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1. Levels of Gemcitabine Transport and Metabolism Proteins Predict Survival Times of Patients Treated With Gemcitabine for Pancreatic Adenocarcinoma

Author

Maréchal, Raphaël, Bachet, Jean–Baptiste, Mackey, John R., Dalban, Cécile, Demetter, Pieter, Graham, Kathryn, Couvelard, Anne, Svrcek, Magali, Bardier–Dupas, Armelle, Hammel, Pascal, Sauvanet, Alain, Louvet, Christophe, Paye, François, Rougier, Philippe, Penna, Christophe, André, Thierry, Dumontet, Charles, Cass, Carol E., Jordheim, Lars Petter, Matera, Eva–Laure, Closset, Jean, Salmon, Isabelle, Devière, Jacques, Emile, Jean–François, and Van Laethem, Jean–Luc

Published
2012
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10. The Purinome and the preBötzinger Complex – A Ménage of Unexplored Mechanisms That May Modulate/Shape the Hypoxic Ventilatory Response

Author

Reklow, Robert J., primary, Alvares, Tucaaue S., additional, Zhang, Yong, additional, Miranda Tapia, Ana P., additional, Biancardi, Vivian, additional, Katzell, Alexis K., additional, Frangos, Sara M., additional, Hansen, Megan A., additional, Toohey, Alexander W., additional, Cass, Carol E., additional, Young, James D., additional, Pagliardini, Silvia, additional, Boison, Detlev, additional, and Funk, Gregory D., additional

Published
2019
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11. 2-Nitroimidazole-Furanoside Derivatives for Hypoxia Imaging—Investigation of Nucleoside Transporter Interaction, 18F-Labeling and Preclinical PET Imaging

Author

Maier, Florian, primary, Schweifer, Anna, additional, Damaraju, Vijaya, additional, Cass, Carol, additional, Bowden, Gregory, additional, Ehrlichmann, Walter, additional, Kneilling, Manfred, additional, Pichler, Bernd, additional, Hammerschmidt, Friedrich, additional, and Reischl, Gerald, additional

Published
2019
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12. Synergistic activity of troxacitabine (Troxatyl™) and gemcitabine in pancreatic cancer

Author

Leblond Lorraine, Mackey John R, Clarke Marilyn L, Wong Clarence KW, Bouffard David Y, Damaraju Vijaya L, Cass Carol E, Grey Mike, and Gourdeau Henriette

Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Background Gemcitabine, a deoxycytidine nucleoside analog, is the current standard chemotherapy used as first-line treatment for patients with locally advanced or metastatic cancer of the pancreas, and extends life survival by 5.7 months. Advanced pancreatic cancer thus remains a highly unmet medical need and new therapeutic agents are required for this patient population. Troxacitabine (Troxatyl™) is the first unnatural L-nucleoside analog to show potent preclinical antitumor activity and is currently under clinical investigation. Troxacitabine was recently evaluated as a first-line therapy in 54 patients with advanced adenocarcinoma of the pancreas and gave comparable overall results to those reported with gemcitabine in recently published randomized trials. Methods The human pancreatic adenocarcinoma cell lines, AsPC-1, Capan-2, MIA PaCa-2 and Panc-1, were exposed to troxacitabine or gemcitabine alone or in combination, for 72 h, and the effects on cell growth were determined by electronic particle counting. Synergistic efficacy was determined by the isobologram and combination-index methods of Chou and Talalay. Mechanistic studies addressed incorporation of troxacitabine into DNA and intracellular levels of troxacitabine and gemcitabine metabolites. For in vivo studies, we evaluated the effect of both drugs, alone and in combination, on the growth of established human pancreatic (AsPC-1) tumors implanted subcutaneously in nude mice. Statistical analysis was calculated by a one-way ANOVA with Dunnett as a post-test and the two-tailed unpaired t test using GraphPad prism software. Results Synergy, evaluated using the CalcuSyn Software, was observed in all four cell-lines at multiple drug concentrations resulting in combination indices under 0.7 at Fa of 0.5 (50% reduction of cell growth). The effects of drug exposures on troxacitabine and gemcitabine nucleotide pools were analyzed, and although gemcitabine reduced phosphorylation of troxacitabine when cells were exposed at equal drug concentrations, there was no effect on phosphorylated pools at drug combinations that were synergistic. The amount of troxacitabine incorporated into DNA was also not affected by the presence of gemcitabine. In vivo testing against a human pancreatic (AsPC-1) xenograft mouse tumor model indicated that both drugs were more than additive at well-tolerated doses and schedule. The biological basis for this synergy is unclear as we did not observe changes in apoptosis, DNA repair, troxacitabine incorporation into DNA or troxacitabine metabolism in the presence of gemcitabine. Conclusion These data, together with phase I clinical data showing tolerability of both agents when combined, suggest combination therapy with troxacitabine and gemcitabine warrants further evaluation in advanced pancreatic cancer patients.

Published
2007
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17. Protecting academic freedom

Author

Guyatt, Gordon H, Cass, Carol E, Jackson, Alan C, Smith, Derryck H, Welch, J Philip, and Turk, James L

Subjects
Analysis and Comment
Published
2008

19. Designing and Testing of Novel Taxanes to Probe the Highly Complex Mechanisms by Which Taxanes Bind to Microtubules and Cause Cytotoxicity to Cancer Cells

Author

St. George, Marc, primary, Ayoub, Ahmed T., additional, Banerjee, Asok, additional, Churchill, Cassandra D. M., additional, Winter, Philip, additional, Klobukowski, Mariusz, additional, Cass, Carol E., additional, Ludueña, Richard F., additional, Tuszynski, Jack A., additional, and Damaraju, Sambasivarao, additional

Published
2015
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21. Electrophysiological characterization of a recombinant human Na+-coupled nucleoside transporter (hCNT1) produced in Xenopus oocytes

Author

Smith, Kyla M, Ng, Amy ML, Yao, Sylvia YM, Labedz, Kathy A, Knaus, Edward E, Wiebe, Leonard I, Cass, Carol E, Baldwin, Stephen A, Chen, Xing-Zhen, Karpinski, Edward, and Young, James D

Subjects
Dose-Response Relationship, Drug, Membrane Transport Proteins, Antineoplastic Agents, Biological Transport, Nucleosides, Research Papers, Recombinant Proteins, Electrophysiology, Xenopus laevis, Oocytes, Animals, Humans, Female, Protein Binding
Abstract

Human concentrative nucleoside transporter 1 (hCNT1) mediates active transport of nucleosides and anticancer and antiviral nucleoside drugs across cell membranes by coupling influx to the movement of Na(+) down its electrochemical gradient. The two-microelectrode voltage-clamp technique was used to measure steady-state and presteady-state currents of recombinant hCNT1 produced in Xenopus oocytes. Transport was electrogenic, phloridzin sensitive and specific for pyrimidine nucleosides and adenosine. Nucleoside analogues that induced inwardly directed Na(+) currents included the anticancer drugs 5-fluorouridine, 5-fluoro-2'-deoxyuridine, cladribine and cytarabine, the antiviral drugs zidovudine and zalcitabine, and the novel thymidine mimics 1-(2-deoxy-beta-d-ribofuranosyl)-2,4-difluoro-5-methylbenzene and 1-(2-deoxy-beta-d-ribofuranosyl)-2,4-difluoro-5-iodobenzene. Apparent K(m) values for 5-fluorouridine, 5-fluoro-2'-deoxyuridine and zidovudine were 18, 15 and 450 microm, respectively. hCNT1 was Na(+) specific, and the kinetics of steady-state uridine-evoked Na(+) currents were consistent with an ordered simultaneous transport model in which Na(+) binds first followed by uridine. Membrane potential influenced both ion binding and carrier translocation. The Na(+)-nucleoside coupling stoichiometry, determined directly by comparing the uridine-induced inward charge movement to [(14)C]uridine uptake was 1: 1. hCNT1 presteady-state currents were used to determine the fraction of the membrane field sensed by Na(+) (61%), the valency of the movable charge (-0.81) and the average number of transporters present in the oocyte plasma membrane (6.8 x 10(10) per cell). The hCNT1 turnover rate at -50 mV was 9.6 molecules of uridine transported per second.

Published
2004

24. Deoxycitidine kinase is associated with prolonged survival after adjuvant gemcitabine for resected pancreatic adenocarcinoma.

Author

Marechal, Raphaël, Mackey, John R, Lai, Raymond, Demetter, Pieter, Peeters, Marc, Polus, Marc, Cass, Carol E, Salmon, Isabelle, Devière, Jacques, Van Laethem, Jean-Luc, Marechal, Raphaël, Mackey, John R, Lai, Raymond, Demetter, Pieter, Peeters, Marc, Polus, Marc, Cass, Carol E, Salmon, Isabelle, Devière, Jacques, and Van Laethem, Jean-Luc

Abstract

Gemcitabine (2',2'-difluorodeoxycytidine) administration after resection of pancreatic cancer improves both disease-free survival (DFS) and overall survival (OS). Deoxycytidine kinase (dCK) mediates the rate-limiting catabolic step in the activation of gemcitabine. The authors of this report studied patient outcomes according to the expression of dCK after a postoperative gemcitabine-based chemoradiation regimen., Journal Article, Research Support, Non-U.S. Gov't, FLWIN, SCOPUS: ar.j, info:eu-repo/semantics/published

Published
2010

25. Human equilibrative nucleoside transporter 1 and human concentrative nucleoside transporter 3 predict survival after adjuvant gemcitabine therapy in resected pancreatic adenocarcinoma.

Author

Marechal, Raphaël, Mackey, John R, Lai, Raymond, Demetter, Pieter, Peeters, Michel, Polus, Marc, Cass, Carol E, Young, James, Salmon, Isabelle, Devière, Jacques, Van Laethem, Jean-Luc, Marechal, Raphaël, Mackey, John R, Lai, Raymond, Demetter, Pieter, Peeters, Michel, Polus, Marc, Cass, Carol E, Young, James, Salmon, Isabelle, Devière, Jacques, and Van Laethem, Jean-Luc

Abstract

PURPOSE: Gemcitabine is a promising adjuvant treatment for patients with resected pancreatic adenocarcinoma and its use in combination with radiotherapy is under exploration. Human equilibrative nucleoside transporter 1 (hENT1) and human concentrative nucleoside transporter (hCNT) 1 and 3 are the major transporters responsible for 2',2'-difluoro-2-deoxycytidine (gemcitabine) uptake into cells. The aim of this study was to determine patients' outcome according to the expression of hENT1 and hCNT3 in tumoral cells after postoperative gemcitabine-based chemoradiation regimen. EXPERIMENTAL DESIGN: We studied tumor blocks from 45 pancreatic adenocarcinoma patients treated with gemcitabine-based chemoradiation after curative resection and assessed hENT1 and hCNT3 expression using immunohistochemistry. RESULTS: When adjusted for the effects of lymph node ratio and tumor diameter, patients with high hENT1 expression had significantly longer disease-free survival and overall survival (OS) than patients with low expression, whereas high hCNT3 expression was only associated with longer OS. In a combined analysis, patients with two favorable prognostic factors (hENT1(high)/hCNT3(high) expression) had a longer survival (median OS, 94.8 months) than those having one (median OS, 18.7 months) or no (median OS, 12.2 months) favorable prognostic factor. CONCLUSIONS: Pancreatic adenocarcinoma patients with a high expression of hENT1 and hCNT3 immunostaining have a significantly longer survival after adjuvant gemcitabine-based chemoradiation. These biomarkers deserve prospective evaluation in patients receiving gemcitabine-based adjuvant therapy., Journal Article, Research Support, Non-U.S. Gov't, SCOPUS: ar.j, info:eu-repo/semantics/published

Published
2009

26. Human Equilibrative Nucleoside Transporter 1 Levels Predict Response to Gemcitabine in Patients With Pancreatic Cancer

Author

Farrell, James, Elsaleh, Hany, Garcia, Miguel, Lai, Raymond, Ammar, Ali, Regine, William, Abrams, Ross, Benson, Bowen, Macdonald, John, Cass, Carol, Dicker, Adam, Mackey, John, Farrell, James, Elsaleh, Hany, Garcia, Miguel, Lai, Raymond, Ammar, Ali, Regine, William, Abrams, Ross, Benson, Bowen, Macdonald, John, Cass, Carol, Dicker, Adam, and Mackey, John

Abstract

Background & Aims: The human equilibrative nucleoside transporter (hENT1) protein transports gemcitabine into cells. Small retrospective studies in pancreatic cancer suggest that levels of hENT1 protein or messenger RNA may have prognostic value. We studied the predictive value of hENT1 levels in a cohort of pancreatic adenocarcinoma patients from the large prospective randomized adjuvant treatment trial RTOG9704. Methods: In RTOG9704, 538 patients were assigned randomly, after surgical resection, to groups that were given either gemcitabine or 5-fluorouracil (5-FU). Immunohistochemistry for hENT1 was performed on a tissue microarray of 229 resected pancreatic tumors from RTOG9704 and scored as having no staining, low staining, or high staining. Associations between hENT1 protein and treatment outcome were analyzed by unconditional logistic regression analysis using the chi-square test and the Cox proportional hazards model. Results: HENT1 expression was associated with overall and disease-free survival in a univariate (hazard ratio [HR], 0.51; 95% confidence interval [CI], 0.29-0.91; P = .02; and HR, 0.57; 95% CI, 0.32-1.00; P = .05) and multivariate model in the group given gemcitabine (HR, 0.40; 95% CI, 0.22-0.75; P = .004; and HR, 0.39; 95% CI, 0.21-0.73; P = .003). hENT1 expression was not associated with survival in the group given 5-FU. Conclusions: In this prospective randomized trial, hENT1 protein expression was associated with increased overall survival and disease-free survival in pancreatic cancer patients who received gemcitabine, but not in those who received 5-FU. These findings are supported by preclinical data; the gemcitabine transporter hENT1 is therefore a molecular and mechanistically relevant predictive marker of benefit from gemcitabine in patients with resected pancreatic cancer.

Published
2009

30. Specimen Quality Evaluation in Canadian Biobanks Participating in the COEUR Repository

Author

Le Page, Cécile, primary, Köbel, Martin, additional, de Ladurantaye, Manon, additional, Rahimi, Kurosh, additional, Madore, Jason, additional, Babinszky, Sindy, additional, Bachvarov, Dimcho R., additional, Bachvarova, Magdalena, additional, Beauchamp, Marie-Claude, additional, Cass, Carol E, additional, Chadwick, Dianne, additional, Colleen, Crane, additional, Damaraju, Sambasivarao, additional, Dufour, Jennifer, additional, Gotlieb, Walter H., additional, Kalloger, Steve E., additional, Portelance, Lise, additional, McAlpine, Jessica N., additional, Matte, Isabelle, additional, Piché, Alain, additional, Shaw, Patricia, additional, Roehrl, Michael H.A., additional, Vanderhyden, Barbara C., additional, Watson, Peter H., additional, Huntsman, David G., additional, Provencher, Diane M., additional, and Mes-Masson, Anne-Marie, additional

Published
2013
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38. Substituted Cysteine Accessibility Method Analysis of Human Concentrative Nucleoside Transporter hCNT3 Reveals a Novel Discontinuous Region of Functional Importance within the CNT Family Motif (G/A)XKX3NEFVA(Y/M/F)

Author

Slugoski, Melissa D., primary, Ng, Amy M.L., additional, Yao, Sylvia Y.M., additional, Lin, Colin C., additional, Mulinta, Ras, additional, Cass, Carol E., additional, Baldwin, Stephen A., additional, and Young, James D., additional

Published
2009
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41. Human Equilibrative Nucleoside Transporter 1 and Human Concentrative Nucleoside Transporter 3 Predict Survival after Adjuvant Gemcitabine Therapy in Resected Pancreatic Adenocarcinoma

Author

Maréchal, Raphaël, primary, Mackey, John R., additional, Lai, Raymond, additional, Demetter, Pieter, additional, Peeters, Marc, additional, Polus, Marc, additional, Cass, Carol E., additional, Young, James, additional, Salmon, Isabelle, additional, Devière, Jacques, additional, and Van Laethem, Jean-Luc, additional

Published
2009
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42. Human Equilibrative Nucleoside Transporter 1 Levels Predict Response to Gemcitabine in Patients With Pancreatic Cancer

Author

Farrell, James J., primary, Elsaleh, Hany, additional, Garcia, Miguel, additional, Lai, Raymond, additional, Ammar, Ali, additional, Regine, William F., additional, Abrams, Ross, additional, Benson, A. Bowen, additional, Macdonald, John, additional, Cass, Carol E., additional, Dicker, Adam P., additional, and Mackey, John R., additional

Published
2009
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43. A Conformationally Mobile Cysteine Residue (Cys-561) Modulates Na+ and H+ Activation of Human CNT3

Author

Slugoski, Melissa D., primary, Smith, Kyla M., additional, Mulinta, Ras, additional, Ng, Amy M.L., additional, Yao, Sylvia Y.M., additional, Morrison, Ellen L., additional, Lee, Queenie O.T., additional, Zhang, Jing, additional, Karpinski, Edward, additional, Cass, Carol E., additional, Baldwin, Stephen A., additional, and Young, James D., additional

Published
2008
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49. Localization of broadly selective equilibrative and concentrative nucleoside transporters, hENT1 and hCNT3, in human kidney

Author

Damaraju, Vijaya L., primary, Elwi, Adam N., additional, Hunter, Charlene, additional, Carpenter, Pat, additional, Santos, Cheryl, additional, Barron, Gerry M., additional, Sun, Xuejun, additional, Baldwin, Stephen A., additional, Young, James D., additional, Mackey, John R., additional, Sawyer, Michael B., additional, and Cass, Carol E., additional

Published
2007
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50. Residues 334 and 338 in Transmembrane Segment 8 of Human Equilibrative Nucleoside Transporter 1 Are Important Determinants of Inhibitor Sensitivity, Protein Folding, and Catalytic Turnover

Author

Visser, Frank, primary, Sun, Lijie, additional, Damaraju, Vijaya, additional, Tackaberry, Tracey, additional, Peng, Yunshan, additional, Robins, Morris J., additional, Baldwin, Stephen A., additional, Young, James D., additional, and Cass, Carol E., additional

Published
2007
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