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1.
Eur J Cancer ; 43(7): 1153-60, 2007 May.
Article in English | MEDLINE | ID: mdl-17398088

ABSTRACT

AIM: To assess the efficacy and safety of epirubicin, capecitabine and cisplatin (EXC) combination therapy in locally advanced breast cancer (LABC) and investigate the predictive value of selected biomarkers. METHODS: Newly diagnosed LABC patients received four 3-weekly cycles of neoadjuvant EXC (epirubicin 60 mg/m(2) day 1; capecitabine 1000 mg/m(2) bid, days 1-14; cisplatin 60 mg/m(2)day 1) and two cycles of post-operative EXC. RESULTS: Eight (17%) of 48 patients had inflammatory breast cancer. Overall response rate was 74% (95% CI: 59-86%), including complete responses in 13% (95% CI: 5-26%). Nine (22%; 95% CI: 11-38%) of 41 patients undergoing surgery achieved pathologic complete response (pCR), giving a pCR rate of 19% (95% CI: 9-33%) in the intent-to-treat population. Haematological toxicity was manageable. The most problematic toxicities were chemotherapy-induced nausea/vomiting and hypercoagulative disorders. None of the biomarkers investigated, including HER2, predicted response. CONCLUSION: EXC showed high efficacy in LABC, with high clinical response and pCR rate. Nausea and vomiting were unexpectedly frequent, and more aggressive prophylaxis and management of these side effects is recommended in future studies of this combination.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Breast Neoplasms/drug therapy , Adult , Aged , Antiemetics/therapeutic use , Biomarkers, Tumor/blood , Breast Neoplasms/surgery , Capecitabine , Chemotherapy, Adjuvant , Cisplatin/administration & dosage , Cisplatin/adverse effects , Deoxycytidine/administration & dosage , Deoxycytidine/adverse effects , Deoxycytidine/analogs & derivatives , Dose-Response Relationship, Drug , Epirubicin/administration & dosage , Epirubicin/adverse effects , Female , Fluorouracil/administration & dosage , Fluorouracil/adverse effects , Fluorouracil/analogs & derivatives , Humans , Infusions, Intravenous , Injections, Intravenous , Mastectomy, Radical , Middle Aged , Neoadjuvant Therapy , Survival Analysis , Treatment Outcome
2.
J Biol Chem ; 281(10): 6776-84, 2006 Mar 10.
Article in English | MEDLINE | ID: mdl-16407243

ABSTRACT

Increased levels of the inflammatory mediator leukotriene D4 (LTD4) are present at sites of inflammatory bowel disease, and such areas also exhibit an increased risk for subsequent cancer development. It is known that LTD4 affects the expression of many proteins that influence survival and proliferation of intestinal epithelial cells. We demonstrate here that after LTD4 exposure, beta-catenin translocates to the nucleus where it signals activation of the TCF/LEF family of transcription factors. These events are mediated via a phosphatidylinositol 3-kinase-dependent phosphorylation of the inhibitory Ser-9 residue of glycogen synthase kinase 3beta. We also show that in the presence of LTD4, free beta-catenin translocates to the mitochondria where it associates with the cell survival protein Bcl-2. We hypothesize that LTD4 may enhance cell survival via activation of beta-catenin signaling, in particular, by promoting the association of beta-catenin with Bcl-2 in the mitochondria. Similar to Wnt-1 signaling, LTD4 signals an increased level of free beta-catenin and elevated TCF/LEF promotor activity. This work in intestinal epithelial cells further lends credence to the idea that inflammatory signaling pathways are intrinsically linked with potential oncogenic signals involved in cell survival and apoptosis.


Subject(s)
Apoptosis/physiology , Leukotriene D4/physiology , Proto-Oncogene Proteins c-bcl-2/metabolism , Signal Transduction/physiology , beta Catenin/metabolism , Cell Line , Cell Survival , Cell Transformation, Neoplastic/metabolism , Glycogen Synthase Kinase 3/metabolism , Glycogen Synthase Kinase 3 beta , Humans , Intestinal Mucosa/enzymology , Intestinal Mucosa/metabolism , Microscopy, Fluorescence , Mitochondria/metabolism , Protein Transport , Proto-Oncogene Proteins c-bcl-2/genetics , TCF Transcription Factors/biosynthesis , TCF Transcription Factors/genetics , beta Catenin/genetics
3.
Cancer Res ; 65(3): 732-42, 2005 Feb 01.
Article in English | MEDLINE | ID: mdl-15705869

ABSTRACT

Searching for a link between inflammation and colon cancer, we have found that the inflammatory mediator leukotriene D(4) (LTD(4)), via its receptor CysLT(1), induces cyclooxygenase-2 expression, survival, and proliferation in intestinal epithelial cells. In conjunction with our previous observation that CysLT(1) receptor expression is increased in colorectal adenocarcinomas, we here found an increased nuclear localization of the CysLT(1) receptor in colorectal adenocarcinomas. This novel discovery of CysLT(1) receptors in the nucleus was further analyzed. It was found to be located in the outer nuclear membrane in colon cancer cells and in the nontransformed epithelial cell line Int 407 cells by Western blot and electron microscopy. Cancer cells displayed higher amounts of the nuclear CysLT(1) receptor, but prolonged LTD(4) exposure induced its nuclear translocation in nontransformed cells. Truncation of a nuclear localization sequence abrogated this translocation as well as the LTD(4)-induced proliferative response. In accordance, nuclear CysLT(1) receptors exhibited proliferative extracellular signal-regulated kinase 1/2 signaling. The significance of these experimental findings is supported by the observed correlation between the proliferative marker Ki-67 and nuclear CysLT(1) receptor localization in colorectal adenocarcinomas. The present findings indicate that LTD(4) cannot only be synthesized but also signal proliferation through nuclear CysLT(1) receptors, stressing the importance of leukotrienes in inflammation-induced colon carcinogenesis.


Subject(s)
Adenocarcinoma/metabolism , Colorectal Neoplasms/metabolism , Membrane Proteins/metabolism , Nuclear Localization Signals/metabolism , Receptors, Leukotriene/metabolism , Adenocarcinoma/enzymology , Adenocarcinoma/genetics , Amino Acid Sequence , Arachidonate 5-Lipoxygenase/metabolism , Caco-2 Cells , Cell Line, Tumor , Cell Membrane/enzymology , Cell Membrane/metabolism , Cell Nucleus/enzymology , Cell Nucleus/metabolism , Colorectal Neoplasms/enzymology , Colorectal Neoplasms/genetics , Epithelial Cells/metabolism , Epithelial Cells/pathology , Gene Expression Regulation, Neoplastic , Humans , Leukotriene D4/pharmacology , Membrane Proteins/biosynthesis , Membrane Proteins/genetics , Molecular Sequence Data , Receptors, Leukotriene/biosynthesis , Receptors, Leukotriene/genetics , Up-Regulation
5.
Biochem Biophys Res Commun ; 302(2): 330-5, 2003 Mar 07.
Article in English | MEDLINE | ID: mdl-12604350

ABSTRACT

Leukotrienes play an important pathophysiological role in chronic inflammatory states and, as previously shown, cause increased levels of cyclooxygenase-2 (COX-2) in intestinal epithelial cells. The anti-apoptotic protein Bcl-2 is also elevated by LTD(4) stimulation, and in colon cancer, so we studied the mechanisms of COX-2 and Bcl-2 regulation. We found that LTD(4) induced a 3-fold elevation of COX-2 transcription in Int 407 cells and a 2-fold equivalent in colon cancer cells, Caco-2. This was mediated through a pertussis toxin (PTX) sensitive G-protein and the MAP kinase Erk-1/2 pathway, and this was also shown to be the route to up-regulation of Bcl-2 by LTD(4). In good agreement with this, we detected a strong activation of Erk-1/2 that was further increased by COX-2 inhibition, pointing towards the existence of negative feedback regulation. Furthermore, COX-2 activity is responsible for the effects on Bcl-2, but this is not conveyed through the production of PGE(2).


Subject(s)
Isoenzymes/biosynthesis , Leukotrienes/pharmacology , Prostaglandin-Endoperoxide Synthases/biosynthesis , Proto-Oncogene Proteins c-bcl-2/biosynthesis , Signal Transduction/physiology , Caco-2 Cells , Cyclooxygenase 2 , Drug Interactions , Enzyme Activation/drug effects , Enzyme Induction/drug effects , Humans , Isoenzymes/genetics , MAP Kinase Kinase 1 , Membrane Proteins , Mitogen-Activated Protein Kinase Kinases/antagonists & inhibitors , Mitogen-Activated Protein Kinase Kinases/metabolism , Mitogen-Activated Protein Kinases/metabolism , Pertussis Toxin/pharmacology , Prostaglandin-Endoperoxide Synthases/genetics , Protein Serine-Threonine Kinases/antagonists & inhibitors , Protein Serine-Threonine Kinases/metabolism , Proto-Oncogene Proteins c-bcl-2/genetics , Transcription, Genetic/drug effects , Up-Regulation
6.
Gastroenterology ; 124(1): 57-70, 2003 Jan.
Article in English | MEDLINE | ID: mdl-12512030

ABSTRACT

BACKGROUND & AIMS: The effects of leukotriene (LT) D(4) on intestinal epithelial cells govern events that are involved in cell survival and colon cancer, notably increased expression of cyclooxygenase (COX)-2 and enhanced production of prostaglandin E(2). We investigated possible correlations between distribution of the recently described LTD(4) receptor CysLT(1)R and factors previously shown to be up-regulated by LTD(4) as well as clinicopathologic traits. METHODS: Immunohistochemistry and in situ hybridization were performed on tissue arrays, which were made using colorectal cancer samples from 84 patients. RESULTS: CysLT(1)R was significantly correlated to COX-2, 5-lipoxygenase, and Bcl-x(L). Male subjects more often exhibited high levels of this receptor relative to female subjects, and Dukes' B patients with elevated CysLT(1)R expression showed markedly poorer survival than those with low-level expression. Furthermore, this was paralleled by an increased viability of CysLT(1)R-overexpressing cells in a colon cancer cell line. CONCLUSIONS: Our results further implicate the involvement of LTs in colorectal carcinoma. Based on our present and earlier findings, we propose that LT/CysLT(1)R signaling facilitates survival of colon cancer cells, which may affect disease outcome. Like COX-2, LTs are accessible targets for pharmacologic treatment.


Subject(s)
Adenocarcinoma/metabolism , Colorectal Neoplasms/metabolism , Isoenzymes/metabolism , Membrane Proteins , Prostaglandin-Endoperoxide Synthases/metabolism , Receptors, Leukotriene/metabolism , Adenocarcinoma/pathology , Aged , Aged, 80 and over , Cell Survival/physiology , Colorectal Neoplasms/pathology , Cyclooxygenase 2 , Female , Humans , Immunohistochemistry , Male , Middle Aged , Survival Analysis , Tumor Cells, Cultured
7.
Adv Exp Med Biol ; 507: 193-8, 2002.
Article in English | MEDLINE | ID: mdl-12664585

ABSTRACT

In this preliminary report we present data showing that leukotrienes increase the baseline cell viability in human intestinal epithelial cells and that LTB4 partially reverses the morphological hallmarks of non-necrotic cell death induced by the COX-2 specific inhibitor NS-398. The proposed signaling mechanisms regulating these events are summarized in fig. 3. Please view the work on LT signal transduction in these cells by Thodeti et al. in this volume.


Subject(s)
Cell Survival/physiology , Intestinal Mucosa/cytology , Leukotrienes/physiology , Cell Line , Cell Survival/drug effects , Cyclooxygenase Inhibitors/pharmacology , Humans , Intestinal Mucosa/drug effects , Intestinal Mucosa/physiology , Nitrobenzenes/pharmacology , Sulfonamides/pharmacology
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