James Forde

Docetaxel maintains its cytotoxic activity under hypoxic conditions in prostate cancer cells

OBJECTIVE The efficacy of docetaxel has recently been shown to be increased under hypoxic conditions through the down-regulation of hypoxia-inducible-factor 1α (HIF1A). Overexpression of the hypoxia-responsive gene class III β-tubulin (TUBB3) has been associated with docetaxel resistance in a number of cancer models. We propose that administration of docetaxel to prostate patients has the potential to reduce the hypoxic response through HIF1A down-regulation and that TUBB3 down-regulation participates in sensitivity to docetaxel. METHODS The cytotoxic effect of docetaxel was determined in both 22Rv1 and DU145 prostate cancer cell lines and correlated with HIF1A expression levels under aerobic and hypoxic conditions. Hypoxia-induced chemoresistance was investigated in a pair of isogenic docetaxel-resistant PC3 cell lines. Basal and hypoxia-induced TUBB3 gene expression levels were determined and correlated with methylation status at the HIF1A binding site. RESULTS Prostate cancer cells were sensitive to docetaxel under both aerobic and hypoxic conditions. Hypoxic cytotoxicity of docetaxel was consistent with a reduction in detected HIF1A levels. Sensitivity correlated with reduced basal and hypoxia-induced HIF1A and TUBB3 expression levels. The TUBB3 HIF1A binding site was hypermethylated in prostate cell lines and tumor specimens, which may exclude transcription factor binding and induction of TUBB3 expression. However, acquired docetaxel resistance was not associated with TUBB3 overexpression. CONCLUSION These data suggest that the hypoxic nature of a tumor may have relevance as regard to their response to docetaxel. Further investigation into the nature of this relationship may allow identification of novel targets to improve tumor control in prostate cancer patients.

Standardization of assay methods reduces variability of total PSA measurements: an Irish study

Study Type – Diagnosis (quality control)

Microtubule-targeting-compound PBOX-15 radiosensitizes cancer cells in vitro

Background We proposed to investigate the radiosensitizing properties of PBOX-15, a novel microtubule-disrupting agent, in a panel of cancer cell lines. Results PBOX-15 treatment was associated with significant cell kill and increased radiosensitivity in all three cell lines tested. The number of surviving cells in response to the combined treatment was significantly less than PBOX -15 alone in 22Rv1 cells. In these cells, radiosensitisation correlated with induction of G2/M cell cycle arrest by PBOX-15. The compound sustained its activity and increased HIF-1Α expression under hypoxic conditions. PBOX-15 prevented onset of hypoxia-induced radioresistance in hypoxic prostate cells and reduced the surviving fraction of irradiated hypoxic cells to levels similar to those achieved under aerobic conditions. Methods Clonogenic assays were used to determine sensitivity of a panel of cancer cell lines (22Rv1, A549, U87) to PBOX-15 alone or in combination with a single 2Gy dose fraction. Induction of cell cycle arrest and apoptosis was investigated in 22Rv1 prostate cancer cells. The cytotoxic properties of the compound under hypoxic conditions were correlated with Hypoxia Inducible Factor 1 alpha (HIF-1Α) gene and protein expression levels and its radiosensitisation potential was investigated in hypoxic 22Rv1 using clonogenic assays. Conclusions This preliminary data identifies the potential of PBOX-15 as a novel radiosensitising agent for the management of solid tumours and eradication of hypoxic cells.

MP42-15 TREATMENT OF SYMPTOMATIC BENIGN PROSTATIC HYPERPLASIA IN PATIENTS OVER 80 YEARS OLD USING 180W HIGH POWER 532NM LASER VAPORIZATION-ENUCLEATION TECHNIQUE

INTRODUCTION AND OBJECTIVES: GreenLight Laser is a safe and efficacious treatment for benign prostatic hyperplasia (BPH). There is limited evidence on its use in very large prostates, for which simple prostatectomy is the traditional procedure. The objective of this study is to demonstrate the safety and efficacy of 180W high power 532 nm laser vaporization-enucleation prostatectomy in prostates measuring over 150cc. METHODS: We performed a retrospective chart analysis of all patients treated with the GreenLight XPS-180W system (AMS, MN, USA) in our institution from Sep 2011 to Oct 2015 with a prostate measuring over 150 cc on transrectal ultrasound preoperatively. Data collected include prostate volume, IPSS and quality of life (QoL) scores, maximum urinary flow rate (Qmax), postvoid residual (PVR), prostate specific antigen (PSA), complications, and reintervention rates. Statistical analysis was performed using SPSS (version 21). All procedures were performed by the same surgeon using a vaporization-enucleation technique that provides tissue for histologic analysis. RESULTS: We included 70 male patients with a total of 72 procedures. The median prostate size was 203 cc (152-376cc). There were 42 patients (58%) with an indwelling catheter preoperatively. Using the ASA physical status classification system, 37 patients were ASA class 2 and 33 were ASA class 3. Median operative time was 180 minutes, laser time 97 minutes, energy utilization 674kJ, and energy density 3.3kJ/cc, with a median 3 fibers used per case. Median length of stay and length of catheterization were both one day. IPSS and QoL scores demonstrated significant improvements at 6, 12, and 24 months postoperatively. Qmax and PVR, measured at 6 and 12 months postoperatively, were also significantly improved (Table 1). All patients had prostate tissue resected with BPH present in all specimens. One patient required a long-term indwelling catheter for refractory urinary retention. Two patients (2.9%) required retreatment with a second PVP procedure. CONCLUSIONS: In our experience, high-power 532 nm laser vaporization-enucleation prostatectomy provides excellent and durable subjective and objective improvements in symptoms and voiding parameters, regardless of prostate size.