This study was undertaken to investigate the role of mouse double minute 2 (MDM2) oncogene in prostate cancer growth and the potential of MDM2 as a target for prostate cancer therapy. An antisense anti-human-MDM2 mixed-backbone oligonucleotide was tested in human prostate cancer models with various p53 statuses, LNCaP (p53 wt/wt ), DU145 (p53 mt/mt ), and PC3 (p53 null ). In a dose-and time-dependent manner, it specifically inhibited MDM2 expression and modified expression of several genes, at both mRNA and protein levels. In LNCaP cells, p53, p21, Bax, and hypophosphorylated retinoblastoma tumor suppressor protein (pRb) levels increased, whereas Bcl2, pRb protein, and E2F transcription factor 1 (E2F1) levels decreased. In DU145 cells, p21 levels were elevated and E2F1 levels decreased, although mutant p53, Rb, and Bax levels remained unchanged. In PC3 cells, MDM2 inhibition resulted in elevated p21, Bax, and pRb levels and decreased ppRb and E2F1 levels. In all three cell lines, MDM2 inhibition reduced cell proliferation, induced apoptosis, and potentiated the effects of the chemotherapeutic agents 10-hydroxycamptothecin and paclitaxel. The anti-MDM2 oligonucleotide showed antitumor activity and increased therapeutic effectiveness of paclitaxel in both LNCaP and PC3 xenografts, causing changes in gene expression similar to those seen in vitro. In summary, this study demonstrates that MDM2 has a role in prostate cancer growth via p53-dependent and p53-independent mechanisms and that multiple genes are involved in the process. MDM2 inhibitors such as second-generation antisense oligonucleotides have a broad spectrum of antitumor activities in human cancers regardless of p53 status, providing novel approaches to therapy of human prostate cancer.ntisense therapy is designed to deliver to the target cells antisense molecules that target to mRNA with which they can hybridize and specifically inhibit the expression of pathogenic genes (1), thus offering the possibility of specific, rational, genetic-based therapy (1, 2). With encouraging results from preclinical and clinical studies in the past decade, significant progress has been made in the field (3-6). Although the firstgeneration phosphorothioate antisense oligonucleotides (oligo) are in clinical trials, a number of factors, including in vivo biostability and sequence motifs that could lead to unwanted effects, have been identified (4). The second-generation antisense oligos are designed to overcome these limitations (7,8). Recently, we have developed several mixed-backbone antisense oligos (MBO) that are being tested for antitumor activity in vitro and in vivo (8-11).Prostate cancer poses a major public health problem in the United States and worldwide. It has the highest incidence and is the second most common cause of cancer deaths in North American men, with estimates of 220,900 new cases and 28,900 deaths in 2003 (12). There is a need to develop novel therapeutic approaches. The molecular mechanisms of development and progression of prostate cancer are compl...

No. of Pages 30 2 G. Rydzek et al. SummaryDuring the last few decades, electrochemistry and electrode modification have seen a tremendous fall off in creativity with the emergence of the nanoarchitectonic-based layerby-layer (LbL) film deposition technique. An unprecedented variety of building blocks can be immobilized on surfaces, leading to progress in several fields including sensing, electrochromic, electro-responsive and energy devices. This review describes the state of the art of electrochemical devices based on LbL assemblies, with a focus on supercapacitors, biosensors, and electroresponsive LbL such as electrodissolution/electroswelling of coatings. Recently, electrochemistry has also been used as an ''active trigger'' to induce the formation of films by covalent coupling, leading to new nanoarchitectonic approaches beyond the LbL strategy. These emerging electro-coupling reactions, including electroclick and carbazole chemistry, open new perspectives toward architecture and patterning of functional films and are extensively reviewed.

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