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Biotech / Medical : Oncolytics Biotech Inc. -- Ignore unavailable to you. Want to Upgrade?

To: blue_chip who wrote (12)	7/7/2000 11:19:28 AM
From: Biomaven	Read Replies (1) \| Respond to of 103

Reovirus in rat bladder cancer: NOVEL VIRAL ONCOLYTIC THERAPY OF SUPERFICIAL BLADDER CANCER IN AN ANIMAL MODEL: A COMPARITIVE STUDY TO BCG. E. Hanel, P. Lee, U. Kosecka, and R. Wittes, and R.B. Moore Cross Cancer Institute, University of Alberta, Edmonton, Alberta Introduction: Superficial transitional cell carcinoma (TCC) of the bladder affects 5000 new patients annually in Canada. High grade multifocal TCC can progress to muscle invasive disease if left untreated (as high as 75%). Recurrence of TCC is high (80% within 5 years). Clinically, Bacillus Calmette-Guerin (BCG) intravesical immunotherapy combined with transurethral resection of the bladder tumor (TURBT) is the best treatment option for TCC. BCG is believed to be tumorcidal via indirect stimulation of the immune system. Combined therapy with interleukin-2 (IL-2) potentially increases efficacy. Not all patients respond to BCG, and there can be complications to BCG administration, including systemic and local infection. Recent virology studies have elucidated the mechanisms by which viruses can cause tumor cell specific oncolysis, especially mammalian reoviruses. Literature review show 50-100% of TCC cells express activated MAP and Ras/Raf kinase (M&R/RK) pathways, which are required for this selective lysis. We have conducted randomized studies of intravesical BCG, intravesical BCG combined with IL-2, and intravesical reovirus in an orthotopic TCC bladder tumor model. Methods: Fisher CDF344 rats (n=10/group) with orthotopic superificial AY-27 transitional cell cancer were randomized to the various treatment groups 14 days post tumor implant. Tumor establishment was confirmed by urine cytology. The agents were administered intravesically by a urethral catheter at 6-weekly intervals. Dose escalation was carried out for BCG (5X105, 5X106, 5X107 CFUs) and reovirus (5x105, 5x106, 5x107 PFUs). IL-2 dose was 1x106U. Animals were followed for 100 days except those exhibiting severe morbidity. Animal survival (Kaplan-Meier), tumor response, and potential side effects were quantified. Necropsy and histology were performed on all rats. Results: To date, reovirus has demonstrated better efficacy with fewer adverse outcomes. Mean survival for; control = 54 days, BCG (5x105) = 73 days, BCG (5x106) = 52 days, BCG (5x107) = 64 days, BCG (5X105) and IL-2 = 81 days, reo (5x105) = 96 days, and reo (5x106, 5x107) > 100 days. Significant toxicity was observed with high dose BCG with histological evidence of granulomatous cystitis and nephritis. Some animals appeared to have died tumor free, from obstructive uropathy. These findings were not observed in the reovirus treated groups. The only adverse outcome was bladder calculi. Conclusion: This preliminary data supports further investigation and potential phase I clinical trials. Currently primary human TCC cell cultures are being assayed for activated M&R/RK pathways and response to reovirus. Peter