Chemosensitization of carmustine with maitake beta-glucan on androgen-independent prostatic cancer cells: involvement of glyoxalase I.

OBJECTIVE: To improve the poor efficacy (< 10%) of chemotherapy for patients with hormone-refractory prostate cancer, we investigated a possible cytotoxic effect of carmustine/beta-glucan combination on prostatic cancer PC-3 cells, focusing on a glutathione-dependent detoxifying enzyme, glyoxalase I (Gly-I). METHODS: Carmustine (BCNU) is an anticancer agent and a putative inhibitor of Gly-I, while beta-glucan is a unique, nontoxic polysaccharide extracted from maitake mushrooms. The cytotoxic effects of BCNU or other anticancer agents with beta-glucan on PC-3 cells were assessed by cell-viability testing and Gly-I activity was measured using the spectrophotometric method. RESULTS: BCNU, 5-fluorouracil (5-FU), and methotrexate (MTX) were capable of inducing approximately a 50% reduction in cell viability at 72 hours, while etoposide, cisplatin, and mitomycin C were all ineffective. Only the combination of BCNU (50 micro ;mol) and beta-glucan (60 micro g/mL) exhibited an enhanced cytotoxicity with an approximate 90% cell viability reduction, but little improvement was seen with any combinations of 5-FU, MTX, or beta-glucon. Gly-I assays revealed that such a profound (approximately 90%) cell death was accompanied by an approximate 80% reduction in Gly-I activity by 6 hours. CONCLUSION: This study demonstrates a sensitized cytotoxic effect of BCNU with beta-glucan in PC-3 cells, which was associated with a drastic (approximately 80%) inactivation of Gly-I. Therefore, the BCNU/beta-glucan combination may help to improve current treatment efficacy by targeting Gly-I, which appears to be critically involved in prostate cancer viability.

Salvage extracorporeal shockwave lithotripsy after failed distal ureteroscopy.

BACKGROUND AND PURPOSE: When intervention is necessary, controversy remains as to the best treatment modality for stones of the distal ureter. In general, ureteroscopy is favored over extracorporeal shockwave lithotripsy (SWL) as the treatment of choice for distal ureteral stones. Although uncommon, ureteroscopy failures have traditionally necessitated repeat ureteroscopy to retrieve retained stone fragments. We evaluated the efficacy of salvage SWL for failed primary distal ureteroscopy in the community setting. PATIENTS AND METHODS: From December 1989 to December 2000, 6099 patients underwent SWL with the Dornier HM4 lithotripter at our institution. We retrospectively identified 31 patients who had undergone the SWL after a failed distal ureteroscopy. RESULTS: The average stone size in these patients was 9.4 mm, the average time interval from ureteroscopy to SWL was 17.2 days, and the average number of shockwaves delivered was 2386. All patients had had stents placed after ureteroscopy. Twenty-seven patients (87%) had resolution of their stone burden after one SWL session. The remaining four patients underwent additional procedures. CONCLUSIONS: Ureteroscopy is an effective modality for the treatment of distal ureteral stones. However, when unsuccessful, a salvage procedure may be necessary. Extracorporeal lithotripsy is a less invasive procedure with comparable success rates in the distal ureter. This report suggests that salvage SWL is an appropriate option for patients in whom distal ureteroscopic stone extraction fails.

A possible regulatory role of glyoxalase I in cell viability of human prostate cancer.

A role of glyoxalase I (Gly-I), a detoxifying enzyme, in cell viability of prostate cancer was investigated. Cell extracts obtained from 66 prostate tissue specimens and prostatic cancer PC-3 cells were assayed for Gly-I activity using the spectrophotometric method. Gly-I activity was consistently more than eightfold higher in prostate cancer (CAP) specimens (n = 37) than in non-cancerous (NCP) specimens (n = 29). To understand the importance of such a high Gly-I activity in CAP specimens, the effects of methylglyoxal (MG) on PC-3 cells were examined in vitro. MG, a putative toxic glycolytic metabolite, was capable of inducing severe (> 99%) cell death in 24 h, along with a significant reduction in activities of Gly-I as well as glyceraldehyde 3-phosphate dehydrogenase (G3PDH), a key glycolytic enzyme. However, such severe cell death was effectively (approximately 85%) prevented with N-acetylcysteine (NAC), a precursor of reduced glutathione (GSH) that is an essential cofactor for Gly-I, accompanied by the intact Gly-I and G3PDH activities. Therefore, Gly-I may play a critical detoxifying role in glycolysis to maintain cellular activity and viability of prostatic cancer cells.