showed better tumour delineation than early scans. Administration of (99m)Tc-BRU 59-21 in head and neck cancer patients appears to be safe and feasible. Uptake and retention in tumour tissue was observed, suggestive of tumour hypoxia, and this was supported by correlations with staining for the hypoxic marker pimonidazole.
Eur J Nucl Med Mol Imaging 2002 Sep
PMID:Phase 1 study to identify tumour hypoxia in patients with head and neck cancer using technetium-99m BRU 59-21. 1219 67

Amino acid transport system A is expressed strongly in neoplastic cells. [ N-methyl-(11)C]alpha-Methylaminoisobutyric acid ((11)C-MeAIB) is a recently developed tracer for PET studies on system A amino acid transport. (11)C-MeAIB is a metabolically stable amino acid analogue which is transported from plasma into the tissue by system A. This study evaluated the kinetics of (11)C-MeAIB uptake from plasma into tumour tissue and normal tissues in 13 patients with untreated head and neck cancer. (11)C-MeAIB uptake in tumour was compared with histological grade and proliferative activity. Tracer uptake was quantitated by calculating the standardised uptake values (SUVs) and the kinetic influx constants ( K(i)) using graphical analysis. All tumours accumulated (11)C-MeAIB and were visualised clearly. In the graphical analysis, linear plots were achieved; the mean K(i) value of tumour was 0.056+/-0.026 min(-1), and the mean SUV was 6.1+/-2.7. A close correlation between graphically obtained K(i) and semi-quantitative SUV in tumours was found ( r=0.887, P=0.00005). We could not demonstrate a correlation between the uptake of (11)C-MeAIB and the grade of malignancy or the proliferative index, as assessed using Ki-67 immunohistochemical assay. Head and neck cancer can be effectively imaged with (11)C-MeAIB PET. (11)C-MeAIB showed active and rapid transport into tumour tissue and salivary glands. Further studies on the applicability of (11)C-MeAIB PET for radiation treatment planning in the head and neck region and the regulation of system A amino acid transport under different metabolic states are warranted.
Eur J Nucl Med Mol Imaging 2003 Jan
PMID:Uptake of [N-methyl-11C]alpha-methylaminoisobutyric acid in untreated head and neck cancer studied by PET. 1248 12

Fluorine-18 fluoroerythronitroimidazole ([(18)F]FETNIM) is a nitroimidazole compound that is potentially useful as a hypoxia marker in positron emission tomography (PET) studies of oncological patients. Our aim was to develop a simple protocol to quantitate uptake of [(18)F]FETNIM in hypoxic tumours. Dynamic imaging data from ten patients with head and neck cancer undergoing [(18)F]FETNIM PET was used in simulations and model fits to assess hypoxia marker uptake under different levels of blood flow. The distribution volume determined from dynamic PET study was compared with simple tumour to plasma and tumour to muscle ratios at 90-120 min. In skeletal muscle having a low but variable blood flow [2-6 ml/(100 gxmin)], differences in hypoxia-specific uptake of [(18)F]FETNIM remain small and may be hard to detect with PET. At higher blood flow [>20 ml/(100 gxmin)], the retention of [(18)F]FETNIM reflects the oxygenation status well and results in satisfactory contrast between hypoxic and well-oxygenated tissue. A good estimate of tissue hypoxia is accomplished by measuring the tissue to plasma [(18)F]FETNIM activity ratio using only a few late time points. The increased hypoxia-specific retention of [(18)F]FETNIM in tissues with high blood flow, such as malignant tumours, may facilitate application of [(18)F]FETNIM as a hypoxia marker in oncological patients. In the assessment of the tumour to non-target uptake ratio, plasma is the preferred reference tissue rather than muscle, which may show a more heterogeneous tracer uptake not easily controlled for.
Eur J Nucl Med Mol Imaging 2003 Jan
PMID:Quantifying tumour hypoxia with fluorine-18 fluoroerythronitroimidazole ([18F]FETNIM) and PET using the tumour to plasma ratio. 1248 16

The purpose of this study was to calculate disease probabilities based on data of patients with head and neck cancer in the register of our institution and to perform a systematic review of the available data on the accuracy of PET in the primary assessment and follow-up of patients with head and neck cancer. The pre-test probability of head and neck cancer among patients in our institutional data registry was assessed. Then the published literature was selected and appraised according to a standard protocol of systematic reviews. Two reviewers independently selected and extracted data on study characteristics, quality and accuracy. Accuracy data were used to form 2 x 2 contingency tables and were pooled to produce summary receiver operating characteristic (ROC) curves and summary likelihood ratios for positive and negative testing. Finally post-test probabilities were calculated on the basis of the pre-test probabilities of this patient group. All patients had cytologically or histologically proven cancer. The prevalence of additional lymph node metastases on PET in staging examinations was 19.6% (11/56), and that of locoregional recurrence on restaging PET was 28.6% (12/42). In the primary assessment of patients, PET had positive and negative likelihood ratios of 3.9 (2.56-5.93) and 0.24 (0.14-0.41), respectively. Disease probabilities were therefore 49.4% for a positive test result and 5.7% for a negative test result. In the assessment of recurrence these values were 3.96 (2.8-5.6) and 0.16 (0.1-0.25), resulting in probabilities of 49.7% and 3.8%. PET evaluation for involvement of lymph nodes had positive and negative likelihood ratios of 17.26 (10.9-27.3) and 0.19 (0.13-0.27) for primary assessment and 11.0 (2.93-41.24) and 0.14 (0.01-1.88) for detection of recurrence. The probabilities were 81.2% and 4.5% for primary assessment and 73.3% and 3.4% for assessment of recurrence. It is concluded that in this clinical setting the main advantage of PET is the ability to reliably rule out the presence of disease in both staging and restaging. Further research is required to derive probabilities for individual patients from sequential testing as applied in the diagnostic work-up of patients with head and neck cancer.
Eur J Nucl Med Mol Imaging 2003 Apr
PMID:Assessment of clinical utility of 18F-FDG PET in patients with head and neck cancer: a probability analysis. 1258 77

The early stages of head and neck cancer are presumed to require a senes of genetic alterations that are not represented by a distinct clinical phenotype. Therefore, genes with altered expression in the preneoplasia may be useful for the early detection of this highly recurrent cancer. In this study, we immortalized normal human oral keratinocytes (NHOK) by retroviral-mediated infection of HPV 16 transforming oncogenes, E6 and E7 (HOK16E6E7). Using the Affymetrix gene chip (U95Av2), we identified 177 known genes and EST that were overexpressed at least 3-fold or above in the immortalized cells, while 133 were down-regulated compared to NHOK. Northern blot analysis showed elevated levels of p55CDC in the immortalized cells, while NHOK showed high basal expression of small proline rich protein (SPRR2). The altered expression of these genes maybe associated with cellular proliferation or differentiation and the early stages of oral carcinogenesis.
Cell Mol Biol (Noisy-le-grand) 2002
PMID:Identification of genes required for immortalization in human papillomavirus-infected human oral keratinocytes. 1264 51


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