Role of plasminogen activator inhibitor-1 (PAI-1) levels in the diagnosis of BMT-associated hepatic veno-occlusive disease and monitoring of subsequent therapy with defibrotide (DF).

UNLABELLED: Hepatic veno-occlusive disease (VOD) is a common and potentially fatal complication of high dose chemotherapy with allogeneic/autologous stem cell transplant (SCT). The diagnosis and treatment of hepatic VOD is controversial. Clinical features are non-specific and may be mimicked by a number of other conditions causing hyperbilirubinaemia post-transplantation. Plasminogen activator inhibitor-1 (PAI-1) has been proposed as a specific marker of VOD [1]. Defibrotide (DF) is a polydeoxyribonucleotide, which has been found to have anti-thrombotic, anti-ischaemic and thrombolytic properties without causing significant anti-coagulation. Recent evidence [2,3] suggests that use of DF in patients with severe VOD results in a promising response rate without attributable significant toxicity. Between January 1998 and July 1999, PAI-1 levels were measured serially in 16 patients undergoing SCT who had subsequently developed hyperbilirubinaemia. Diagnosis of VOD was made by established clinical criteria [4,5]. At the time of diagnosis, PAI-1 levels (mean+/-SD) were significantly elevated in patients with VOD (90.7+/-47 ng/ml, n=7) when compared with patients with jaundice from other causes post transplantation (12.1+/-6.4 ng/ml, n=9). Five of the patients with VOD received treatment with DF. Four out of five patients showed an initial response to DF (significant fall in bilirubin and improvement in other signs/symptoms) with one of these patients having a complete response (bilirubin < 2.0 mg/dl and full resolution of signs/symptoms and end-organ toxicity). Following treatment with DF, a corresponding fall in PAI-1 levels was noted in those responding, with non-responders maintaining raised levels. CONCLUSION: Raised PAI-1 levels post stem cell transplant are specific for VOD and a subsequent decrease in levels following treatment with DF may be associated with response to treatment.

Allogeneic whole-cell vaccine: a phase I/II study in men with hormone-refractory prostate cancer.

OBJECTIVE: To establish the safety and toxicity of an allogeneic human tumour cell vaccine in patients with hormone-refractory prostate cancer, and to determine any biochemical, immunological or clinical response to vaccination. PATIENTS AND METHODS: Sixty patients with hormone-refractory prostate cancer were recruited and randomly allocated into four equal groups. Three cell lines (from a bank of four) were administered initially every 2 weeks and then monthly, in conjunction with the immunostimulant Mycobacterium vaccae (SRL-172), each group receiving a different combination of the four cell lines. The patients' serum prostate-specific antigen (PSA) levels were monitored regularly, and the immune response to the vaccine measured using nonspecific intracellular cytokines and specific humoral and cell-mediated assays. RESULTS: The vaccine was safe and well tolerated with no major side-effects. Whilst several patients had a decline in PSA from the entry level, there was no significant decrease that could be attributed solely to the vaccine. However, the immunological data were more encouraging, with several patients from each arm of the trial having an increase in cytokine production, increases in specific antibodies and evidence of T-cell proliferation in response to the vaccinations. CONCLUSION: The failure of the vaccine to produce a PSA response in the patients in the trial is not surprising considering the stage of the disease. The high PSA levels on entry indicate that the burden of disease was probably high and thus this was an extremely challenging group of patients in which to try and elicit a response through immunotherapy. However, the immunological evidence of a response to the vaccine was encouraging and suggests that further exploration of immunotherapy in less advanced disease may yield more encouraging clinical responses.

Genetic prodrug activation therapy (GPAT) in two rat prostate models generates an immune bystander effect and can be monitored by magnetic resonance techniques.

Treatment of hormone refractory prostate cancer requires new treatment strategies. Genetic prodrug activation therapy (GPAT) may provide a new therapeutic avenue. In this study the antitumour efficacy of the gene encoding herpes simplex virus thymidine kinase (HSVtk) activating the prodrug ganciclovir (GCV) was compared in two models of ectopic (subcutaneous) rat prostate cancer. Both models, which differ in their characteristics, were previously shown to be weakly immunogenic but susceptible to immunotherapy. Tumour cell lines were stably transfected with HSVtk and were rendered highly sensitive to GCV. Little or no bystander killing effect was observed by tk-transfected cells on wild-type cells in vitro. However, a significant in vivo bystander effect was observed suggesting an immune-mediated response. Indeed, such an immune response was capable of slowing the growth of distant wild-type tumours and increased overall animal survival. A T helper 1 immune response was generated as a result of GCV activation and cell kill, demonstrated by the secretion of IFNgamma by cultured splenocytes in response to tumour cells. BrDU staining of tk-transfected cells treated with GCV in vitro suggested apoptotic cell death, but Annexin V staining was less marked for one of the cell lines. Serial in vivo monitoring by non-invasive magnetic resonance spectroscopy (MRS) of the tk-transfected MATLyLu tumours demonstrated a decreased ATP/Pi ratio (a measure of cell energy status) during growth and an increase in the ATP/Pi ratio during regression initiated by treatment with GCV. Further, significant differences were found in the phosphomonester (PME) to total phosphate (SigmaP) ratios in treated compared with untreated tumours, a result rarely seen in animal models, but commonly observed in patients. This study showed that a Th1-biased immune response generated by killing prostate tumour cells with tk/GCV can kill distant as well as local wild-type tumour cells. These findings suggest that GPAT may have a potential application in patients with both confined and metastatic prostate cancer and MRS may provide a method of monitoring response to treatment.

The immunotherapy of prostate cancer.

Advanced prostate cancer remains incurable with standard treatment options. Immunotherapy may be a realistic alternative given the growing evidence that the immune response can affect the growth of other solid tumours and the regulation of both specific and shared prostate cancer antigens. Early studies suggest that both non-specific and specific vaccines can effect relevant animal models and clinical trials based on these observations are now in progress. A number of other approaches including gene therapy with HSVtk are already undergoing clinical studies (Herman et al. Hum Gene Ther 1999; 10: 1239-1249). Prostate Cancer and Prostatic Diseases (2000) 3, 303-307

The clinical role of alpha-blockers in the treatment of benign prostatic hyperplasia.

Benign prostatic hyperplasia (BPH) is a highly prevalent condition that represents a significant health problem, which is likely to worsen as the population continues to age. alpha-1 adrenoceptor antagonists have been used in the treatment of this condition for well over 20 years and much is now known about their effects on the urinary tract. As these drugs have improved, their use as a first line treatment option in patients with lower urinary tract symptoms (LUTS), secondary to BPH, has continued to increase. This review details some of the background and rationale for the use of these drugs and, using the available information, compares their efficacy and tolerability profiles.

Defibrotide for the treatment of hepatic veno-occlusive disease: results of the European compassionate-use study.

Severe hepatic veno-occlusive disease (VOD) is a recognized complication of autologous and allogeneic stem cell transplantation (SCT) that is often fatal. Defibrotide (DF) is a polydeoxyribonucleotide that has been found to have anti-thrombotic, anti-ischaemic and thrombolytic properties without causing significant anticoagulation. Preliminary studies have demonstrated activity for DF in the treatment of VOD, with minimal associated toxicity. In the present study, 40 patients who fulfilled established criteria for VOD were treated with DF on compassionate grounds in 19 European centres; 28 patients met risk criteria predicting progression of VOD and fatality or had evidence of multiorgan failure (MOF), and were defined as 'poor-risk'. DF was commenced intravenously at a median of 14 d (range, -2 d to 53 d) post SCT at doses ranging from 10 to 40 mg/kg. The median duration of therapy was 18 d (range, 2--71 d). Twenty-two patients showed a complete response (CR) (bilirubin < 34.2 micromol/l and resolution of signs/symptoms of VOD and end-organ dysfunction) [CR = 55%, confidence interval (CI) 40--70%] and 17 patients (43%) are alive beyond d +100. Ten poor-risk patients showed a complete response (CR = 36%, CI 21--51%). These results demonstrate that DF is an active treatment for VOD following SCT and a randomized trial is now underway in order to further evaluate its role.