Pigment epithelial-derived factor (PEDF), an angiogenesis inhibitor with neurotrophic properties, balances angiogenesis in the eye and blocks tumor progression. Its neurotrophic function and the ability to block vascular leakage is replicated by the PEDF 44-mer peptide (residues 58-101). We analyzed PEDFs' three-dimensional structure and identified a potential receptor-binding surface. Seeking PEDF-based antiangiogenic agents we generated and tested peptides representing the middle and lower regions of this surface. We identified previously unknown antiangiogenic epitopes consisting of the 34-mer (residues 24-57) and a shorter proximal peptide (TGA, residues 16-26) with the critical stretch L 19 VEEED 24 and a fragment within the 44-mer (ERT, residues 78-94), which retained neurotrophic activity. The 34-mer and TGA, but not the 44-mer reproduced PEDF angioinhibitory signals hinged on c-jun-NH 2 -kinase-dependent nuclear factor of activated T cell deactivation and caused apoptosis. Conversely, the ERT, but not the 34-mer/TGA induced neuronal differentiation. For the 44-mer/ERT, we showed a novel ability to cause neuroendocrine differentiation in prostate cancer cells. PEDF and the peptides bound endothelial and PC-3 prostate cancer cells. Bound peptides were displaced by PEDF, but not by each other, suggesting multiple receptors. PEDF and its active fragments blocked tumor formation when conditionally expressed by PC-3 cells. The 34-and 44-mer used distinct mechanisms: the 34-mer acted on endothelial cells, blocked angiogenesis, and induced apoptosis whereas 44-mer prompted neuroendocrine differentiation in cancer cells. Our results map active regions for the two PEDF functions, signaling via distinct receptors, identify candidate peptides, and provide their mechanism of action for future development of PEDFbased tumor therapies. (Cancer Res 2005; 65(12): 5144-52)

Blocking angiogenesis is a promising approach in cancer therapy. Natural inhibitors of angiogenesis and derivatives induce receptor-mediated signals, which often result in the endothelial cell death. Low-dose chemotherapy, given at short regular intervals with no prolonged breaks (metronomic chemotherapy), also targets angiogenesis by obliterating proliferating endothelial cells and circulating endothelial cell precursors. ABT-510, a peptide derivative of thrombospondin, kills endothelial cell by increasing CD95L, a ligand for the CD95 death receptor. However, CD95 expression itself is unaffected by ABT-510 and limits its efficacy. We found that multiple chemotherapy agents, cyclophosphamide (cytoxan), cisplatin, and docetaxel, induced endothelial CD95 in vitro and in vivo at low doses that failed to kill endothelial cells (cytoxan > cisplatin > docetaxel). Thus, we concluded that some of these agents might complement each other and together block angiogenesis with maximal efficacy. As a proof of principle, we designed an antiangiogenic cocktail combining ABT-510 with cytoxan or cisplatin. Cyclophosphamide and cisplatin synergistically increased in vivo endothelial cell apoptosis and angiosuppression by ABT-510. This synergy required CD95, as it was reversible with the CD95 decoy receptor. In a mouse model, ABT-510 and cytoxan, applied together at low doses, acted in synergy to delay tumor take, to stabilize the growth of established tumors, and to cause a long-term progression delay of PC-3 prostate carcinoma. These antitumor effects were accompanied by major decreases in microvascular density and concomitant increases of the vascular CD95, CD95L, and apoptosis. Thus, our study shows a ''complementation'' design of an optimal cancer treatment with the antiangiogenic peptide and a metronomic chemotherapy.Thrombospondin-1 is a well-known antiangiogenic agent (1).Its mechanism of action and structure-function relationship have been analyzed in considerable depth, resulting in the discovery of a minimal active heptapeptide in which antiangiogenic activity is greatly enhanced by L-isoleucine to D-isoleucine replacement (2). ABT-526 and ABT-510 are modified versions of this minimal peptide with increased potencies (3) and improved clearance; ABT-510 is currently under evaluation in phase II clinical trials (4). Thrombospondin-1 has also been identified as a host-derived mediator of the antiangiogenic action of low-dose metronomic chemotherapy (5, 6). Thrombospondin-1 and ABT-510 act by inducing endothelial cell apoptosis in some cases via CD36 cell surface receptor (7,8). Proapoptotic signal elicited by thrombospondin-1 generates CD95L, a ligand for the CD95 death receptor (9). However, CD95 expression on vascular endothelial cell is independent of thrombospondin-1; thus, accessible CD95 limits the rate of apoptosis and antiangiogenesis due to thrombospondin-1 and consequently determines, at least in part, the efficacy of thrombospondin-1-based cancer treatments.Seeking agents to improve the efficacy of ABT-...

Antiangiogenic thrombospondin-1 (TSP1) induces endothelial cell death via a CD95-mediated cascade. We used this signaling pathway, where CD95/Fas is a rate-limiting intermediate, as a target to optimize the efficacy of TSP1 active peptide, DI-TSP. Like TSP1, DI-TSP upregulated endothelial CD95L in vivo. To modulate CD95 levels, we chose chemotherapy agent doxorubicin (DXR). DXR caused sustained upregulation of CD95 in the activated endothelium at 1/ 100 of the maximal tolerated dose. DI-TSP and DXR synergistically induced endothelial apoptosis in vitro, and in vivo, in developing murine vessels. Fas decoy, TSP1 receptor antibody and Pifithrin, a p53 inhibitor, severely decreased apoptosis and restored angiogenesis by DXR-DI-TSP combination, evidencing critical roles of CD95 and TSP1. Combined therapy synergistically blocked neovascularization and progression of the bladder and prostate carcinoma. Such informed design of a complex antiangiogenic therapy based on the rate-limiting molecular targets is a novel concept, which may yield new approaches to cancer treatment.

Compared to the high prevalence of CaP found in autopsy studies there is a lower detection rate using current screening protocols. Although the outcomes are unknown if these tumors had been left untreated, the majority met pathological criteria for significant cancer.

Laparoscopic renal cryosurgery appears to be a safe and effective minimally invasive alternative for the treatment of small renal masses. Careful selection of patients with lesions that are less than 3.0 cm and close monitoring of the iceball is necessary to treat these patients successfully.

What ' s known on the subject? and What does the study add? Laser prostatectomy is a commonly performed procedure for BOO, and has been shown to have short-and medium-term results equivalent to the gold standard procedure (i.e. TURP) in various studies. It also has an advantage over TURP in that it can be performed on patients who are taking anticoagulant medication. However, patients in most studies are admitted to the hospital overnight on continuous bladder irrigation and are discharged home the next day.

Information about benign prostatic hyperplasia (BPH) has become increasingly accessible on the Internet. Though the ability to find such material is encouraging, its readability and impact on informing patient decision making are not known. To evaluate the readability of Internet-based information about BPH in the context of website ownership and Health on the Net certification, three search engines were queried daily for 1 month with BPH-related keywords. Website ownership data and Health on the Net certification status were verified. Three readability analyses were performed: SMOG test, Dale–Chall readability formula, and Fry readability graph. An adjusted SMOG calculation was performed to reduce overestimation from medical jargon. After a total of 270 searches, 52 websites met inclusion criteria. Mean SMOG grade was 10.6 (SD = 1.4) and 10.2 after adjustment. Mean Dale–Chall score was 9.1 (SD = 0.6), or Grades 13 to 15. Mean Fry graph coordinates (173 syllables, 5.1 sentences) corresponded to Grade 15. Seven sites (13%) were at or below the average adult reading level based on SMOG; none of the sites qualified based on the other tests. Readability was significantly poorer for academic versus commercial sites and for Health on the Net-certified versus noncertified sites. In conclusion, online information about BPH treatment markedly exceeds the reading comprehension of most U.S. adults. Websites maintained by academic institutions and certified by the Health on the Net standard have more difficult readability. Efforts to improve literacy with respect to urological health should target content readability independent of reliability.

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