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Huang R.,Simon Fraser University | Langille G.,Simon Fraser University | Gill R.K.,Cancer Agency Research Center | Li C.M.J.,Simon Fraser University | And 4 more authors.
Journal of Biological Inorganic Chemistry | Year: 2013

Two new rhenium complexes containing pyridine-triazole (pyta) and quinoline-triazole (quinta) ligands with attached glutamine-targeting agents have been characterized and tested for uptake in the HT-29 human colon adenocarcinoma cell line. The glutamine moiety in Re(CO)3Br(pyta) (1) and Re(CO)3Br(quinta) (2) remains pendant in solution. Both complexes exhibit absorptions in the 300-400-nm range with metal-to-ligand charge transfer (MLCT) character, as predicted by time-dependent density functional theory calculations. Geometrical analysis by theoretical calculations provides information on the cationic complexes 1 + and 2 + resulting from aquo for halide ligand exchange under aqueous conditions. The emissive properties of both complexes were studied under aqueous conditions, and the measured quantum yields were 0.46 % for 1 + and 0.18 % for 2 +. The large Stokes shifts and oxygen sensitivity of the emission suggest a 3MLCT process for both complexes. Cell studies in the HT-29 cell line demonstrate that both complexes are nontoxic over a large concentration range (0-1.4 mM). Preliminary uptake studies show that 2 +, but not 1 +, displays significant concentration- dependent uptake at 3 and 24 h. Graphical abstract: [Figure not available: see fulltext.] © 2013 SBIC.

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.

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.

Malek M.,Cancer Agency Research Center | Taghiyar M.J.,Cancer Agency Research Center | Chong L.,University of British Columbia | Finak G.,Fred Hutchinson Cancer Research Center | And 2 more authors.
Bioinformatics | Year: 2015

flowDensity facilitates reproducible, high-throughput analysis of flow cytometry data by automating a predefined manual gating approach. The algorithm is based on a sequential bivariate gating approach that generates a set of predefined cell populations. It chooses the best cut-off for individual markers using characteristics of the density distribution. The Supplementary Material is linked to the online version of the manuscript. © 2014 The Author.

Yu J.,University of British Columbia | Zeng H.,Cancer Agency Research Center | Zeng H.,Vancouver Coastal Health Research Institute | Lui H.,Cancer Agency Research Center | And 5 more authors.
Optics Express | Year: 2014

Fiber delivery of ultrashort pulses is important for multiphoton endoscopy. A chirped photonic crystal fiber (CPCF) is first characterized for its transmission bandwidth, propagation loss, and dispersion properties. Its extremely low dispersion ( ̃150 fs2 m) enables the delivery of sub-30 fs pulses through a ̃1 m-long CPCF. The CPCF is then incorporated into a multiphoton imaging system and its performance is demonstrated by imaging various biological samples including yew leaf, mouse tendon, and human skin. The imaging quality is further compared with images acquired by a multiphoton imaging system with free-space or hollow-core photonic band-gap fiber (PBF) delivery of pulses. Compared with free-space system, the CPCF delivered system maintains the same ultrashort pulsewidth and the image qualities are comparable. Compared with the PBF delivery, CPCF provides a 35 times shorter pulsewidth at the sample location, which results in a ̃12 and 50 times improvement in two-photon excitation fluorescence (TPEF) and second harmonic generation (SHG) signals respectively. Our results show that CPCF has great potential for fiber delivery of ultrashort pulses for multiphoton endoscopy. © 2014 Optical Society of America.

Ait-Mohand S.,Université de Sherbrooke | Fournier P.,Université de Sherbrooke | Dumulon-Perreault V.,Université 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.

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.

Liu Z.,University of British Columbia | Pourghiasian M.,Cancer Agency Research Center | Benard F.,Cancer Agency Research Center | Pan J.,Cancer Agency Research Center | And 2 more authors.
Journal of Nuclear Medicine | Year: 2014

Recent studies have highlighted the high sensitivity of PET imaging with 68Ga-labeled octreotide derivatives for the detection and staging of neuroendocrine tumors. A somatostatin receptor ligand that is easily radiolabeled with 18F-fluoride could improve the availability of PET imaging of neuroendocrine tumors. We report an alkyltrifluoroborate-octreotate conjugate that is radiolabeled in a 1-step 18F exchange reaction in high yield and with high specific activity. Methods: We conjugated a new alkyltrifluoroborate to octreotate to obtain AMBF3-TATE, which was stored in 50-nmol aliquots for radiolabeling. 18F labeling was performed by 18F-19F isotope exchange with 18F-fluoride, and the tracer was purified by C18 cartridge separation. The radiochemical yield was 20%-25%. PET imaging and biodistribution were performed on mice bearing AR42J tumor xenografts. Results: AMBF3-TATE bound the somatostatin receptor subtype 2 with high affinity (inhibition constant, 0.13 ± 0.03 nM). Starting with 29.6-37 GBq (0.8-1 Ci) of 18F-fluoride, more than 7.4 GBq (>200 mCi) of 18FAMBF3-TATE were obtained in 25 min (n 5 5) with greater than 99% radiochemical purity at high specific activity (>111 GBq [3 Ci]/μmol). 18F-AMBF3-TATE was stable in plasma. PET imaging and biodistribution showed rapid renal excretion with low liver activity. High tumor uptake (10.11% ± 1.67% injected dose/g, n 5 5) was detected at 60 min after injection. Bone uptake was negligible. Tumor-to-liver, tumor-to-blood, tumor-to-muscle, and tumor-to-bone ratios (at 60 min) were 26.2 ± 0.8, 25.1 ± 1.0, 89.0 ± 3.1, and 21.3 ± 3.6, respectively. Conclusion: 18FAMBF3- TATE was radiolabeled in high yield and at high specific activity, did not require high-performance liquid chromatography purification, exhibited unexpectedly high binding affinity to somatostatin receptor subtype 2, and showed excellent pharmacokinetic properties in vivo, with high tumor uptake and high contrast ratios. COPYRIGHT © 2014 by the Society of Nuclear Medicine and Molecular Imaging, Inc.

Majewski I.J.,Netherlands Cancer Institute | Kluijt I.,Netherlands Cancer Institute | Cats A.,Netherlands Cancer Institute | Scerri T.S.,Walter and Eliza Hall Institute | And 12 more authors.
Journal of Pathology | Year: 2013

Diffuse gastric cancers typically present as late-stage tumours and, as a result, the 5 year survival rate is poor. Some gastric cancers are hereditary and these tend to be of the diffuse type; 30-40% of hereditary diffuse gastric cancers (HDGCs) can be explained by defective germline alleles of E-cadherin (CDH1), but for the remaining families the factors driving susceptibility remain unknown. We had access to a large HDGC pedigree with no obvious mutation in CDH1, and applied exome sequencing to identify new genes involved in gastric cancer. We identified a germline truncating allele of α-E-catenin (CTNNA1) that was present in two family members with invasive diffuse gastric cancer and four in which intramucosal signet ring cells were detected as part of endoscopic surveillance. The remaining CTNNA1 allele was silenced in the two diffuse gastric cancers from the family that were available for screening, and this was also true for signet ring cells identified in endoscopic biopsies. Since α-E-catenin functions in the same complex as E-cadherin, our results call attention to the broader signalling network surrounding these proteins in HDGC. We also detected somatic mutations in one tumour and found substantial overlap with genes mutated in sporadic gastric cancer, including PIK3CA, ARID1A, MED12 and MED23. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Fournier P.,Université de Sherbrooke | Dumulon-Perreault V.,Université de Sherbrooke | Ait-Mohand S.,Université de Sherbrooke | Tremblay S.,Université 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.

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