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Title: Asparagine synthetase as a causal, predictive biomarker forL-asparaginase activity in ovarian cancer cells

Abstract

No abstract prepared.

Authors:
; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ;
Publication Date:
Research Org.:
COLLABORATION - NIH
OSTI Identifier:
910326
Report Number(s):
LBNL-62643
R&D Project: 443180; BnR: KP1104010; TRN: US200724%%70
DOE Contract Number:
DE-AC02-05CH11231
Resource Type:
Journal Article
Resource Relation:
Journal Name: Molecular Cancer Therapeutics; Journal Volume: 5; Journal Issue: 11; Related Information: Journal Publication Date: 11/2006
Country of Publication:
United States
Language:
English
Subject:
59; ASPARAGINE; NEOPLASMS; LAWRENCE BERKELEY LABORATORY

Citation Formats

Lorenzi, Philip L., Reinhold, William C., Rudelius, Martina, Gunsior, Michele, Shankavaram, U., Bussey, Kimberly J., Scherf, U., Eichler, Gabriel S., Martin, Scott E., Chin, Koei, Gray, Joe W., Kohn,Elise C., Horak, Ivan D., Von Hoff, Daniel D., Raffeld, Mark, Goldsmith,Paul K., Caplen, Natasha J., and Weinstein, John N. Asparagine synthetase as a causal, predictive biomarker forL-asparaginase activity in ovarian cancer cells. United States: N. p., 2007. Web.
Lorenzi, Philip L., Reinhold, William C., Rudelius, Martina, Gunsior, Michele, Shankavaram, U., Bussey, Kimberly J., Scherf, U., Eichler, Gabriel S., Martin, Scott E., Chin, Koei, Gray, Joe W., Kohn,Elise C., Horak, Ivan D., Von Hoff, Daniel D., Raffeld, Mark, Goldsmith,Paul K., Caplen, Natasha J., & Weinstein, John N. Asparagine synthetase as a causal, predictive biomarker forL-asparaginase activity in ovarian cancer cells. United States.
Lorenzi, Philip L., Reinhold, William C., Rudelius, Martina, Gunsior, Michele, Shankavaram, U., Bussey, Kimberly J., Scherf, U., Eichler, Gabriel S., Martin, Scott E., Chin, Koei, Gray, Joe W., Kohn,Elise C., Horak, Ivan D., Von Hoff, Daniel D., Raffeld, Mark, Goldsmith,Paul K., Caplen, Natasha J., and Weinstein, John N. Fri . "Asparagine synthetase as a causal, predictive biomarker forL-asparaginase activity in ovarian cancer cells". United States. doi:.
@article{osti_910326,
title = {Asparagine synthetase as a causal, predictive biomarker forL-asparaginase activity in ovarian cancer cells},
author = {Lorenzi, Philip L. and Reinhold, William C. and Rudelius, Martina and Gunsior, Michele and Shankavaram, U. and Bussey, Kimberly J. and Scherf, U. and Eichler, Gabriel S. and Martin, Scott E. and Chin, Koei and Gray, Joe W. and Kohn,Elise C. and Horak, Ivan D. and Von Hoff, Daniel D. and Raffeld, Mark and Goldsmith,Paul K. and Caplen, Natasha J. and Weinstein, John N.},
abstractNote = {No abstract prepared.},
doi = {},
journal = {Molecular Cancer Therapeutics},
number = 11,
volume = 5,
place = {United States},
year = {Fri May 11 00:00:00 EDT 2007},
month = {Fri May 11 00:00:00 EDT 2007}
}
  • Abstract not provided.
  • Ovarian cancer is the fifth leading cause of cancer-related mortalities in women. Epithelial ovarian cancer (EOC) represents approximately 90% of all ovarian malignancies. Most EOC patients are diagnosed at advanced stages and current chemotherapy regimens are ineffective against advanced EOC due to the development of chemoresistance. It is important to better understand the molecular mechanisms underlying acquired resistance to effectively manage this disease. In this study, we examined the expression of the Wnt/β-catenin signaling components in the paired cisplatin-sensitive (A2780s) and cisplatin-resistant (A2780cp) EOC cell lines. Our results showed that several negative regulators of Wnt signaling are downregulated, whereas amore » few Wnt ligands and known Wnt/β-catenin target genes are upregulated in A2780cp cells compared to A2780s cells, suggesting that Wnt/β-catenin signaling is more active in A2780cp cells. Further analysis revealed nuclear localization of β-catenin and higher β-catenin transcriptional activity in A2780cp cells compared to A2780s cells. Finally, we demonstrated that chemical inhibition of β-catenin transcriptional activity by its inhibitor CCT036477 sensitized A2780cp cells to carboplatin, supporting a role for β-catenin in carboplatin resistance in A2780cp cells. In conclusion, our data suggest that increased Wnt/β-catenin signaling activity contributes to carboplatin resistance in A2780cp cells. - Highlights: • Wnt ligands and target genes are upregulated in cisplatin resistant A2780cp cells. • Negative regulators of Wnt signaling are down-regulated in A2780cp cells. • β-catenin transcriptional activity is higher in A2780cp cells compared to A2780s cells. • Inhibition of β-catenin activity increases carboplatin cytotoxicity in A2780cp cells.« less
  • Antibody-cytotoxin conjugates are complex novel therapeutic agents whose toxicological properties are not presently well understood. The objective of this study was to identify serum biomarkers that correlate with MLN8866 (an Antibody-Cytotoxic Conjugate, mAb8866-CT) pathological events in monkeys and to predict the maximal tolerated dose (MTD) level using biomarkers. Cynomolgus monkeys were administered a single dose MLN8666 (5, 15 or 30 mg/kg) by intravenous infusion and evaluated over a 7-day period. Exposure levels were determined by quantifying MLN8866 levels (C{sub max} and AUC{sub 0-96h}) in serum. The increase in MLN8866 C{sub max} and AUC{sub 0-96h} was approximately dose proportional. Two biomarkersmore » in serum (m/z 316 and m/z 368) were identified to be correlated with MLN8866 toxicological outcomes. The predicted MTD, 11.4 mg/kg, was within the MTD range set by pathology results (5-15 mg/kg). Administration of MLN8866 at 15 mg/kg and 30 mg/kg dose levels resulted in changes in hematology parameters associated with impaired hematopoiesis and bone marrow toxicity. The projected MLN8866 MTD exposure level was integrated with toxicokinetic analysis and showed C{sub max} = 236 {mu}g/mL and AUC{sub 0-96h} = 7246 h mg/mL. The safety of three different MLN8866 dosing regimens with three dosing schedules was explored with pharmacokinetic modeling.« less
  • Highlights: • DCN is significantly up-regulated in chemoresistant cancer cell lines. • DCN is a key regulator for chemoresistant mechanisms in vitro and in vivo. • DCN predicts the clinical responses to S-1 NAC for patients with oral cancer. - Abstract: We reported previously that decorin (DCN) is significantly up-regulated in chemoresistant cancer cell lines. DCN is a small leucine-rich proteoglycan that exists and functions in stromal and epithelial cells. Accumulating evidence suggests that DCN affects the biology of several types of cancer by directly/indirectly targeting the signaling molecules involved in cell growth, survival, metastasis, and angiogenesis, however, the molecularmore » mechanisms of DCN in chemoresistance and its clinical relevance are still unknown. Here we assumed that DCN silencing cells increase chemosusceptibility to S-1, consisted of tegafur, prodrug of 5-fluorouracil. We first established DCN knockdown transfectants derived from oral cancer cells for following experiments including chemosusceptibility assay to S-1. In addition to the in vitro data, DCN knockdown zenografting tumors in nude mice demonstrate decreasing cell proliferation and increasing apoptosis with dephosphorylation of AKT after S-1 chemotherapy. We also investigated whether DCN expression predicts the clinical responses of neoadjuvant chemotherapy (NAC) using S-1 (S-1 NAC) for oral cancer patients. Immunohistochemistry data in the preoperative biopsy samples was analyzed to determine the cut-off point for status of DCN expression by receiver operating curve analysis. Interestingly, low DCN expression was observed in five (83%) of six cases with complete responses to S-1 NAC, and in one (10%) case of 10 cases with stable/progressive disease, indicating that S-1 chemosensitivity is dramatically effective in oral cancer patients with low DCN expression compared with high DCN expression. Our findings suggest that DCN is a key regulator for chemoresistant mechanisms, and is a predictive immunomarker of the response to S-1 NAC and patient prognosis.« less