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Biomedical subjects

Nick R Lemoine

Publications and source records attributed to Nick R Lemoine.

10 recordsLinked to original sources
PubMed2006

Bacterial gene therapy strategies.

The ability of bacteria to mediate gene transfer has only recently been established and these observations have led to the utilization of various bacterial strains in gene therapy. The types of bacteria used include attenuated strains of Salmonella, Shigella, Listeria, and Yersinia, as well as non-pathogenic Escherichia coli. For some of these vectors, the mechanism of DNA transfer from the bacteria to the mammalian cell is not yet fully understood but their potential to deliver therapeutic molecules has been demonstrated in vitro and in vivo in experimental models. Therapeutic benefits have been observed in vaccination against infectious diseases, immunotherapy against cancer, and topical delivery of immunomodulatory cytokines in inflammatory bowel disease. In the case of attenuated Salmonella, used as a tumour-targeting vector, clinical trials in humans have demonstrated the proof of principle but they have also highlighted the need for the generation of strains with reduced toxicities and improved colonization properties. Altogether, the encouraging results obtained in the studies presented in this review justify further development of bacteria as a therapeutic vector against many types of pathology.

Antigens, Bacterial↗
PubMed2006

Gene therapy developments for pancreatic cancer.

Treatment options for pancreatic cancer have limited success and it is therefore an appropriate target for the development of new strategies, including gene therapy. Gene therapy approaches include inhibition of activated oncogenes (KRAS, LSM1) with antisense and RNA interference strategies, replacement of inactivated tumour suppressor genes (TP53, CDKN2A, CDKN1A), targeting of cell signalling pathways, gene-directed prodrug-activation therapies and the use of replication-competent oncolytic viruses. Angiogenesis and apoptosis have also been targeted for gene therapy. Clinical trials of gene therapy have shown only moderate anti-tumour effects. As there are many genetic abnormalities in pancreatic cancer, strategies combining different targets or indeed different modalities of treatment, may be more successful. Identification of new targets and improvements in delivery and targeting may further improve the efficacy of gene therapy in pancreatic cancer.

Adenoviridae↗
PubMed2006

Caspase-1 as a radio- and chemo-sensitiser in vitro and in vivo.

The cytotoxic effect of anticancer drugs has been shown to involve induction of apoptosis. This observation raises the possibility that factors affecting caspase activation might be important determinants of anticancer drug sensitivity. Ectopic expression of caspase-1 has been shown to trigger apoptosis. However, the role of caspase-1 in apoptosis is now considered as minor compared to other caspases. In patients, high levels of caspase-1 expression may be associated with spontaneous regression in neuroblastomas and with a good clinical response to chemotherapy in acute myeloid leukemia and osteosarcoma. In experimental therapeutics for cancer, caspase-1 has been related to some anticancer activity. These observations led us to examine the effect of over-expression on the response to chemotherapy and radiotherapy in vitro and in vivo. Caspase-1 expression mediated by an adenoviral vector was able to kill directly cells and to sensitise the remaining cells to cisplatin or gamma-radiation in vitro. In HeLa cells stably transfected with caspase-1, sensitisation to cisplatin was due to an amplification of the cisplatin-induced mitochondrial apoptotic pathway activation. Caspase-1 mediated sensitisation to cisplatin and gamma-radiation was also observed in vivo. Altogether, we conclude that caspase-1 can act as a radio- and chemo-sensitiser, in vitro and in vivo.

Adenoviridae↗
PubMed2005

Virus-associated RNA I-deleted adenovirus, a potential oncolytic agent targeting EBV-associated tumors.

Given the growing number of tumor types recognizably associated with EBV infection, it is critically important that therapeutic strategies are developed to treat such tumors. Replication-selective oncolytic adenoviruses represent a promising new platform for anticancer therapy. Virus-associated I (VAI) RNAs of adenoviruses are required for efficient translation of viral mRNAs. When the VAI gene is deleted, adenovirus replication is impeded in most cells (including HEK 293 cells). EBV-encoded small RNA1 is uniformly expressed in most EBV-associated human tumors and can functionally substitute for the VAI RNAs of adenovirus. It enables replication to proceed through complementation of VAI-deletion mutants. We hypothesized that VAI-deleted adenovirus would selectively replicate in EBV-positive tumor cells due to the presence of EBV-encoded small RNA1 with no (or poor) replication in normal or EBV-negative tumor cells. In this report, we show that high levels of replication occurred in the VAI-deleted mutant in the EBV-positive tumor cells compared with low (or negligible) levels in EBV-negative and normal human primary cells. Correspondingly, high toxicity levels were observed in EBV-positive tumor cells but not in EBV-negative tumor or normal human primary cells. In vivo, VAI-deleted adenovirus showed superior antitumoral efficacy to wild-type adenovirus in EBV-positive tumor xenografts, with lower hepatotoxicity than wild-type adenovirus. Our data suggest that VAI-deleted adenovirus is a promising replication-selective oncolytic virus with targeting specificity for EBV-associated tumors.

Adenoviruses, Human↗
PubMed2005

Expression of S100P and its novel binding partner S100PBPR in early pancreatic cancer.

S100P is a member of the S100 family of calcium-binding proteins and there have been several recent reports of its overexpression in pancreatic ductal adenocarcinoma (PDAC). We have used Far Western screening and in vitro interaction assays to identify and confirm a novel target protein for S100P. We have named this protein S100PBPR, and shown that its interaction with S100P is dependent on Ca(2+) or Mg(2+). S100PBPR was found to localize to cell nuclei where S100P is also present, and the two proteins co-immunoprecipitate. By in situ hybridization, S100PBPR transcript was found in islet cells but not duct cells of the healthy pancreas. Both S100P and S100PBPR were detected by quantitative real-time polymerase chain reaction in pancreatic intraepithelial neoplasia (PanIN) and PDAC samples, and in situ hybridization revealed the presence of S100PBPR transcript in malignant PDAC cells. These data suggest that an interaction between S100P and S100PBPR may be involved in early pancreatic cancer. S100P was further investigated in PanIN lesions and immunohistochemical analysis showed its expression to correlate significantly with increasing grade of PanINs, being found as early as PanIN-1 with more prevalent expression in PanIN-2 and -3. These data suggest that S100P can be added to the genetic progression model for PDAC.

Adenocarcinoma↗
PubMed2005

Mechanisms of disease: the impact of antithrombotic therapy in cancer patients.

Venous thromboembolism is a common complication in patients with malignant disease. It is associated with a systemic hypercoagulable state that is secondary to tumor elaboration of tissue factor (the physiological initiator of blood coagulation), activation of other procoagulant mechanisms and downregulation of anticoagulant mechanisms. The consequent generation of activated coagulation serine protease in the peritumoral environment influences tumor growth, invasion, metastasis and angiogenesis. The use of antithrombotic agents, such as the low-molecular-weight heparins, might influence survival in cancer patients through several mechanisms. These mechanisms include a reduction in the frequency of overt and silent fatal thromboembolic events, interference with the activation of blood coagulation and generation of coagulation serine proteases that affect the tumor phenotype, and direct cellular effects of heparin on both epithelial and endothelial tumor elements.

Blood Coagulation↗
PubMed2004

Suicide gene therapy: conversion of ethanol to acetaldehyde mediated by human beta 2 alcohol dehydrogenase.

Acetaldehyde (AcH) produced in the physiological metabolism of ethanol can be potentially toxic and immunomodulating. The antitumour activity of a suicide gene system using adenovirus delivered alcohol dehydrogenase (ADH) to convert ethanol to acetaldehyde inside cancer cells has been investigated in vitro and in vivo. In vitro experiments confirmed the toxicity of acetaldehyde to a number of tumour cell lines. Daudi lymphoma cells grown in normal media increased by Day 4 to 650% of their starting number, while those exposed to 250 microM, 500 microM and 1 mM acetaldehyde reached 138, 30 and 5% respectively. Adenocarcinoma cells appeared to be less sensitive with CMT-64 cells and HeLa cells numbering 105 and 53% of their starting number by Day 4 with 1 mM acetaldehyde. After transduction with an adenovirus containing the human ADH beta 2 cDNA, CMT-64 cells exposed to 20 mM ethanol had a reduction in number to 74% by Day 2 and to 36% by Day 4. In a preclinical model with Ad-ADH CMT-64 cells, mice exposed to daily pulses of ethanol for 5 days formed tumours only 30% on Day 6 and 42% on Day 13 of the volume of those in mice exposed to water. The ability of this easily administered suicide gene system to produce significant effects on cell proliferation in vivo suggests that further optimized development is warranted.

Acetaldehyde↗
PubMed2003

Novel immunocompetent murine tumor models for the assessment of replication-competent oncolytic adenovirus efficacy.

Oncolytic replication-selective adenoviruses constitute a rapidly expanding experimental approach to the treatment of cancer. However, due to the lack of an immunocompetent and replication-competent efficacy model, the role of the host immune response and viral E3 immunoregulatory genes remained unknown. We screened nine murine carcinoma lines for adenovirus (Ad5) uptake, gene expression, replication, and cytopathic effects. In seven of these murine cell lines the infectability and cytopathic effects were similar to those seen with human carcinoma lines. Surprisingly, productive viral replication was demonstrated in several lines; replication varied from levels similar to those for some human carcinoma lines (e.g., CMT-64) to very low levels. Seven of these lines were grown as subcutaneous xenografts in immunocompetent mice and were subsequently injected directly with Ad5, saline, or a replication-deficient control adenovirus particle to assess intratumoral viral gene expression, replication, and antitumoral effects. E1A, coat protein expression, and cytopathic effects were documented in five xenografts; Ad5 replication was demonstrated in CMT-64 and JC xenografts. Ad5 demonstrated significant efficacy compared to saline and nonreplicating control Ad particles in both replication-permissive xenografts (CMT-64, JC) and poorly permissive tumors (CMT-93); efficacy against CMT-93 tumors was significantly greater in immunocompetent mice compared to athymic mice. These murine tumor xenograft models have potential for elucidating viral and host immune mechanisms involved in oncolytic adenovirus antitumoral effects.

Adenoviridae↗
PubMed2002

Oncolytic biotherapy: a novel therapeutic plafform.

There is a clear need for new, selective, cancer treatments that do not cause the cross-resistance which occurs with currently available chemotherapeutic agents. Gene therapy is a promising approach, but to date, it has shown limited effectiveness in clinical trials because of insufficient gene transduction. Many investigators are now revisiting the 'old' idea of using tumour-specific, replication-selective viruses or bacteria to treat cancer. These agents can be directly oncolytic, but can also be used to simultaneously express therapeutic genes in target cells or induce tumour-specific, cell-mediated immunity. We discuss the promise of this rapidly evolving field and examine the potential barriers to its success.

Adenoviridae↗