Akt1 rs2498801 is related to survival in head and neck squamous cell cancer treated with radiotherapy.

Background: Radiotherapy (RT) with or without chemotherapy (CT) plays an important role as exclusive treatment in patients with head and neck squamous cell cancer (HNSCC). Unfortunately, in some cases, benefit for patients is not recorded and only treatment-related complications are registered.

Materials And Methods: Data relating to Akt1 single nucleotide polymorphism (SNP) and response to treatment of 46 patients treated with exclusive RT or RT-CT for HNSCC were evaluated.

Synthesis of Novel 3,5-Disubstituted-2-oxindole Derivatives As Antitumor Agents against Human Nonsmall Cell Lung Cancer.

This study was aimed at investigating the antitumor activity of novel 2-oxindole derivatives against a well-characterized human nonsmall cell lung cancer (NSCLC) cell line. Test compounds produced an antiproliferative activity in the low micromolar/submicromolar range of concentrations and significantly induced typical apoptotic morphology with cell shrinkage, nuclear condensation and fragmentation, and rupture of cells into debris in a relatively low percentage of A549 cells. Cell cycle arrest occurred at the G1/S phase (1a and 2), and Akt phosphorylation was significantly inhibited at Thr308 and Ser473.

Synergistic cytotoxicity, inhibition of signal transduction pathways and pharmacogenetics of sorafenib and gemcitabine in human NSCLC cell lines.

Introduction: Lung cancer is one of the most lethal tumors and, although standard chemotherapy produces clinical response, there has been little improvement in prognosis. Therefore, research effort has focused on target-specific agents, such as sorafenib, which blocks both the RAF/MEK/ERK signalling pathways and receptors involved in neovascularization and tumor progression, including VEGFR-2 and c-Kit. We investigated whether sorafenib would be synergistic with gemcitabine against NSCLC cell lines.

Synergistic cytotoxicity and molecular interaction on drug targets of sorafenib and gemcitabine in human pancreas cancer cells.

Background: Current treatments have a modest impact on survival of pancreatic cancer patients and this study investigates the interaction between sorafenib and gemcitabine and the molecular pharmacodynamics of this combination.

Methods: The pancreatic cancer cells were treated with sorafenib and gemcitabine, alone or in combination. The effects of treatments were evaluated on cell proliferation, cell cycle, apoptosis, phosphorylation of Akt, c-Kit, ERK and VEGFR2, and expression of genes related to drug activity.

Cellular and molecular mechanisms for the synergistic cytotoxicity elicited by oxaliplatin and pemetrexed in colon cancer cell lines.

Purpose: Oxaliplatin effect in the treatment of colorectal cancer is improved upon combination with thymidylate synthase (TS) inhibitors. Pemetrexed is polyglutamated by the folylpolyglutamate synthase (FPGS) and blocks folate metabolism and DNA synthesis by inhibiting TS, dihydrofolate reductase (DHFR) and glycinamide ribonucleotide formyltransferase (GARFT). The present study evaluates the pharmacological interaction between oxaliplatin and pemetrexed in colorectal cancer cells.

Expression of nucleoside transporters, deoxycitidine kinase, ribonucleotide reductase regulatory subunits, and gemcitabine catabolic enzymes in primary ovarian cancer.

Purpose: Gemcitabine (2',2'-difluorodeoxycytidine) (GEM) is one of the most actively investigated drugs in ovarian cancer. Many molecular mechanisms have been proposed to be involved in GEM sensitivity/resistance including the equilibrative nucleoside transporter-1 (hENT1), the concentrative nucleoside transporter-1 (hCNT1), and deoxycytidine kinase (dCK). The expression of the ribonucleotide reductase regulatory subunits M1 (RRM1) and M2 (RRM2), and the catabolic enzymes 5'nucleotidase (5'NT), and cytidine deaminase (CDA) play also an important role.

Epigenetic mechanisms of irinotecan sensitivity in colorectal cancer cell lines.

Irinotecan is a topoisomerase-I (Top-I) inhibitor used for the treatment of colorectal cancer. DNA demethylating agents, including 5-azacytidine (5-aza), display synergistic antitumor activity with several chemotherapy drugs. 5-Aza may enhance irinotecan cytotoxicity by at least one of the following mechanisms: (a) Top-I promoter demethylation, (b) activation of genes involved in Top-I transcriptional regulation (p16 or Sp1), and (c) modulation of the cell cycle and apoptosis after DNA damage.

Laser microdissection and primary cell cultures improve pharmacogenetic analysis in pancreatic adenocarcinoma.

A key focus of research on pancreatic ductal adenocarcinoma (PDAC) is identifying new techniques to tailor gemcitabine and 5-fluorouracil treatments. Availability of tumor tissue is critical for the accurate assessment of gene expression, and laser microdissection (LMD) and primary cell cultures may be useful tools to separate tumor cells from the stromal reaction. The aim of this study was (1) to address the genetic profile relevant to drug activity and (2) to evaluate differences between microdissected and non-microdissected tumors, normal tissues, and primary cell cultures.

Correlation of CDA, ERCC1, and XPD polymorphisms with response and survival in gemcitabine/cisplatin-treated advanced non-small cell lung cancer patients.

Purpose: Selecting patients according to key genetic characteristics may help to tailor chemotherapy and optimize the treatment in non-small cell lung cancer (NSCLC). Polymorphisms at the xeroderma pigmentosum group D (XPD), excision repair cross-complementing 1 (ERCC1), and cytidine deaminase (CDA) genes have been associated with alterations in enzymatic activity and may change sensitivity to the widely used cisplatin-gemcitabine regimen.

Experimental Design: Analyses of CDA, XPD, and ERCC1 polymorphisms were done on blood samples of 65 chemotherapy-naïve, advanced NSCLC patients treated with cisplatin-gemcitabine.

A case of drug resistant clear cell ovarian cancer showing responsiveness to gemcitabine at first administration and at re-challenge.

Introduction: Gemcitabine (2',2'-difluorodeoxycytidine) (GEM) has been demonstrated to be active in the salvage setting of ovarian cancer (OC) patients.

Case Report: A 57-year-old woman, with a diagnosis of FIGO Stage IIIC clear cell OC, judged inoperable to optimal residual tumor, was administered neo-adjuvant chemotherapy with carboplatin/paclitaxel/topotecan, and cytoreduction. After 5 months the patient progressed, and pegylated liposomal doxorubicin was started with rapid progression.

Cytotoxic activity of gemcitabine and correlation with expression profile of drug-related genes in human lymphoid cells.

Gemcitabine is an inhibitor of ribonucleotide reductase (RR) and DNA polymerization with promising activity in hematologic malignancies. Gemcitabine enters the cell mostly via the human equilibrative nucleoside transporter-1 (hENT1), while drug metabolism occurs by phosphorylation by deoxycytidine kinase (dCK), 5'-nucleotidase (cN-II) and cytidine deaminase (CDA) are the main inactivating enzymes. The aim of this study was to investigate the role of these determinants in gemcitabine cytotoxicity and analyze their expression in lymphoid cells.

Synergistic antitumor activity of ZD6474, an inhibitor of vascular endothelial growth factor receptor and epidermal growth factor receptor signaling, with gemcitabine and ionizing radiation against pancreatic cancer.

Purpose: Standard treatments have modest effect against pancreatic cancer, and current research focuses on agents targeting molecular pathways involved in tumor growth and angiogenesis. This study investigated the interactions between ZD6474, an inhibitor of tyrosine kinase activities of vascular endothelial growth factor receptor-2 and epidermal growth factor receptor (EGFR), gemcitabine, and ionizing radiation in human pancreatic cancer cells and analyzed the molecular mechanisms underlying this combination.

Experimental Design: ZD6474, ionizing radiation, and gemcitabine, alone or in combination, were given in vitro to MIA PaCa-2, PANC-1, and Capan-1 cells and in vivo to MIA PaCa-2 tumor xenografts.

Pharmacogenetics of anticancer drug sensitivity in pancreatic cancer.

Chemotherapy has produced unsatisfactory results in pancreas cancer and novel approaches, including treatment tailoring by pharmacogenetic analysis and new molecular-targeted drugs, are required. The scarcity of effective therapies may reflect the lack of knowledge about the influence of tumor-related molecular abnormalities on responsiveness to drugs. Advances in the understanding of pancreas cancer biology have been made over the past decade, including the discovery of critical mutations in oncogenes (i.

Transcription analysis of human equilibrative nucleoside transporter-1 predicts survival in pancreas cancer patients treated with gemcitabine.

Gene expression analysis may help the management of cancer patients, allowing the selection of subjects responding to treatment. The aim of this study was the characterization of expression pattern of genes involved in gemcitabine activity in pancreas tumor specimens and its correlation with treatment outcome. The role of drug transport and metabolism on gemcitabine cytotoxicity was examined with specific inhibitors, whereas transcription analysis of human equilibrative nucleoside transporter-1 (hENT1), deoxycytidine kinase (dCK), 5'-nucleotidase (5'-NT), cytidine deaminase (CDA), and ribonucleotide reductase subunits M1 and M2 (RRM1 and RRM2) was done by quantitative reverse transcription-PCR in tumor tissue isolated by laser microdissection from surgical or biopsy samples of 102 patients.

Cellular and pharmacogenetics foundation of synergistic interaction of pemetrexed and gemcitabine in human non-small-cell lung cancer cells.

Gemcitabine and pemetrexed are effective agents in the treatment of non-small-cell lung cancer (NSCLC), and the present study investigates cellular and genetic aspects of their interaction against A549, Calu-1, and Calu-6 cells. Cells were treated with pemetrexed and gemcitabine, and their interaction was assessed using the combination index. The role of drug metabolism in gemcitabine cytotoxicity was examined with inhibitors of deoxycytidine kinase (dCK), 5'-nucleotidase, and cytidine deaminase, whereas the role of pemetrexed targets, thymidylate synthase (TS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyltransferase (GARFT) in drug chemosensitivity was analyzed in cytotoxicity rescue studies.

Synergistic cytotoxicity and pharmacogenetics of gemcitabine and pemetrexed combination in pancreatic cancer cell lines.

Purpose: Gemcitabine is an inhibitor of ribonucleotide reductase (RR) and DNA synthesis and is an effective agent in the treatment of pancreas cancer. The present study investigates whether the multitargeted antifolate pemetrexed would be synergistic with gemcitabine against MIA PaCa-2, PANC-1, and Capan-1 pancreatic cancer cell lines.

Experimental Design: Cells were treated with gemcitabine and pemetrexed, and the type of drug interaction was assessed using the combination index.