Randomized, single-blind, placebo-controlled pilot study of catheter-based myocardial gene transfer for therapeutic angiogenesis using left ventricular electromechanical mapping in patients with chronic myocardial ischemia.

BACKGROUND: Catheter-based myocardial gene transfer (GTx) has not been previously tested in human subjects. Accordingly, we performed a pilot study to investigate the feasibility and safety of catheter-based myocardial GTx of naked plasmid DNA encoding vascular endothelial growth factor-2 (phVEGF-2) in patients with chronic myocardial ischemia. METHODS AND RESULTS: A steerable, deflectable 8F catheter incorporating a 27-guage needle was advanced percutaneously to the left ventricular myocardium of 6 patients with chronic myocardial ischemia. Patients were randomized (1:1) to receive phVEGF-2 (total dose, 200 microgram), which was administered as 6 injections into ischemic myocardium (total, 6.0 mL), or placebo (mock procedure). Injections were guided by NOGA left ventricular electromechanical mapping. Patients initially randomized to placebo became eligible for phVEGF-2 GTx if they had no clinical improvement 90 days after their initial procedure. Catheter injections (n=36) caused no changes in heart rate or blood pressure. No sustained ventricular arrhythmias, ECG evidence of infarction, or ventricular perforations were observed. phVEGF-2-transfected patients experienced reduced angina (before versus after GTx, 36.2+/-2.3 versus 3.5+/-1.2 episodes/week) and reduced nitroglycerin consumption (33.8+/-2.3 versus 4.1+/-1.5 tablets/week) for up to 360 days after GTx; reduced ischemia by electromechanical mapping (mean area of ischemia, 10.2+/-3.5 versus 2.8+/-1.6 cm(2), P=0.04); and improved myocardial perfusion by SPECT-sestamibi scanning for up to 90 days after GTx when compared with images obtained after control procedure. Conclusions-This randomized trial of catheter-based phVEGF-2 myocardial GTx provides preliminary indications regarding the feasibility, safety, and potential efficacy of percutaneous myocardial GTx to human left ventricular myocardium.

Allosteric effectors of hemoglobin as modulators of chemotherapy and radiation therapy in vitro and in vivo.

INTRODUCTION: A series of molecules designed to be allosteric effectors of hemoglobin were examined for their potential as radiation sensitizers in vitro and in vivo and for their potential as chemosensitizers in vivo as well as for their antimetastatic effect. RESULTS: At a concentration of 100 microM for 1 h prior to, during and for 1.5 h after radiation exposure, the allosteric effectors decreased the shoulder of the radiation survival curve of normally oxygenated EMT-6 cells and increased the slope of the radiation survival curves of hypoxic EMT-6 cells resulting in dose-modifying factors of 1.8 to 2.1. In vivo the allosteric effectors had antitumor activity against the Lewis lung carcinoma and produced primarily additive tumor growth delay when administered along with fractionated radiation therapy. When administered on days 4 through 18 after tumor implantation, the allosteric effectors, especially JP-7, RSR-13 and RSR-4, were highly effective antimetastatic agents in animals bearing Lewis lung carcinoma. In cell culture, simultaneous exposure to the allosteric effectors (at 100 microM) effectively sensitized EMT-6 cells to the effects of 4-hydroperoxycyclophosphamide, thiotepa and carboplatin. The allosteric effectors were not very cytotoxic toward EMT-6 tumor cells from tumors treated in vivo with single doses of each molecule nor were these agents very cytotoxic toward bone marrow CFU-GM taken from the same animals. CONCLUSIONS: It is likely that the allosteric effectors have a molecular target in addition to hemoglobin. Other possible targets include hydroxymethyl-glutaryl-CoA reductase or microsomal cytochrome b5.

Antitumor activity of creatine analogs produced by alterations in pancreatic hormones and glucose metabolism.

When rats bearing the 13,762 mammary carcinoma were treated with intravenously administered creatine analogs, cyclocreatine, beta-guanidinopropionic acid or creatine phosphate on days 4 through 8 and 14 through 18 post tumor implantation, the tumor growth delay produced varied with whether the animals were drinking water or sugar water over the course of the study. The tumor growth delays increased when the animals drank sugar water from 9.3, 1.6 and 7.6 days for cyclocreatine, beta-guanidinopropionic acid and creatine phosphate, respectively, to 15.0, 6.3 and 12.6 days. Blood glucose was decreased over the course of the creatine analog treatment regimen and the skeletal muscle transport protein GLUT-4 increased 1.5 to 2-fold with the creatine analog treatments. Plasma insulin was profoundly decreased to 20-25% of normal by the creatine analog treatment while plasma glucagon levels were increased. Plasma somatostatin increased 3- to 4-fold during the administration of the creatine analogs. These results implicate alterations in pancreatic hormone balance in the antitumor activity of these creatine analogs.