Cancer therapy最新文献

{"title":"Novel peptides from the RAS-p21 and p53 proteins for the treatment of cancer.","authors":"Wilbur B Bowne,&nbsp;Josef Michl,&nbsp;Martin H Bluth,&nbsp;Michael E Zenilman,&nbsp;Matthew R Pincus","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>We have employed a novel computer-based molecular modeling method to design peptides from the ras-p21 and p53 proteins that block proliferation of cancer cells. The rationale of our approach is to identify peptide domains from each protein that alter conformation in response to oncogenic amino acid substitutions in their polypeptide chain. We accomplish this by first generating and comparing low energy average structures for oncogenic and wild-type proteins using conformational energy calculations. Peptides are then synthesized corresponding to these domains. These domains are then linked to a trans-membrane-penetrating sequence (called penetratin) and tested against cancer and untransformed cell lines. Remarkably, we have found that two ras-p21 peptides, 35-47 and 96-110, called PNC-7 and PNC-2, respectively, can induce phenotypic reversion of ras-transformed TUC-3 pancreatic cancer cells and ras-transformed HT1080 human fibrosarcoma cells to their untransformed phenotypes. Moreover, both peptides were found to be cytotoxic to ras-transformed human MIA-PaCa-2 pancreatic carcinoma cells and human U-251 astrocytoma cells. Importantly, these peptides have no effect on the growth of their normal cellular counterparts. We have also synthesized peptides from the p53 protein corresponding to its hdm-2-binding domain sequences (residues 12-26), also linked to the penetratin sequence. Surprisingly, we have found that these peptides induce 100 percent tumor cell necrosis, not apoptosis, in 13 different human cancer cell lines but have no effect on normal pancreatic acinar cells, breast epithelial cells, and human stem cells. Moreover, these peptides are cytotoxic to TUC-3 pancreatic tumor cells in nude mice plus eradicate these tumor cells when administered at sites near these tumors. These novel peptides appear to hold much promise as new, non-toxic anti-cancer agents.</p>","PeriodicalId":87393,"journal":{"name":"Cancer therapy","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2007-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2078333/pdf/nihms31235.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"27083493","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Suppression of breast cancer metastasis through the inhibition of VEGF-mediated tumor angiogenesis.","authors":"Jun Zhang, Andrew Lu, Derrick Beech, Binghua Jiang, Yi Lu","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>One of the major causes of failure in the treatment of breast cancer is the occurrence of metastasis, the spreading of the primary tumor to distant organs. It is thus important to intervene at a key step of metastatic process, such as angiogenesis, for effective breast cancer treatment. Vascular endothelial growth factor (VEGF) plays a pivotal role in tumor angiogenesis. Because degree of tumor malignancy directly correlates with the expression of VEGF but inversely correlates with the expression of tumor suppressor gene p16, we examined whether restoration of p16 in breast cancer cells that lack p16 expression would modulate VEGF expression, and if so, how are the effects of p16 expression on tumor angiogenesis and metastasis. To facilitate induction of p16 expression, a recombinant adenovirus expressing p16 (AdRSVp16) was used to transduce breast cancer cell lines MDA-MB-231 and JygMC(A). This study showed that adenoviral-mediated p16 expression downregulated VEGF gene expression in breast cancer cells, inhibited breast cancer cell-induced angiogenesis, and suppressed breast tumor metastasis in a spontaneous metastasis model in mice. Moreover, the mechanism of how p16 regulates VEGF expression is also investigated.</p>","PeriodicalId":87393,"journal":{"name":"Cancer therapy","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2007-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2424245/pdf/nihms51573.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"27494418","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Chemotherapy in Androgen-Independent Prostate Cancer (AIPC): What's next after taxane progression?","authors":"Jeanny B Aragon-Ching,&nbsp;William L Dahut","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>SummaryProstate cancer is the most common non-cutaneous cancer in the United States. Although most are diagnosed at earlier stages of disease, a significant number of patients will eventually progress to metastatic androgen-independent prostate cancer (AIPC) and will receive chemotherapy. The benefit of chemotherapy in overall survival has been demonstrated in studies utilizing docetaxel. However, duration of response is short and therapeutic options are limited after taxane failure. There is a need for effective chemotherapeutic agents in the second-line setting, either alone or in combination. Some of these regimens may also ultimately translate to the front-line chemotherapeutic setting as an alternative or perhaps in combination with a taxane.</p>","PeriodicalId":87393,"journal":{"name":"Cancer therapy","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2007-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1950481/pdf/nihms23039.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"26901247","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Advantages of a unique DNA-based vaccine in comparison to paclitaxel in treatment of an established intracerebral breast cancer in mice.","authors":"Terry Lichtor,&nbsp;Roberta P Glick,&nbsp;Henry Lin,&nbsp;Amla Chopra,&nbsp;Insug O-Sullivan,&nbsp;Edward P Cohen","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>In this study we compared the benefits of treating C3H/He mice with an established intracerebral breast carcinoma by immunization with a unique DNA-based vaccine to chemotherapy with paclitaxel. Prior studies revealed the immunotherapeutic properties of a vaccine prepared by transfer of genomic DNA from breast cancer cells into a highly immunogenic cell line. Here, C3H/He mice with an established intracerebral breast cancer were treated either by injection into the tumor bed through a unique cannula system with the cell based vaccine or with paclitaxel administered intraperitoneally. Both treatment strategies were effective in prolonging survival and stimulating a systemic anti-tumor immune response (p< 0.025). However, unlike mice treated with the vaccine, the animals that received paclitaxel alone displayed significant toxic side effects. No additional therapeutic advantage was detected when these two treatment strategies were combined. The vaccine tended to provide a somewhat better therapeutic and clearly better systemic immunologic effect based on two independent spleen cell assays in comparison to paclitaxel.</p>","PeriodicalId":87393,"journal":{"name":"Cancer therapy","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2006-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1540401/pdf/nihms9977.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"26200281","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Glioma cell integrin expression and their interactions with integrin antagonists: Research Article.","authors":"Ralph-Heiko Mattern,&nbsp;Susana B Read,&nbsp;Michael D Pierschbacher,&nbsp;Chun-I Sze,&nbsp;Brian P Eliceiri,&nbsp;Carol A Kruse","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>A panel of human glioma cell explants was screened for integrin expression by flow cytometry using α(ν)β-specific antibodies. A lower percentage of the glioma cells were positive for the α(ν)β3 (mean % positive = 20.8%) integrin, whereas higher percentages were positive for the ανβ5 (mean % positive = 72.7%), VLA5α (mean % positive = 87%) and VLAβ1 (mean % positive = 41.7%) integrins. A series of RGD peptides was designed, synthesized and tested for binding to integrin receptors. Based on the results of the binding to the isolated integrin receptors and the expression of integrins on glioma cell lines, a peptide that binds potently to the α(ν)β3, α(ν)β5 and α(5)β(1) was selected for further investigations with regards to its effect on glioma cells. The peptide, Ac-c[(Pen)-Tyr(Me)-Ala-Arg-Gly-Asp-Asn-Tic-Cys]NH(2) (RGD peptide), exhibited high potential for use in clinical intracranial administration since it had good stability in rat brain cell homogenates placed into artificial cerebrospinal fluid. Using an HPLC method for quantification of peptides in rat brain cell homogenates, we could demonstrate the half-life of the RGD peptide approximated 20 hr. Relative to a scrambled peptide control (non-RGD sequence, same amino acids), the experimental RGD peptide significantly decreased glioma cell proliferation of the entire panel of rat and human glioma cells tested. Adhesion of recently passaged glioma cells to glioma-derived extracellular matrix protein-coated plates was inhibited significantly by the RGD peptide. The peptide also reversed attachment of plated glioma cells. The RGD peptide caused some, but not substantial, glioma cell injury, as evidenced by a quantitative in vitro nuclear DNA morphologic assay and by a flow cytometric assay employing 7-amino actinomycin D (7AAD). We histologically monitored for toxicity caused by various doses of the RGD peptide infused repeatedly into normal cannulated rat brain. At safe doses, the experimental RGD peptide-treated brains did not show significant differences from those infused with scrambled peptide or buffer-treated controls. In tumor-bearing brains, slightly smaller tumor areas were measured with a higher necrotic-to-tumor index in the RGD peptide treated relative to the scrambled peptide-treated controls. This was obtained with intracranial peptide administrations or combined intracranial and intraperitoneal injections. From this in vitro work, we conclude that the anti-glioma effects of the RGD peptide tested resulted from lowered glioma proliferation and adhesion/mobility, rather than from significant glioma cell injury in the timeframe analyzed. Although other mechanisms not discerned from our limited histopathological observations may be operational, from our in vivo work, we conclude that repeated administration of RGD peptide into brain is safe but that better delivery of the peptides to infiltrating tumor cells is necessary.</p>","PeriodicalId":87393,"journal":{"name":"Cancer therapy","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2005-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1351132/pdf/nihms-5196.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25847174","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pre-treatment with a non-therapeutic dose of cisplatin increases solid tumour response to liposomal-p53 gene therapy- An in vivo study.","authors":"Jason C Steel,&nbsp;Wouter H J Kalle,&nbsp;Daniel J Dingwall,&nbsp;Heather M A Cavanagh,&nbsp;Mark A Burton","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Successful liposomal-mediated gene therapy is often limited by poor transfection efficiencies. One method previously shown to increase the efficiency of liposomal gene delivery is through the administration of a non-therapeutic dose of the chemotherapeutic drug cisplatin prior to lipofection. The currents study aims to utilise this method to deliver lipoplexes containing the p53 tumour suppressor gene with the aim of increasing therapeutic effect of the p53 gene on a solid tumour in vivo. Rats, implanted with solid salivary adenocarcinomas, were pre-treated with a low dose of cisplatin seven days prior to liposomal mediated p53 treatment. Following treatment with p53, tumour growth, p53 expression and levels of apoptosis were examined and compared to animals treated with p53 without cisplatin pre-treatment and a saline control. Tumours that had been pre-treated with cisplatin prior to p53-lipofection were significantly smaller than both the saline control and the non-cisplatin treated tumours. Saline treated tumours increased in size by an average of 164% over a 96-hour period compared to 64% and 101% for the cisplatin and non-cisplatin p53-liposome treated tumours. The cisplatin pre-treated tumours resulted in significantly higher levels of apoptosis surrounding the treatment site and exhibited prolonged p53 expression when compared to the non-cisplatin pre-treated tumours. The results suggest that the use of cisplatin to pre-sensitise tumours to lipofection has significant benefits when used in conjunction with p53.</p>","PeriodicalId":87393,"journal":{"name":"Cancer therapy","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2004-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2441639/pdf/nihms54965.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40543382","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cisplatin nephrotoxicity: molecular mechanisms.","authors":"Marie H Hanigan,&nbsp;Prasad Devarajan","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Cisplatin is one of the most widely used chemotherapeutic agents for the treatment of several human malignancies. The efficacy of cisplatin is dose dependent, but the significant risk of nephrotoxicity frequently hinders the use of higher doses to maximize its antineoplastic effects. Several advances in our understanding of the biochemical and molecular mechanisms underlying cisplatin nephrotoxicity have recently emerged, and are reviewed in this article. Evidence is presented for distinct mechanisms of cisplatin toxicity in actively dividing tumor cells versus the normally quiescent renal proximal tubular epithelial cells. The unexpected role of gamma-glutamyl transpeptidase in cisplatin nephrotoxicity is elucidated. Recent studies demonstrating the ability of proximal tubular cells to metabolize cisplatin to a nephrotoxin are reviewed. The evidence for apoptosis as a major mechanism underlying cisplatin-induced renal cell injury is presented, along with the data exploring the role of specific intracellular pathways that may mediate the programmed cell death. The information gleaned from this review may provide critical clues to novel therapeutic interventions aimed at minimizing cisplatin-induced nephrotoxicity while enhancing its antineoplastic efficacy.</p>","PeriodicalId":87393,"journal":{"name":"Cancer therapy","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2003-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2180401/pdf/nihms36123.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"27215114","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}