Inverse correlation of epidermal growth factor receptor messenger RNA induction and suppression of anchorage-independent growth by OSI-774, an epidermal growth factor receptor tyrosine kinase inhibitor, in glioblastoma multiforme cell lines.

OBJECT: Quantitative and qualitative alterations in the epidermal growth factor receptor (EGFR) commonly occur in many cancers in humans, including malignant gliomas. The aim of the current study was to evaluate molecular and cellular effects of OSI-774, a novel EGFR tyrosine kinase inhibitor, on nine glioblastoma multiforme (GBM) cell lines. METHODS: The effects of OSI-774 on expression of EGFR messenger (m)RNA and protein, proliferation, anchorage-independent growth, and apoptosis were examined using semiquantitative reverse transcription-polymerase chain reaction, immunocytochemical analysis, Coulter counting, soft agar cloning, and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling/fluorescence-activated cell sorting, respectively. All p53 genes were completely and bidirectionally sequenced. Suppression of anchorage-independent growth by OSI-774 was inversely correlated to the induction of EGFR mRNA during relative serum starvation (r = -0.74) and was unrelated to p53 status. Overall, suppression of anchorage-independent growth was a considerably stronger effect of OSI-774 than inhibition of proliferation. The extent of OSI-774-induced apoptosis positively correlated with both proliferation and anchorage-independent growth of GBM cell lines (r = 0.75 and 0.79, respectively). In a single cell line derived from a secondary GBM, exposure to concentrations of greater than or equal to 1 micromol/L resulted in a substantial net cell loss during proliferation studies. CONCLUSIONS: The induction of EGFR mRNA may constitute a cellular mechanism to counteract the inhibitory effect of OSI-774 on the anchorage-independent growth of GBM cells. In contrast, no considerable correlation could be established between baseline expression levels of EGFR (both mRNA and protein) in GBM cell lines and their biological response to OSI-774. The OSI-774 induced greater (p53-independent) apoptosis in more malignant GBM phenotypes and may be a promising therapeutic agent against secondary GBM.

Subthreshold test pulses versus low energy shock delivery to estimate high energy lead impedance in implanted cardioverter defibrillator patients.

The high energy lead impedance is valuable for detecting lead failure in ICDs, but until recently shock delivery was necessary for high energy impedance measurement. This study compared the use of subthreshold test pulses and low energy test shocks to estimate the high energy impedance. Immediately after implantation of Ventak Prizm ICDs in 29 patients, the lead impedance was measured with five subthreshold (0.4 microJ) test pulses, 5 low energy (1.1 J) shocks, and two to three high energy (16 +/- 4.5 J) shocks. The mean impedances measured using high energy shocks, low energy shocks, and subthreshold pulses were 42.0 +/- 7.3 omega, 46.5 +/- 8.1 omega, and 42.4 +/- 7.1 omega, respectively. The impedances measured using high and low energy shocks differed significantly (P < 0.0001), while those obtained by high energy shocks and low energy pulses did not (P = 0.63). According to the Pearson correlation coefficient, the impedance measurements with subthreshold pulses and low energy shocks were both closely correlated (P < 0.0001) with impedance values determined with high energy shocks. However, while the impedance values tended to be higher when measured with low energy shocks, the concordance correlation coefficient (c) was higher for subthreshold test pulse versus high energy shock (c = 0.92) than for low versus high energy shock (c = 0.73). Furthermore, the intraindividual variability of impedance measurements was lower with subthreshold pulse measurements than with low energy shocks. Compared with low energy shocks, impedance measurement with subthreshold pulses has higher reproducibility and a higher correlation with the impedance obtained by high energy shock delivery. Safe and painless high energy impedance estimation with subthreshold pulses might, therefore, help to detect ICD lead failure during routine follow-up.