A phase I trial of CV706, a replication-competent, PSA selective oncolytic adenovirus, for the treatment of locally recurrent prostate cancer following radiation therapy.

CV706 is a prostate-specific antigen (PSA)-selective, replication-competent adenovirus that has been shown to selectively kill human prostate cancer xenografts in preclinical models. To study the safety and activity of intraprostatic delivery of CV706, a Phase I dose-ranging study for the treatment of patients with locally recurrent prostate cancer after radiation therapy was conducted. Twenty patients in five groups were treated with between 1 x 10(11) and 1 x 10(13) viral particles delivered by a real-time, transrectal ultrasound-guided transperineal technique using a three-dimensional plan. The primary end point was the determination of treatment-related toxicity. Secondary objectives included evaluation of the antitumor activity of CV706 and monitoring for other correlates of antineoplastic action. In this study, CV706 was found to be safe and was not associated with irreversible grade 3 or any grade 4 toxicity. No grade >1 alterations in liver function tests associated with CV706 administration were observed. Posttreatment prostatic biopsies and detection of a delayed "peak" of circulating copies of virus provided evidence of intraprostatic replication of CV706. The study defined the timing of CV706 shedding into blood and urine as well as the appearance of circulating Ad5 neutralizing antibodies. Finally, this study documents the serum PSA response of treated patients and reveals a dose response showing that all five patients who achieved a > or =50% reduction in PSA were treated with the highest two doses of CV706. This study represents the first clinical translation of a prostate-specific, replication-restricted adenovirus for the treatment of prostate cancer. Taken together, this study documents that intraprostatic delivery of CV706 can be safely administered to patients, even at high doses, and the data also suggest that CV706 possesses enough clinical activity, as reflected by changes in serum PSA, to warrant additional clinical and laboratory investigation.

A simple and accurate coordinate transformation for a stereotactic radiotherapy system.

A global registration algorithm using only two CT slices was developed to transform target points known in the Brown-Roberts-Wells frame back to a CT-simulator coordinate system. The algorithm uses exact solutions to determine all of the points of interest based on BRW pins in the two CT-slices. In comparison with the algorithms based on individual slices, there is no requirement of digitization of BRW pins in every CT slice. There is no approximation (or linear interpolation) for determination of the target points that fell in between two CT slices. Results in 60 clinical cases demonstrate that the accuracy and precision of the isocentric positions are within the digitization uncertainty. Application of this global image registration can simplify the coordinate transformation in stereotactic radiation therapy.

Formation of o-tyrosine and dityrosine in proteins during radiolytic and metal-catalyzed oxidation.

To evaluate their usefulness as chemical indicators of cumulative oxidative damage to proteins, we studied the kinetics and extent of formation of ortho-tyrosine (o-Tyr), dityrosine (DT), and dityrosine-like fluorescence (Ex = 317 nm, Em = 407 nm) in the model proteins RNase and lysozyme exposed to radiolytic and metal-catalyzed (H2O2/Cu2+) oxidation (MCO). Although there were protein-dependent differences, o-Tyr, DT, and fluorescence increased coordinately during oxidation of the proteins in both oxidation systems. The contribution of DT to total dityrosine-like fluorescence in oxidized proteins varied from 2-100%, depending on the protein, type of oxidation, and extent of oxidative damage. In proteins exposed to MCO, DT typically accounted for > 50% of the fluorescence at DT wavelengths. These studies indicate that o-Tyr and DT should be useful chemical markers of cumulative exposure of proteins to MCO in vitro and in vivo.

Correlation of mechanical properties of vertebral trabecular bone with equivalent mineral density as measured by computed tomography.

We tried to determine whether mineral-equivalent measurements that were obtained using computed tomography could be used to predict the mechanical properties of vertebral trabecular bone. Vertebral bodies that had been obtained during routine autopsy were evaluated by computed tomography. The mechanical properties of the vertebral trabecular bone were determined by subjecting cylindrical specimens to simple compression until failure occurred. The ultimate strength and elastic modulus were determined from load time curves, using constant displacement rate loading. Atomic absorption spectrophotometry was used to determine the weight per cent calcium of each specimen, and quantitative light microscopy was used to determine area fraction bone. Significant positive correlations were found between the observed mechanical properties of the trabecular bone and the equivalent mineral density as measured by computed tomography. Compressive strength (r = 0.720), elastic modulus (r = 0.574), trabecular calcium density (r = 0.780), and area fraction bone (r = 0.579) were all correlated with the equivalent mineral density.

Performance of a gas target neutron source for radiotherapy.

The performance of a compact and efficient neutron generator, using the 3H(d, n) reaction and a gas target, is reported. The target is formed in a windowless, differentially pumped vessel pressurised to 7.5 Torr. An extended source of 15 MeV neutrons is produced when the target is bombarded by a 10 mA beam of 210 keV deuterons. Measurements are reported of the neutron energy spectra, neutron and gamma-ray dose rates, target lifetime and tritium handling. The neutron flux distribution of the extended target was measured and compared with the predictions of a simple beam-gas interaction model. The measured neutron source strength is 1.7 +/- 0.4 X 10(12) neutrons per second. The source output is limited by target beam current, not target power considerations.