PNC-28 is a p53 peptide from its mdm-2-binding domain (residues 17-26), which contains the penetratin sequence enabling cell penetration on its carboxyl terminal end. We have found that this peptide induces necrosis, but not apoptosis, of a variety of human tumor cell lines, including several with homozygous deletion of p53, and a ras-transformed rat acinar pancreatic carcinoma cell line, BMRPA1. Tuc3. On the other hand, PNC-28 has no effect on untransformed cells, such as rat pancreatic acinar cells, BMRPA1, and human breast epithelial cells and no effect on the differentiation of human stem cells. In this study, we now test PNC-28 in vivo for its ability to block the growth of BMRPA1. Tuc3 cells. When administered over a 2-week period in the peritoneal cavities of nude mice containing simultaneously transplanted tumors, PNC-28 causes complete destruction of these tumors. When delivered concurrently with tumor explantation at a remote site, PNC-28 causes a complete blockade of any tumor growth during its 2-week period of administration and 2 weeks posttreatment, followed by weak tumor growth that plateaus at low tumor sizes compared with tumor growth in the presence of a control peptide. When administered after tumor growth has occurred at a site remote from the tumor, PNC-28 causes a decrease in tumor size followed by a slow increase in tumor growth that is significantly slower than growth in the presence of control peptide. These results suggest that PNC-28 may be effective in treating cancers especially if delivered directly to the tumor. ' 2006 Wiley-Liss, Inc.Key words: PNC-28 peptide; p53; pancreatic cancer; nude mice Activation of latent wild-type p53 in cancer cells is an emerging strategy in the treatment of human cancers. 1 p53 is known to bind to the mdm-2 (hdm-2 in humans) protein, that targets p53 for ubiquitination and ultimate proteosomal degradation, 1 using residues 12-27 in its trans-activating amino terminal regulatory domain.2 The X-ray crystal structure of the p53 12-27 fragment bound to the p53-binding domain of hdm-2 has been determined 3,4 and shows that the p53 peptide forms an amphipathic alpha-helix and binds with residues Phe 19, Trp 23 and Leu 26 to a deep hydrophobic pocket of hdm-2.3,4 Since the hdm-2 binding domain of p53 contains many conserved residues and since the 12-27 p53 peptide forms a stable, structurally well-defined complex with hdm-2, several groups have proposed to utilize this p53 segment or analogues of it to block the p53-hdm-2 interaction 5,6 thereby prolonging the half-life of wild-type p53. A study utilizing in vitro binding 5 or phage-display peptide libraries 6 has found that the p53 12-26 peptide blocks the p53-hdm-2 interaction and that other homologous peptides are even more effective than the parent p53 peptide in blocking this interaction. 6 Modified peptides and small molecules that block p53-hdm-2 interactions, with affinities for hdm-2 several thousand-fold greater than that of the parent p53 sequence, have been introduced into human cancer cells con...
The design of Ge–He provides feasible strategies for mimicking HRP enzyme to fabricate biomedical hydrogels.
Adjustably biodegradable materials have gained much attention in biomedical applications. Among of them, various hydrogel-based scaffolds have applied for regenerating soft and hard tissues. In this study, according to differently biological properties of gelatin or chitosan as well as biphasic calcium phosphate nanoparticles (BCPNPs), several injectable nanocomposite hydrogels (INgel) were enzymatically fabricated from a phenolic chitosan derivative (PCD), phenolic gelatin derivative (PGD) and BCPNPs. According the change of H2O2 concentration with follow-up the time, the in situ formation of INgel was varied from 35 to 80 s. The degradation rate of the nanocomposite materials significantly related to in presence of collagenase that expended from 3 days to over one month depending on amount of the formulated PCD. The BCPNPs-encapsulated PCD-PGD INgel enhanced mineralization in the simulated biofluid. Fluorescent cytotoxicity assay indicated that the INgel was fabricated from a higher amount of the PGD resulting in a significant proliferation of bone marrow mesenchymal stem cells. These preliminary results exhibited a great potential of the INgel for bone regeneration.
Alternative medicine has become more common as patients seek approaches to diseases where traditional medicine has failed. Treatment with ozone has been purported to have benefits for a variety of infectious, inflammatory and neoplastic conditions. Treatment can be administered by the intra arterial, intravenous, intra rectal and subcutaneous routes as well as ozonated autohaemotherapy. We describe a 44 year old woman who received treatment at an alternative medical center for recurrent breast cancer including laetrile, perflurocarbon emulsion, high dose ascorbic acid, vitamin K and extracorporeal treatment of her blood with ozone and ultraviolet light. After receiving her second treatment, she presented to our hospital with a syncopal episode and was found to be anemic (Hb 4 gm/dl). The LDH was 8X> ULN, the serum haptoglobin was undetectable, and the reticulocyte count was increased. The peripheral blood smear showed aniscocytosis, poikilocytosis and polychromasia. There was also severe acanthocytosis. Heinz bodies were not detected. The patient refused blood products and after 48h of hospitalization, her Hb rose to 7gm and she was discharged. She did not return for follow-up evaluation. Acanthocytosis has been associated with impairment of cholesterol membrane fluidity seen with acquired hepatic disease as well as some congenital diseases. Oxidative stress can lead to peroxidation of membrane phospholipids, and if the intrinsic repair mechanism of the RBC is overwhelmed, the RBCs transform into acanthocytes. To date, there has been no literature describing hemolysis associated with any of the individual treatments which this patient received; however the combination of treatments exposed the RBC’s to multiple oxidative stresses which might lead to lipid peroxidation and formation of acanthocytes. This case illustrates the potential problems that face clinicians when encountering patients who seek alternative therapy.
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