Candidate apoptotic and DNA repair gene approach confirms involvement of ERCC1, ERCC5, TP53 and MDM2 in radiation-induced toxicity in head and neck cancer.

Introduction: Single nucleotide polymorphisms (SNPs) of DNA repair and apoptosis genes have been associated with outcome in head and neck squamous cell carcinoma (HNSCC) patients receiving radiotherapy (RT). Our goal was to conduct a candidate gene study in HNSCC patients receiving RT or chemoRT.

Methods: 122 non-resectable HNSCC patients undergoing RT (N=38) or chemoRT (N=84) between 1992 and 2006 were retrospectively analyzed.

Molecular patterns in deficient mismatch repair colorectal tumours: results from a French prospective multicentric biological and genetic study.

Background: To test the prognostic value of tumour protein and genetic markers in colorectal cancer (CRC) and examine whether deficient mismatch repair (dMMR) tumours had a distinct profile relative to proficient mismatch repair (pMMR) tumours.

Methods: This prospective multicentric study involved 251 stage I-III CRC patients. Analysed biomarkers were EGFR (binding assay), VEGFA, thymidylate synthase (TS), thymidine phosphorylase (TP) and dihydropyrimidine dehydrogenase (DPD) expressions, MMR status, mutations of KRAS (codons 12-13), BRAF (V600E), PIK3CA (exons 9 and 20), APC (exon 15) and P53 (exons 4-9), CpG island methylation phenotype status, ploidy, S-phase, LOH.

Gait event detection during stair walking using a rate gyroscope.

Gyroscopes have been proposed as sensors for ambulatory gait analysis and functional electrical stimulation systems. These applications often require detection of the initial contact (IC) of the foot with the floor and/or final contact or foot off (FO) from the floor during outdoor walking. Previous investigations have reported the use of a single gyroscope placed on the shank for detection of IC and FO on level ground and incline walking.

Cognitive and MRI correlates of orthostatic hypotension in Parkinson's disease.

Orthostatic hypotension (OH) is a frequent nonmotor feature of Parkinson's disease (PD), and its occurrence has been associated with cognitive impairment. The underlying mechanism could be mediated by development of cerebrovascular disease induced by chronic or episodic hypoperfusion, but the extent of brain vascular load in PD patients with OH has never been investigated. This study aimed to assess the relationship between OH and cognitive function in PD patients and to investigate the contribution of brain vascular lesions.

Combination of bevacizumab and irradiation on uveal melanoma: an in vitro and in vivo preclinical study.

Background: Radiotherapy (RT) is the standard treatment for uveal melanoma. However it can cause damage to the retina and optic nerve. This study examined the in vitro and in vivo effects of the anti-VEGF monoclonal antibody bevacizumab associated with radiotherapy (RT) on tumor growth and tumor proliferation and vasculature on OCM-1 human uveal melanoma cell line.

Contrasted effects of the multitarget TKi vandetanib on docetaxel-sensitive and docetaxel-resistant prostate cancer cell lines.

Objectives: Overexpression of epidermal growth factor receptor (EGFR) and angiogenic factors is associated with the progression of androgen-independent prostate cancer (AIPC). We examined the effects of vandetanib, an inhibitor of vascular endothelial growth factor (VEGFR), EGFR, and rearranged during transfection (RET) tyrosine-kinase activities, alone or combined with docetaxel, on PC3 docetaxel-sensitive (PC3wt) or docetaxel-resistant (PC3R) AIPC cell growth in vivo and in vitro.

Methods: Mice bearing PC3wt or PC3R tumors were treated for 3 weeks with vandetanib (25 or 50 mg/kg/d p.

Positive interaction between lapatinib and capecitabine in human breast cancer models: study of molecular determinants.

The combination of lapatinib and capecitabine is approved in Her2+ metastatic breast cancer. However, the pharmacological mechanisms for this association have not been fully elucidated. In this non-clinical study, we evaluated the efficacy of this association on a panel of six human breast cancer cell lines as a means to identify the molecular determinants of response to this combination.

The mTOR-targeting drug temsirolimus enhances the growth-inhibiting effects of the cetuximab-bevacizumab-irradiation combination on head and neck cancer xenografts.

We previously reported on head and neck tumor xenografts that the tumor regression induced by a triple combination of irradiation (RT), anti-EGFR and anti-angiogenic therapies was followed, after treatment arrest, by tumor re-growth characterized by activation of the AKT signaling pathway. Since mTOR is the main AKT-related messenger, the aim of this study was to add the mTOR inhibitor temsirolimus to a tri-therapy with RT plus anti-EGFR and anti-angiogenic drugs in order to improve anti-tumor effects. The human head and neck cancer cell line CAL33 (over-expressing EGFR and secreting VEGF-A) was xenografted in nude mice.

Prospective analysis of the impact of VEGF-A gene polymorphisms on the pharmacodynamics of bevacizumab-based therapy in metastatic breast cancer patients.

What Is Already Known About This Subject: • Functional polymorphisms on the VEGF-A gene, known to be linked to cancer risk or to VEGF-A plasma concentrations, have been identified. So far, limited knowledge has been published on the relationships between toxicity/efficacy of bevacizumab-based therapy and VEGF-A polymorphisms (tumoral DNA). We therefore prospectively tested the impact of these five gene polymorphisms (blood DNA) on the pharmacodynamics of bevacizumab-based treatment administered in metastatic breast cancer patients.

Erlotinib in combination with capecitabine (5'dFUR) in resistant pancreatic cancer cell lines.

The combination of capecitabine and the tyrosine kinase inhibitor erlotinib has recently been tested in patients with gemcitabine-refractory pancreatic tumors, with limited success. To understand this lack of efficacy, we studied the molecular effects of these agents in Capan-1 and Capan-2 human pancreatic resistant cancer cells. Erlotinib up-regulated thymidine phosphorylase (+50%) and downregulated dihydropyrimidine dehydrogenase (+55%) in a cell-dependent manner, thus suggesting that the combination should result in synergism.

Tapered dose versus constant drug exposure to anti-EGFR drugs on head-and-neck cancer xenografts. A comparison between cetuximab and gefitinib.

Head-and-neck (H&N) tumor re-growth is clinically observed after arrest of anti-EGFR therapies. In the present study, we compared, for a similar dose exposure to anti-EGFR therapies, constant (CS) with tapered (TS) schedules (i.e.

Influence of the VEGF-A 936C>T germinal polymorphism on tumoral VEGF expression in head and neck cancer.

Aims: Elevated tumoral vascular endothelial growth factor A (VEGF-A) expression is linked to poor survival in head and neck cancer patients. The aim of the present study was to analyze the influence of VEGF-A gene polymorphisms on tumoral VEGF-A expression and to test their prognostic value in head and neck cancer patients.

Materials & Methods: VEGF-A polymorphisms at position -2578C>A, -1498T>C, -1154G>A, -634G>C and 936C>T were analyzed (PCR-RFLP) in tumoral DNA, along with tumoral VEGF-A expression (ELISA), in 49 Caucasian head and neck cancer patients.

Impact of erythropoietin on the effects of irradiation under hypoxia.

Purpose: Head and neck squamous cell carcinoma (HNSCC) represents an ideal model for assessing the impact of anemia and tumor hypoxia on the response to radiotherapy (RT). Various treatment strategies aimed at increasing tumor oxygenation in HNSCC patients have been studied and these studies have been fueled by evidence that hypoxia and, unexpectedly, erythropoietin (EPO), adversely affect the radiosensitivity of cells. The purpose of the present study was to experimentally examine the relationship between hypoxia, EPO, its receptor EPOR, EGFR and their effects on the survival and radiosensitivity of HNSCC cells underwent hypoxia.

Vertical VEGF targeting: A combination of ligand blockade with receptor tyrosine kinase inhibition.

The aim of this study was to examine the anti-tumour effects of dual vertical VEGF targeting consisting in the association between bevacizumab, a VEGF-depleting drug, and the VEGF receptor antityrosine kinase AZD2171. Mice bearing human head and neck CAL33 xenografted tumours were treated once daily for 11 d with either vehicle (controls), AZD2171 (2.5mg/kg/day, p.

K-Ras mutations and treatment outcome in colorectal cancer patients receiving exclusive fluoropyrimidine therapy.

Purpose: K-Ras mutations predict resistance to anti-epidermal growth factor receptor (EGFR) monoclonal antibodies. Because combinations of anti-EGFR with 5-fluorouracil (5-FU)-based chemotherapy are promising treatments, we analyzed the effect of K-Ras mutations in patients having received exclusive 5-FU therapy.

Experimental Design: This study was conducted on 93 stage IV colorectal cancer patients with unresectable measurable liver metastasis receiving 5-FU-leucovorin (56 men and 37 women; 77 cancer deaths).

The combination of docetaxel and the somatostatin analogue lanreotide on androgen-independent docetaxel-resistant prostate cancer: experimental data.

Objective: To evaluate the effects of the association between docetaxel and the somatostatin analogue lanreotide on the androgen-independent prostate cancer cell line PC3, either sensitive or made resistant to docetaxel (PC3R), as new drugs and new combinations have promising clinical activity in hormone-refractory prostate cancer.

Materials And Methods: We examined the effect of docetaxel and lanreotide on cell proliferation, with analysis of the mitogen-activated protein kinase pathway and expression of cell-cycle regulatory proteins.

Results: Combined treatment with docetaxel and lanreotide inhibited PC3 cell growth in vitro through an enhanced induction of cell death, compared with treatment with either agent alone; this result was particularly evident on PC3R cells.

Role of the HER2 [Ile655Val] genetic polymorphism in tumorogenesis and in the risk of trastuzumab-related cardiotoxicity.

Background: To examine the impact of a frequent her2 gene polymorphism (Ile655Val) on tumor growth and on the pharmacodynamics of treatment by trastuzumab.

Patients And Methods: Experimental study: The growth characteristics of cells expressing the Ile or Val isoform were examined in vitro and after injection into nude mice. The effect of trastuzumab was determined in both experimental models.

Supra-additive antitumor effect of sunitinib malate (SU11248, Sutent) combined with docetaxel. A new therapeutic perspective in hormone refractory prostate cancer.

Purpose: Physiological and molecular findings indicate over-expression of HER proteins and dysregulation of neo-angiogenesis during progression of advanced prostate cancer. The aim of this study was to test a novel rational therapeutic approach by combining docetaxel with an EGFR-targeting agent (cetuximab) and with an anti-angiogenic agent (sunitinib, SUTENT).

Methods: Mice bearing well-established PC3 prostate tumors (mean tumor volume/treatment group approximately 250 mm(3)) were treated every week with vehicle alone (controls), sunitinib (40 mg/kg/day, 5 days/week for 3 weeks, 0.

Dual inhibition of EGFR and VEGFR pathways in combination with irradiation: antitumour supra-additive effects on human head and neck cancer xenografts.

The aim of this study was to investigate the effects of combining antiangiogenic treatment, epidermal growth factor receptor (EGFR) targeting and irradiation (RT). We evaluated AZD2171, a highly potent, orally active, vascular endothelial growth factor (VEGF) signalling inhibitor, gefitinib, an EGFR tyrosine kinase inhibitor and RT. The antitumour efficacy of these treatments, administered alone and in combination for 2 weeks, was assessed in a VEGF-secreting human head and neck tumour cell line, CAL33 that highly expresses EGFR, established as xenografts (250 mm(3)) in nude mice.

Enhanced tumour antiangiogenic effects when combining gefitinib with the antivascular agent ZD6126.

Current experimental and clinical knowledge supports the optimisation of endothelial cell targeting using a strategy combining anti-EGFR drugs with antivascular agents. The purpose of the present study was to examine the effects of the association of ZD6126, an antivascular microtubule-destabilising agent, with gefitinib and irradiation on the growth of six head and neck human cancer cell lines xenografted in nude mice and to study predictive and molecular factors responsible for antitumour effects. CAL33- and Hep-2-grafted cell lines were the most sensitive to ZD6126 treatment, with VEGF levels significantly higher (P=0.

Synergistic cytotoxic interaction in hormone-refractory prostate cancer with the triple combination docetaxel-erlotinib and 5-fluoro-5'-deoxyuridine.

The current reference treatment of hormone-refractory prostate cancer consists mainly of chemotherapy with docetaxel. To improve the management of advanced prostate cancer, one should examine the benefits of adding other agents to docetaxel. We examined the growth inhibitory effects of a triple combination, including the anti-epidermal growth factor receptor drug erlotinib, docetaxel and 5-fluoro-5'-deoxyuridine (the main intermediary metabolite of capecitabine), on the human prostate cancer cell lines PC3 and DU145, which are both devoid of androgen receptors.

Response of endothelial cells to a dual tyrosine kinase receptor inhibition combined with irradiation.

Recent studies suggest the possibility of a direct antiangiogenic effect of anti-epidermal growth factor receptor (EGFR) drugs due to the presence of EGFR on endothelial cells. The aim of this study was to analyze the direct effect on endothelial cells of associating EGFR targeting, vascular endothelial growth factor receptor (VEGFR)-2 targeting, and irradiation. We examined both the cytotoxic effects and the effect on molecular markers resulting from the combined action of gefitinib (Iressa; anti-EGFR), ZM317450 [VEGFR tyrosine kinase inhibitor (VTKI); anti-VEGFR-2], and irradiation (radiation therapy) on HMME7 cells, an immortalized microvascular endothelial cell of human origin.

Gefitinib-trastuzumab combination on hormone-refractory prostate cancer xenograft.

New drugs and new combinations of drugs have recently shown promising clinical activity in hormone refractory prostate cancer. We studied the association of gefitinib with trastuzumab on the androgen-refractory prostate cancer cell line DU145 expressing both epidermal growth factor receptor (EGFR) and HER-2. Drug combinations with radiotherapy (RT) were considered along with the analysis of factors linked to cell proliferation and apoptosis.

Epidermal growth factor receptor double targeting by a tyrosine kinase inhibitor (Iressa) and a monoclonal antibody (Cetuximab). Impact on cell growth and molecular factors.

Among the recent advances in the molecular targeted therapy of cancer, the applications focused on epidermal growth factor receptor (EGFR) are currently the most promising and the most advanced at clinical level. In view of the different modes of action of monoclonal antibodies and tyrosine kinase inhibitors (TKI), it is tempting to examine the effect of a combination between these two EGFR targeting approaches. It was the purpose of the present study to test this combination at experimental level by using two epidermoid human cell lines CAL 33 and CAL 39.

Taxotere-5'-deoxy-5-fluorouridine combination on hormone-refractory human prostate cancer cells.

Single-agent docetaxel (Taxotere) treatment has recently demonstrated promising clinical activity in patients with advanced hormone-refractory prostate cancer. Taxanes were recently found to upregulate the tumoral activity of thymidine phosphorylase (TP), a key cellular enzyme [transformation of 5'-deoxy-5-fluorouridine (5'-DFUR) into 5-fluorouracil] in the activation cascade of capecitabine (Xeloda). We tested (cytotoxic effects and molecular mechanisms) the Taxotere-5'-DFUR combination on hormone-refractory prostate cancer cell lines (DU145 and PC3).