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A prostate-specific antigen-activated channel-forming toxin as therapy for prostatic disease.

ABSTRACT: Most men will develop prostatic abnormalities, such as benign prostatic hyperplasia (BPH) or prostate cancer, as they age. Prostate-specific antigen (PSA) is a serine protease that is secreted at high levels by the normal and diseased prostate. Therapies that are activated by PSA may prove effective in treating prostatic malignancies.We modified proaerolysin (PA), the inactive precursor of a bacterial cytolytic pore-forming protein, to produce a PSA-activated protoxin (PRX302). The viability of the prostate adenocarcinoma cell lines LNCaP, PC-3, CWR22H, and DU145 and the bladder cancer cell line TSU after treatment with PA or PRX302 in the presence or absence of purified PSA was assayed. Mice carrying xenograft tumors derived from LNCaP, CWR22H, or TSU cells were treated with intratumoral injection of PA or PRX302, and tumor size was monitored. To test the safety of PRX302, we administered it into the PSA-secreting prostate glands of cynomolgus monkeys. All statistical tests were two-sided.Native PA was highly toxic in vitro but had no tumor-specific effects in vitro or in vivo. Picomolar concentrations of PRX302 led to PSA-dependent decreases in cell viability in vitro (PRX302 versus PRX302 + PSA: DU145 cells, mean viability = 78.7% versus mean = 1.6%, difference = 77.1%, 95% confidence interval [CI] = 70.6% to 86.1%; P<.001; TSU cells, mean = 100.2% versus mean = 1.4%, difference = 98.8%, 95% CI = 96.4% to 104.0%; P<.001). Single intratumoral injections of PRX302 produced substantial and often complete regression of PSA-secreting human prostate cancer xenografts (5 microg dose, complete regression in 6 of 26 mice bearing LNCap or CWR22H xenografts [23%]; 10 microg dose, complete regression in 10 of 26 mice [38.5%]) but not PSA-null bladder cancer xenografts. The prostates of cynomolgus monkeys injected with a single dose of PRX302 displayed extensive but organ-confined damage, with no toxicity to neighboring organs or general morbidity.Our observations demonstrate the potential safe and effective intraprostatic application of this engineered protoxin.

SUBMITTER: Williams SA

PROVIDER: S-EPMC4133793 | biostudies-literature | 2007 Mar

REPOSITORIES: biostudies-literature

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A prostate-specific antigen-activated channel-forming toxin as therapy for prostatic disease.

Williams Simon A SA Merchant Rosemina F RF Garrett-Mayer Elizabeth E Isaacs John T JT Buckley J Thomas JT Denmeade Samuel R SR

Journal of the National Cancer Institute 20070301 5

<h4>Background</h4>Most men will develop prostatic abnormalities, such as benign prostatic hyperplasia (BPH) or prostate cancer, as they age. Prostate-specific antigen (PSA) is a serine protease that is secreted at high levels by the normal and diseased prostate. Therapies that are activated by PSA may prove effective in treating prostatic malignancies.<h4>Methods</h4>We modified proaerolysin (PA), the inactive precursor of a bacterial cytolytic pore-forming protein, to produce a PSA-activated p ...[more]

PMID: 17341729

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Project description:ObjectiveProstate cancer (PCa) is the second most common male malignancy globally. Prostate-specific antigen (PSA) is an important biomarker for PCa diagnosis. However, it is not accurate in the diagnostic gray zone of 4-10 ng/ml of PSA. In the current study, the performance of serum metabolomics profiling in discriminating PCa patients from benign prostatic hyperplasia (BPH) individuals with a PSA concentration in the range of 4-10 ng/ml was explored.MethodsA total of 220 individuals, including patients diagnosed with PCa and BPH within PSA levels in the range of 4-10 ng/ml and healthy controls, were enrolled in the study. Liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS)-based non-targeted metabolomics method was utilized to characterize serum metabolic profiles of participants. Principal component analysis (PCA) and partial least squares discriminant analysis (PLS-DA) methods were used for multivariate analysis. Receiver operating characteristic (ROC) curve analysis was performed to explore the diagnostic value of candidate metabolites in differentiating PCa from BPH. Correlation analysis was conducted to explore the relationship between serum metabolites and common clinically used fasting lipid profiles.ResultsSeveral differential metabolites were identified. The top enriched pathways in PCa subjects such as glycerophospholipid and glycerolipid metabolisms were associated with lipid metabolism. Lipids and lipid-like compounds were the predominant metabolites within the top 50 differential metabolites selected using fold-change threshold >1.5 or <2/3, variable importance in projection (VIP) > 1, and Student's t-test threshold p < 0.05. Eighteen lipid or lipid-related metabolites were selected including 4-oxoretinol, anandamide, palmitic acid, glycerol 1-hexadecanoate, dl-dihydrosphingosine, 2-methoxy-6Z-hexadecenoic acid, 3-oxo-nonadecanoic acid, 2-hydroxy-nonadecanoic acid, N-palmitoyl glycine, 2-palmitoylglycerol, hexadecenal, d-erythro-sphingosine C-15, N-methyl arachidonoyl amine, 9-octadecenal, hexadecyl acetyl glycerol, 1-(9Z-pentadecenoyl)-2-eicosanoyl-glycero-3-phosphate, 3Z,6Z,9Z-octadecatriene, and glycidyl stearate. Selected metabolites effectively discriminated PCa from BPH when PSA levels were in the range of 4-10 ng/ml (area under the curve (AUC) > 0.80). Notably, the 18 identified metabolites were negatively corrected with total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and Apo-B levels in PCa patients; and some were negatively correlated with high-density lipoprotein cholesterol (HDL-C) and Apo-A levels. However, the metabolites were not correlated with triglycerides (TG).ConclusionThe findings of the present study indicate that metabolic reprogramming, mainly lipid metabolism, is a key signature of PCa. The 18 lipid or lipid-associated metabolites identified in this study are potential diagnostic markers for differential diagnosis of PCa patients and BPH individuals within a PSA level in the gray zone of 4-10 ng/ml.

Dataset Information

A prostate-specific antigen-activated channel-forming toxin as therapy for prostatic disease.

Publications

A prostate-specific antigen-activated channel-forming toxin as therapy for prostatic disease.

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