© The Author 2007. Published by Oxford University Press.
ARTICLES |
A Prostate-Specific Antigen–Activated Channel-Forming Toxin as Therapy for Prostatic Disease
Affiliations of authors: Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD (SAW, EGM, JTI, SRD); Protox Therapeutics, Inc, Vancouver, BC, Canada (RFM, JTB)
Correspondence to: Samuel R. Denmeade, MD, Department of Oncology, The Johns Hopkins University School of Medicine, CRBI 1M43, 1650 Orleans St, Baltimore, MD 21231 (e-mail: denmesa{at}jhmi.edu).
Background: 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.
Methods: 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.
Results: 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 µg dose, complete regression in 6 of 26 mice bearing LNCap or CWR22H xenografts [23%]; 10 µg 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.
Conclusions: Our observations demonstrate the potential safe and effective intraprostatic application of this engineered protoxin.
| CONTEXT AND CAVEATS Prior knowledge PSA is a serine protease that is secreted by the prostate gland. Study Design PRX302, a PSA-activated protoxin, was synthesized and tested in prostate cancer cell lines and in several animal models. Contributions PRX302 treatment led to PSA-dependent decreases in cell viability and tumor growth. No toxicity to non-PSA expressing cells and tissues, neighboring organs, or general morbidity was observed. Implications PRX302 may be effective and safe for the treatment of locally recurrent prostate cancer and BPH. Limitations Although PSA-expressing cells were used in mouse models of prostate cancer, mice do not express PSA. Long-term effects of PRX302 treatment are unknown.
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Manuscript received June 13, 2006; revised December 20, 2006; accepted January 23, 2007.
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J Natl Cancer Inst 2007 99: 337.
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