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R C Rintoul

Publications and source records attributed to R C Rintoul.

8 recordsLinked to original sources
PubMed2006

ECM overrides DNA damage-induced cell cycle arrest and apoptosis in small-cell lung cancer cells through beta1 integrin-dependent activation of PI3-kinase.

The emergence of resistance to chemotherapy remains a principle problem in the treatment of small-cell lung cancer (SCLC). We demonstrate that extracellular matrix (ECM) activates phosphatidyl inositol 3-kinase (PI3-kinase) signaling in SCLC cells and prevents etoposide-induced caspase-3 activation and subsequent apoptosis in a beta1 integrin/PI3-kinase-dependent manner. Crucially we show that etoposide and radiation induce G2/M cell cycle arrest in SCLC cells prior to apoptosis and that ECM prevents this by overriding the upregulation of p21(Cip1/WAF1) and p27(Kip1) and the downregulation of cyclins E, A and B. These effects are abrogated by pharmacological and genetic inhibition of PI3-kinase signaling. Importantly we show that chemoprotection is not mediated by altered SCLC cell proliferation or DNA repair. Thus, ECM via beta1 integrin-mediated PI3-kinase activation overrides treatment-induced cell cycle arrest and apoptosis, allowing SCLC cells to survive with persistent DNA damage, providing a model to account for the emergence of acquired drug resistance.

Antineoplastic Agents↗
PubMed2005

Endobronchial and endoscopic ultrasound-guided real-time fine-needle aspiration for mediastinal staging.

Accurate staging of the mediastinum in lung cancer is essential for optimising treatment strategies. Conventional transbronchial needle aspiration (TBNA) is a blind procedure, reliant upon prior computed tomography (CT) or ultrasound imaging, but has low sensitivity. The current study reports the initial experience of using a prototype endobronchial ultrasound (EBUS) probe that allows TBNA under real-time imaging. In 20 patients selected by CT scanning, a linear-array ultrasound bronchoscope was used to visualise paratracheal and hilar lymph nodes, and TBNA was performed under direct ultrasonic control. In seven cases, sequential endoscopic ultrasound (EUS) was used to assess postero-inferior mediastinal lymph nodes. All procedures were performed under conscious sedation. EBUS-TBNA was undertaken in 18 out of 20 cases and EUS-guided fine-needle aspiration in six out of seven cases. Cytology showed node (N)2/N3 disease in 11 out of 18 EBUS-TBNA cases and provided a primary diagnosis for eight patients. EBUS-TBNA cytology was negative in six cases, which was confirmed by mediastinoscopy or clinical follow-up in four. EUS provided additional information in all cases. There were no procedural complications. Sensitivity, specificity and accuracy for EBUS-TBNA were 85%, 100% and 89%, respectively. In conclusion, endobronchial ultrasound with real-time transbronchial needle aspiration offers improved sensitivity and accuracy for staging of the middle mediastinum, and, combined with endoscopic ultrasound, should allow investigation of the majority of the mediastinum.

Aged↗
PubMed2001

The role of extracellular matrix in small-cell lung cancer.

Lung cancer is the most common fatal malignant disease in the western world, accounting for 42,000 deaths each year in the UK alone. Small-cell lung cancer (SCLC), accounts for 25% of all lung cancers. It is a particularly aggressive form of the disease, characterised by widespread metastases and the development of resistance to chemotherapy. Even with combination chemotherapy and radiotherapy treatments, the 5-year survival is only about 5%. We review recent insights into the mechanisms underlying the development of metastases and resistance to chemotherapeutic agents in SCLC, focusing on the role of the extracellular matrix (ECM). We discuss the regulation of the interactions between cells and the ECM and the effects of these interactions on cellular phenotypes, together with some of the new approaches for combating drug resistance and metastases in this disease.

Carcinoma, Small Cell↗
PubMed2000

Phosphoinositide 3-kinase: a critical signalling event in pulmonary cells.

Phosphoinositide 3-kinases (PI-3Ks) are enzymes that generate lipid second messenger molecules, resulting in the activation of multiple intracellular signalling cascades. These events regulate a broad array of cellular responses including survival, activation, differentiation and proliferation and are now recognised to have a key role in a number of physiological and pathophysiological processes in the lung. PI-3Ks contribute to the pathogenesis of asthma by influencing the proliferation of airways smooth muscle and the recruitment of eosinophils, and affect the balance between the harmful and protective responses in pulmonary inflammation and infection by the modulation of granulocyte recruitment, activation and apoptosis. In addition they also seem to exert a critical influence on the malignant phenotype of small cell lung cancer. PI-3K isoforms and their downstream targets thus provide novel therapeutic targets for intervention in a broad spectrum of respiratory diseases.

Animals↗
PubMed1999

Extracellular matrix proteins protect small cell lung cancer cells against apoptosis: a mechanism for small cell lung cancer growth and drug resistance in vivo.

Resistance to chemotherapy is a principal problem in the treatment of small cell lung cancer (SCLC). We show here that SCLC is surrounded by an extensive stroma of extracellular matrix (ECM) at both primary and metastatic sites. Adhesion of SCLC cells to ECM enhances tumorigenicity and confers resistance to chemotherapeutic agents as a result of beta1 integrin-stimulated tyrosine kinase activation suppressing chemotherapy-induced apoptosis. SCLC may create a specialized microenvironment, and the survival of cells bound to ECM could explain the partial responses and local recurrence of SCLC often seen clinically after chemotherapy. Strategies based on blocking beta1 integrin-mediated survival signals may represent a new therapeutic approach to improve the response to chemotherapy in SCLC.

Amino Acid Chloromethyl Ketones↗
PubMed1998

The presence of a constitutively active phosphoinositide 3-kinase in small cell lung cancer cells mediates anchorage-independent proliferation via a protein kinase B and p70s6k-dependent pathway.

Small cell lung cancer (SCLC) is characterized by early and widespread metastases. Anchorage-independent growth is pivotal to the ability of tumor cells to survive and metastasize in vivo and, under in vitro conditions, allows transformed cells to form colonies in semisolid medium. Here, we report that of five SCLC cell lines tested, all exhibited high basal constitutive phosphoinositide 3-kinase (PI 3-kinase) activity, which results in high basal protein kinase B (PKB) and ribosomal p70 S6 kinase activity (p70s6k). Inhibition of PI 3-kinase activity markedly inhibited SCLC cell proliferation in liquid culture as a result of stimulating apoptosis and promoting cell cycle delay in G1. Furthermore, PI 3-kinase inhibition reduced basal SCLC cell colony formation in agarose semisolid medium that could not be overcome by the addition of neuropeptide growth factors. Thus, constitutive PI 3-kinase activity in SCLC cells plays an important role in promoting the growth and anchorage independence of SCLC. This is not due to activating ras mutations or increased basal src or focal adhesion kinase activity. These data represent the first description of constitutively activated PI 3-kinase/PKB in any human cancer. Constitutive activation of these integrin-dependent signaling events provides a molecular explanation for the anchorage-independent growth of SCLC cells and may account for the nonadherent phenotype and highly metastatic nature of this aggressive cancer. Up-regulation of the PI 3-kinase/PKB pathway may, therefore, represent a novel target for therapeutic intervention in SCLC.

Androstadienes↗