Preclinical development of non-viral gene therapy for patients with advanced pancreatic cancer.

Pancreatic cancer remains one of the greatest challenges in oncology for which therapeutic intervention is urgently needed. We previously demonstrated that the intra-tumoral gene transfer of somatostatin receptor 2, to combat tumor aggressiveness, or of deoxycytidine kinase and uridylate monophosphate kinase, to sensitize to gemcitabine chemotherapy, has anti-tumoral potential in experimental models of cancer. Here, we describe the development of the CYL-02 non-viral gene therapy product that comprises a DNA-plasmid encoding for the three aforementioned genes, which expression is targeted to tumor cells, and complexed with polyethyleneimine non-viral vector.

First-in-man phase 1 clinical trial of gene therapy for advanced pancreatic cancer: safety, biodistribution, and preliminary clinical findings.

This phase 1 trial was aimed to determine the safety, pharmacokinetics, and preliminary clinical activity of CYL-02, a nonviral gene therapy product that sensitizes pancreatic cancer cells to chemotherapy. CYL-02 was administrated using endoscopic ultrasound in 22 patients with pancreatic cancer that concomitantly received chemotherapy (gemcitabine). The maximum-tolerated dose (MTD) exceeded the maximal feasible dose of CYL-02 and was not identified.

Inhibition of Na,K-ATPase by external electrical cardioversion in a sheep model of atrial fibrillation.

Introduction: Electrical external cardioversion commonly used to treat atrial fibrillation (AF) is associated with myocardial membrane damage and disturbances in ionic homeostasis (hemodynamically unstable). The present study was designed to investigate whether alterations in ionic homeostasis observed were due in part to changes in the myocardial activity of Na,K-ATPase.

Methods And Results: AF was induced by pacing in ten anesthetized sheep divided into two groups.

Specific up-regulation of mitochondrial F0F1-ATPase activity after short episodes of atrial fibrillation in sheep.

Introduction: Ventricular fibrillation induced by either digitalis intoxication or electrical stimulation is reported to alter myocardial energy by impairing the sarcolemmal Na,K-ATPase or the receptor for digitalis and the mitochondrial ATPase synthase or F0F1-ATPase. However, little is known about these membrane functions during atrial fibrillation (AF).

Methods And Results: We analyzed the effects of electrically induced AF on biochemical activities of atrial F0F1-ATPase and Na,K-ATPase in sheep.

Dietary fish oil promotes positive inotropy of ouabain in the rat heart.

We tested the hypothesis that a fish oil (FO) diet promotes positive inotropy of ouabain without increased toxicity. For 2 mo, two groups of adult male rats were fed 1) a regular food diet supplemented with dietary long-chain polyunsaturated fatty acid from FO or 2) a regular food diet (control). The responsiveness to ouabain was evaluated for the two groups in Langendorff-perfused hearts, by (31)P nuclear magnetic resonance spectroscopy, and on purified membrane-bound Na-K-ATPase.