Objective To investigate the incidence of bone fractures in patients receiving luteinizing hormone-releasing hormone agonists (LHRH-a) for prostate cancer (in whom a continued low testosterone level after the long-term administration of these drugs reduces bone mineral density), and thus determine the risk of secondary osteoporosis. Between 1994 and 1999, 218 patients (mean age 77.3 years) were treated for o 6 months with LHRH-a for prostate cancer; of these, 14 (6%) had a bone fracture during their treatment. Patients with fracture associated with motor vehicle accidents were excluded. The bone density in the third lumbar vertebra was measured using quantitative computed tomography. Osteocalcin, 1,25-(OH) 2 vitamin D, urinary type 1 collagen cross-linked N-telopeptides (NTx), parathyroid hormone and calcitonin were measured as metabolic markers. Results The mean age of the patients with fracture was 78 years; the mean (range) interval from the start of treatment to fracture was 28 (11±46) months. There was no case of a bone fracture at the site of a metastasis from prostate cancer. The bone density was signi®cantly lower in the patients with a fracture than in those without. Of the bone metabolic markers, NTx was higher in those with a fracture. Conclusion There is a need to measure bone mineral density and bone metabolic markers periodically, and to evaluate secondary osteoporosis in patients receiving long-term LHRH-a for prostate cancer.
Patients and methods
A conjugate of doxorubicin and glutathione via glutaraldehyde (GSH-DXR) inhibited glutathione S-transferase (GST) activity of rat hepatoma AH66 cells, and treatment of the cells with GSH-DXR induced caspase-3 activation and DNA fragmentation. After treatment of AH66 cells with 0.1 M GSH-DXR, GST-P (placental type of rat GST isozymes) mRNA and its protein increased transiently and then decreased thereafter compared with the levels in nontreated cells. Caspase-3 activation and DNA fragmentation were induced following the suppression of GST-P expression by treatment with GSH-DXR. When the cells were treated with 100 M ethacrynic acid (ECA), an inhibitor of GST, DNA fragmentation and caspase-3 activation were observed. In contrast, treatment of AH66 cells with a low concentration of ECA (1 M) that showed little inhibition of GST activity induced slight, but significantly enhanced expression and activity of GST-P, and consequent prevention of DXR-and GSH-DXR-induced DNA fragmentation. Overexpression of GST-(placental type of human GST isozymes) by transfection of GST-sense cDNA into AH66 cells decreased sensitivities to DXR and GSH-DXR, and the suppression of GST-P by transfection of the antisense cDNA into the cells increased drug sensitivity. On the other hand, there was little change in drug sensitivity caused by overexpression of site-directedly mutated GST-P in which the active-site residue Tyr39 was replaced with His (W39H) or the substrate-binding site residue Cys48 was replaced with Ser (C48S) by transfection of those cDNAs into AH66 cells. These results suggested that the suppression of GST-P in AH66 cells treated with GSH-DXR must play an important role in the induction of apoptosis.
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