A phase II clinical trial of neoadjuvant ketoconazole and docetaxel chemotherapy before radical prostatectomy in high risk patients.

PURPOSE: Patients with high risk prostate cancer (prostate specific antigen greater than 20 ng/ml, Gleason score greater than 7, or clinical stage T2b or greater) have been shown to have a 30% to 40% biochemical recurrence rate after definitive local therapy. Looking for improvement on these outcomes, we conducted a phase II clinical trial examining the combination of ketoconazole and docetaxel in the neoadjuvant setting before radical prostatectomy. MATERIALS AND METHODS: A total of 22 patients with clinically localized, high risk prostate cancer were enrolled in the study. For 12 weeks they were treated with neoadjuvant docetaxel and ketoconazole, with dosing based on phase I data. Patients were monitored for tolerance of therapy and dosing adjustments were made for significant toxicities. Radical prostatectomy with extended lymph node dissection was subsequently performed and patients were followed postoperatively for biochemical recurrence. RESULTS: At a median followup of 18 months 8 patients remained biochemically free of recurrence after surgery alone. An additional 6 patients received salvage therapy and had an undetectable prostate specific antigen. Of the 22 patients 16 experienced National Cancer Institute grade 3 or 4 toxicity at some point during the therapy. However, 16 patients completed all 4 cycles of chemotherapy. CONCLUSIONS: Neoadjuvant ketoconazole combined with docetaxel has appreciable but acceptable toxicity with 73% of the patients completing all 4 courses of therapy. Of those who underwent radical prostatectomy 36% remained continuously biochemically free of recurrence at a median followup of 18 months.

Dopamine alleviation of diaphragm contractile dysfunction and reduction of deoxyribonucleic acid damage in rats.

BACKGROUND: Weaning difficulties from mechanical ventilation are associated with diaphragm fatigue and reduced respiratory muscle endurance capacity. Often the work of breathing is increased during the weaning process as a result of inspiratory resistance loading (IRL). IRL produces increased free radical formation that contributes to deoxyribonucleic acid (DNA) damage. The purpose of this study was to determine whether dopamine reduced nuclei DNA damage when the work of breathing was increased. We hypothesized that the administration of low-dose dopamine (2 microg/kg/min) during IRL decreases myonuclei DNA damage associated with free radical formation. METHODS: In this in vivo study, 30 male Sprague-Dawley rats were divided into three groups: (1) the sham group receiving no IRL or no intravenous fluids, (2) IRL with administration intravenous saline, and (3) IRL with intravenous low-dose dopamine (2 microg/kg/min). All rats from the same breed and similar colonies were purchased from one laboratory facility to ensure homogeneity. The animals were anesthetized and tracheotomized, and an ultrasonic sensor was attached to the right hemidiaphragm to measure diaphragm shortening. Diaphragm fatigue was produced by IRL. Dopamine (2 microg/kg/min) was infused intravenously before and during loading. The diaphragms were excised, and myonuclei DNA damage was measured using the fluorescent dyes ethidium bromide and acridine orange and comet analyses as indices of free radical injury. RESULTS: In rats receiving saline, diaphragm shortening decreased by 37% after 45 minutes of IRL (P = .002) compared with baseline. In contrast, rats infused with dopamine exhibited a 31% increase in diaphragm shortening after 45 minutes of IRL (P = .037). With the use of differential dye uptake, in the saline group 59% of the nuclei were apoptotic, and 18% were necrotic. However, in the dopamine group there was significantly less apoptotic nuclei (16%, P < .001) and necrotic nuclei (7%, P = .005). Myonuclei DNA damage, measured by comet analyses, was associated with tail length and tail olive moment, which were 37% and 60% greater, respectively, in the saline group than in the dopamine group (P < .05). CONCLUSION: These data support the hypothesis that low-dose dopamine during IRL reduced myonuclei DNA damage as measured by the fluorescent dyes and comet analysis. In addition, diaphragm fatigue was prevented by the administration of dopamine during IRL.