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Lin R.J.,Cancer Agency Research Center
Journal of otolaryngology - head & neck surgery = Le Journal d'oto-rhino-laryngologie et de chirurgie cervico-faciale | Year: 2013

To determine the biological characteristics of oropharyngeal squamous cell carcinoma (OpSCC) and related outcome. Retrospective study. Patients (N=60) with primary OpSCC from 2000 to 2005 were retrospectively identified from Pathology database and the outcome was confirmed through chart review. Among these, 41 biopsy samples with enough tissues were retrieved to construct a tissue microarray for detection of the presence of high-risk human papillomavirus (HPV) using Chromogenic in situ hybridization (CISH) as well as the expression of p16 and cyclin D1 using immunohistochemistry. Disease-free survival. Among 60 patients, 39 (65%) patients had no recurrence or died without disease at the last follow-up (disease-free survival or Group 1), and 21 (35%) patients had persistent disease or died of disease (progression-free survival or Group 2). Although follow-up time was twice as long in group 1 (4.7 ± 2.2 vs. 2.0 ± 1.6 years; P < 0.0001), there was no difference between the 2 groups in age, gender, smoking/alcohol habits, TNM staging and treatment modalities. Among those 41 cases with available tumour tissues, there was no difference in HPV status and p16 expression between the 2 groups but a significant difference in cyclin D1 expression (P = 0.05). Using Kaplan-Meir survival analysis and log-rank test, cyclin D1 overexpression was highly associated with a poor prognosis when comparing time to outcome (P < 0.0001). Cyclin D1 overexpression is a potential prognostic marker of OpSCC. Source

Fournier P.,Universite de Sherbrooke | Dumulon-Perreault V.,Universite de Sherbrooke | Ait-Mohand S.,Universite de Sherbrooke | Tremblay S.,Universite de Sherbrooke | And 3 more authors.
Bioconjugate Chemistry | Year: 2012

Bombesin (BBN)-based radiolabeled peptides exhibit promising properties for targeted imaging of gastrin-releasing peptide receptors (GRPR)-positive tumors. The aim of this study was to evaluate with positron emission tomography (PET) the pharmacokinetic and imaging properties of two novel BBN-based radiolabeled peptides, 64Cu/and 68Ga/NOTA-PEG-BBN(6-14), for diagnosis of breast and prostate cancers using small animal models. Competitive binding assays on T47D breast and PC3 prostate cancer cells showed that the affinity for GRPR depends on the complexed metal and can vary up to a factor of about 3; 64Cu/NOTA-PEG-BBN(6-14) was found to have the lowest inhibition constant (1.60 ± 0.59 nM). 64Cu/and 68Ga/NOTA-PEG- BBN(6-14) presented similar cell uptake on T47D and PC3 cells and were stable in vivo. Biodistribution studies of radiolabeled peptides carried out in Balb/c and tumor-bearing Balb/c nude mice showed that 64Cu/NOTA-PEG-BBN(6- 14) presented higher GRPR-mediated uptake in pancreas and adrenal glands, but comparable PC3 tumor uptake as 68Ga/NOTA-PEG-BBN(6-14). Finally, receptor-dependent responses were observed during blocking studies with unlabeled peptide in both biodistribution and small-animal PET imaging studies. Our results confirmed the dependence of the affinity and pharmacokinetics of BBN-based radiopeptides on the complexed radiometal. Interspecies differences between mouse and human GRPR binding properties were also noted in these preclinical studies. Considering their good imaging characteristics, both 64Cu/NOTA-PEG-BBN(6-14) and 68Ga/NOTA-PEG-BBN(6-14) are promising candidates for GRPR-targeted PET imaging of breast and prostate cancers. © 2012 American Chemical Society. Source

Auf Dem Keller U.,University of British Columbia | Auf Dem Keller U.,ETH Zurich | Bellac C.L.,University of British Columbia | Li Y.,University of British Columbia | And 12 more authors.
Cancer Research | Year: 2010

Matrix metalloproteinases (MMP), strongly associated pathogenic markers of cancer, have undergone extensive drug development programs. Marimastat, a noncovalent MMP inhibitor, was conjugated with FITC to label cellular metalloproteinase cancer targets in MDA-MB-231 cells in vitro. Punctate localization of active transmembrane MMP14 was observed. For molecular-targeted positron emission tomography imaging of syngeneic 67NR murine mammary carcinoma in vivo, marimastat was 18F-labeled using a shelf-stable arylboronic ester conjugate as a captor for aqueous [18F]fluoride in a novel, rapid one-step reaction at ambient temperature. [18F]Marimastat- aryltrifluoroborate localized to the tumors, with labeling being blocked in control animals first loaded with >10-fold excess unlabeled marimastat. The labeled drug cleared primarily via the hepatobiliary and gastrointestinal tract, with multiple animals imaged in independent experiments, confirming the ease of this new labeling strategy. ©2010 AACR. Source

Ait-Mohand S.,Universite de Sherbrooke | Fournier P.,Universite de Sherbrooke | Dumulon-Perreault V.,Universite de Sherbrooke | Kiefer G.E.,Macrocyclics | And 4 more authors.
Bioconjugate Chemistry | Year: 2011

Several bifunctional chelates (BFCs) were investigated as carriers of 64Cu for PET imaging. The most widely used chelator for 64Cu labeling of BFCs is DOTA (1,4,7,10-tetraazacyclododecane-N, N′,N″,N″-tretraacetic acid), even though this complex exhibits only moderate in vivo stability. In this study, we prepared a series of alternative chelator-peptide conjugates labeled with 64Cu, measured in vitro receptor binding affinities in human breast cancer T47D cells expressing the gastrin-releasing peptide receptor (GRPR) and compared their in vivo stability in mice. DOTA-, NOTA-(1,4,7-triazacyclononane-1,4,7-triacetic acid), PCTA-(3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1(15),11,13-triene-3,6,9- triacetic acid), and Oxo-DO3A-(1-oxa-4,7,10-triazacyclododecane-4,7,10-triacetic acid) peptide conjugates were prepared using H 2N-Aoc-[d-Tyr 6,βAla 11,Thi 13,Nle 14] bombesin(6-14) (BBN) as a peptide template. The BBN moiety was selected since it binds with high affinity to the GRPR, which is overexpressed on human breast cancer cells. A convenient synthetic approach for the attachment of aniline-BFC to peptides on solid support is also presented. To facilitate the attachment of the aniline-PCTA and aniline-Oxo-DO3A to the peptide via an amide bond, a succinyl spacer was introduced at the N-terminus of BBN. The partially protected aniline-BFC (p-H 2N-Bn-PCTA(Ot-Bu) 3 or p-H 2N-Bn-DO3A(Ot-Bu) 3) was then coupled to the resulting N-terminal carboxylic acid preactivated with DEPBT/ClHOBt on resin. After cleavage and purification, the peptide-conjugates were labeled with 64Cu using [ 64Cu]Cu(OAc) 2 in 0.1 M ammonium acetate buffer at 100 °C for 15 min. Labeling efficacy was >90% for all peptides; Oxo-DO3A-BBN was incubated an additional 150 min at 100 °C to achieve this high yield. Specific activities varied from 76 to 101 TBq/mmol. Competition assays on T47D cells showed that all BFC-BBN complexes retained high affinity for the GRPR. All BFC-BBN 64Cu-conjugates were stable for over 20 h when incubated at 37 °C in mouse plasma samples. However, in vivo, only 37% of the 64Cu/Oxo-DO3A complex remained intact after 20 h while the 64Cu/DOTA-BBN complex was completely demetalated. In contrast, both 64Cu/NOTA- and 64Cu/PCTA-BBN conjugates remained stable during the 20 h time period. Our results indicate that it is possible to successfully conjugate aniline-BFC with peptide on solid support. Our data also show that 64Cu-labeled NOTA- and PCTA-BBN peptide conjugates are promising radiotracers for PET imaging of many human cancers overexpressing the GRP receptor. © 2011 American Chemical Society. Source

Banath J.P.,Cancer Agency Research Center | Klokov D.,Cancer Agency Research Center | Klokov D.,Atomic Energy of Canada Ltd | MacPhail S.H.,Cancer Agency Research Center | And 2 more authors.
BMC Cancer | Year: 2010

Background: Evidence suggests that tumor cells exposed to some DNA damaging agents are more likely to die if they retain microscopically visible γH2AX foci that are known to mark sites of double-strand breaks. This appears to be true even after exposure to the alkylating agent MNNG that does not cause direct double-strand breaks but does produce γH2AX foci when damaged DNA undergoes replication.Methods: To examine this predictive ability further, SiHa human cervical carcinoma cells were exposed to 8 DNA damaging drugs (camptothecin, cisplatin, doxorubicin, etoposide, hydrogen peroxide, MNNG, temozolomide, and tirapazamine) and the fraction of cells that retained γH2AX foci 24 hours after a 30 or 60 min treatment was compared with the fraction of cells that lost clonogenicity. To determine if cells with residual repair foci are the cells that die, SiHa cervical cancer cells were stably transfected with a RAD51-GFP construct and live cell analysis was used to follow the fate of irradiated cells with RAD51-GFP foci.Results: For all drugs regardless of their mechanism of interaction with DNA, close to a 1:1 correlation was observed between clonogenic surviving fraction and the fraction of cells that retained γH2AX foci 24 hours after treatment. Initial studies established that the fraction of cells that retained RAD51 foci after irradiation was similar to the fraction of cells that retained γH2AX foci and subsequently lost clonogenicity. Tracking individual irradiated live cells confirmed that SiHa cells with RAD51-GFP foci 24 hours after irradiation were more likely to die.Conclusion: Retention of DNA damage-induced γH2AX foci appears to be indicative of lethal DNA damage so that it may be possible to predict tumor cell killing by a wide variety of DNA damaging agents simply by scoring the fraction of cells that retain γH2AX foci. © 2010 Banáth et al; licensee BioMed Central Ltd. Source

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