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At least 397 records · Page 22Linked to original sources
PubMed2001

In situ prostate cancer gene therapy using a novel adenoviral vector regulated by the caveolin-1 promoter.

Caveolin-1, a structural component of caveolae, is overexpressed in metastatic and androgen-resistant prostate cancer and highly expressed in tumor-associated endothelial cells. The mouse cav-1 promoter was cloned and placed upstream of the HSV-tk gene in an adenoviral vector (Adcav-1tk) and compared with a cytomegalovirus (CMV) or Rous sarcoma virus (RSV) promoter-driven HSV-tk, AdCMVtk and AdRSVtk vectors, respectively. Mouse and human prostate cancer cells and mouse endothelial cells were infected with Adcav-1tk, AdCMVtk or control vectors without the HSV-tk gene (Adcav-1 and AdCMV) and subsequently treated with ganciclovir (GCV). GCV-mediated in vitro cytotoxicity induced by the Adcav-1tk vector was comparable to that for AdCMVtk in multiple mouse and human prostate cancer cell lines. To evaluate the activity of Adcav-1tk in vivo, orthotopic mouse prostate cancer tumors were generated with RM-9 cells and injected in situ with Adcav-1tk, AdCMVtk, AdRSVtk, or AdCMVbetagal (control) and treated with GCV. All three HSV-tk transducing vectors produced statistically significant reductions in wet weight and increased apoptotic indices compared with the control vector. However, only Adcav-1tk produced significant necrosis, and only Adcav-1tk and AdRSVtk caused significant decreases in microvessel density. In conclusion, Adcav-1tk demonstrated efficacy in vitro and in vivo in preclinical models of prostate cancer. Our results suggest that the cav-1 promoter may have unique benefits in targeting gene therapy to prostate cancer and its associated vasculature.

Adenoviridae↗
PubMed2006

MDA-7/IL-24-based cancer gene therapy: translation from the laboratory to the clinic.

Despite recent advances in treatment strategies, the overall 5-year survival rate for patients with common epithelial cancers is poor largely because of the difficulty in treating metastatic cancers. Therefore, therapeutic agents are urgently needed that can effectively inhibit both primary epithelial tumors and their metastases. One such agent that has shown promise in preclinical studies is the tumor suppressor/cytokine, melanoma differentiation associated gene-7 also known as interleukin-24 (mda-7/IL-24). Preclinical studies from our and other laboratories have shown that overexpression of MDA-7/IL-24 causes a strong tumor- suppressive effect in many human cancer cells but spares normal cells. This gene therapy also enhances the tumor-suppressive activity of radiotherapy and chemotherapy. Secreted MDA-7 protein that is glycosylated also has been shown to have potent antiangiogenic activity both in vitro and in vivo. Studies examining the immune properties of mda-7 have shown that MDA-7/IL-24 unlike the related IL-10, functions as a Th1 cytokine. Recently, an MDA-7 protein-mediated "bystander effect" on tumor cells has been documented. Building on these findings we successfully completed a Phase I clinical trial of adenovirus-based mda-7 cancer therapy that confirmed the safety of this gene therapy. Phase II trials evaluating the efficacy of mda-7-based gene therapy are warranted. The outcome of such ongoing mda-7-based gene therapy trials will allow us to better understand this therapy's clinical utility.

Adjuvants, Immunologic↗
PubMed2002

Cytochrome P450-based cancer gene therapy: current status.

Results from a number of preclinical studies have demonstrated that a P450-based gene-directed enzyme prodrug therapy (GDEPT) strategy for the treatment of cancer is both safe and efficacious. This strategy has now moved forward into the clinic. At least two different approaches using different delivery methods (retroviral vector MetXia [Oxford BioMedica] and encapsulated P450 expressing cells), different cytochrome P450 isoforms (human CYP2B6 versus rat CYP2B1) and different prodrugs (cyclophosphamide [CPA] versus ifosfamide [IFA]) have concluded Phase I/II clinical trial with encouraging results. In the future, P450-based GDEPT can potentially be further enhanced by improved vectors for P450 gene delivery and disease-targeted promoters for focused gene expression at the target site. In addition, there is scope for developing synthetic P450s and their respective prodrugs to improve both enzyme kinetics and the profile of the active moiety.

Animals↗
PubMed2006

Targeting transcription factors for cancer gene therapy.

A high proportion of oncogenes and tumor suppressor genes encode transcription factors. Deregulated expression or activation and inactivation of transcription factors as well as mutations and translocations play critical roles in tumorigenesis. Furthermore, the majority of oncogenic signaling pathways converge on sets of transcription factors that ultimately control gene expression patterns resulting in tumor formation and progression as well as metastasis. Under normal physiological conditions whole sets of genes with similar functions are regulated by highly specific, tightly regulated upstream transcriptional regulators, whereas in cancer aberrant activation of these transcription factors leads to deregulated expression of multiple gene sets associated with tumor development and progression. The activity of these transcription factors can be modulated by multiple mechanisms including posttranslational modifications. Activation or inactivation of transcription factors promote cancer development, cell survival and proliferation and induce tumor angiogenesis. Since many of these transcription factors are inactive under normal physiological conditions and their expression and activities are tightly regulated, these transcription factors represent highly desirable and logical points of therapeutical interference in cancer development and progression. Three major families of transcription factors have emerged as important players in human cancer and are validated targets in drug discovery for cancer therapy: 1) the NF-kappaB and AP-1 families of transcription factors, 2) the STAT family members and 3) the steroids receptors. This review aims to elucidate the divergent molecular mechanisms involved in the deregulated activation of transcription factor signaling in malignant transformation, although additional transcription factor families such as the Ets factors, ATF family members, basic helix-loop-helix transcription factors etc. are additional critical transcriptional regulators in human cancer. We explore new approaches to specifically inhibit these transcription factors in cancer in order to validate them as a drug targets. Efforts to develop novel viral vectors for therapeutic applications are also discussed.

Animals↗
PubMed2004

Cancer gene suppression strategies: issues and potential.

Oncogenes are ideal targets for therapies which down-regulate gene expression. However, effective modalities for altering gene expression in vivo have thus far proven to be elusive. Whilst there has been recent success with small molecule inhibitors of oncoprotein function, evolution of resistance to these agents has been observed in the clinical setting, indicating the need for combinations of therapies for cancer treatment. Strategies for in vivo gene down-regulation still hold promise for the treatment of cancer. The technologies relevant to such therapeutic strategies are discussed in terms of molecular action, delivery and choice of target gene. Consideration is given to the pre-clinical and clinical efficacy these agents have demonstrated to date.

Animals↗
PubMed2003

Breast cancer gene 1 (BRCA1): role in cell cycle regulation and DNA repair--perhaps through transcription.

Mutations of BRCA1 gene are associated with more than half the cases of hereditary breast cancer. Breast cancer formation in BRCA1 mutation carriers is generally accompanied by loss of the wild-type allele, suggesting that BRCA1 protein may function as a tumor suppressor. The human BRCA1 gene encodes a nuclear protein of 1863 amino acids. Although several lines of evidences suggest that BRCA1 protein may have a role to play in cell cycle regulation, DNA repair, and other processes, the exact mechanism of functioning by BRCA1 protein is not clear. Recent evidences from several laboratories suggest that BRCA1 may regulate the expression of many genes like p21(WAF1/CIP1), Gadd45, Cyclin B1, DBB2, XPC, 14-3-3ó and others at the level of transcription. These BRCA1-regulated gene products have been implicated directly or indirectly in cell cycle regulation and DNA repair. Thus a plausible model is proposed in which BRCA1 protein may bring its effects on cell cycle and DNA repair through its ability to modulate gene expression at the level of transcription.

BRCA1 Protein↗
PubMed2003

WWOX, the common chromosomal fragile site, FRA16D, cancer gene.

Gross chromosomal rearrangements and aneuploidy are among the most common somatic genomic abnormalities that occur during cancer initiation and progression, in particular in human solid tumor carcinogenesis. The loss of large chromosomal regions as consequence of gross rearrangements (e.g. deletions, monosomies, unbalanced translocations and mitotic recombination) have been traditionally associated with the existence of tumor suppressor genes within the areas affected by the loss of genetic material. The long arm of chromosome 16 was identified as being frequently associated with structural abnormalities in multiple neoplasias, that led us to focus attention on the detailed genetic dissection of this region resulting in the cloning of the putative tumor suppressor gene, WWOX (WW domain containing Oxidoreductase). Interestingly, the WWOX gene resides in the very same region as that of the common chromosomal fragile site 16D (FRA16D). The WWOX gene encodes a protein that contains two WW domains, involved in protein-protein interactions, and a short chain dehydrogenase (SDR) domain, possibly involved in sex-steroid metabolism. We have identified the WWOX WW domain ligand as the PPXY motif confirming the biochemical activity of this domain. WWOX normally resides in the Golgi and we will demonstrate that Golgi localization requires an intact SDR. Inactivation of the WWOX gene during tumorigenesis can occur by homozygous deletions and possibly mutation, however, aberrantly spliced forms of WWOX mRNA have been observed even when one allele is still intact. The aberrantly spliced mRNAs have deletions of the exons that encode the SDR and these WWOX protein isoforms display abnormal intracellular localization to the nucleus possibly functioning as dominant negative inhibitors of full length WWOX. Thus, generation of aberrant transcripts of WWOX may represent a novel mechanism to functionally inactivate WWOX without genomic alteration of the remaining allele. In this article we will review the cloning and identification of WWOX as the target of FRA16D. In addition, we will discuss the possible biochemical functions of WWOX and present evidence that ectopic WWOX expression inhibits tumor growth.

Alternative Splicing↗
PubMedDate not supplied

Assessment of pathogenicity criteria for constitutional missense mutations of the hereditary nonpolyposis colorectal cancer genes MLH1 and MSH2.

To determine the role played by MLH1 and MSH2 missense variants in cancer susceptibility, we have investigated the following genetic and biological characteristics associated with six MLH1 and four MSH2 missense changes identified in Italian hereditary nonpolyposis colorectal cancer (HNPCC) families: co-segregation with disease phenotype and/or bonafide pathogenetic mutations; presence of the variant in healthy control subjects; evolutionary conservation of the involved aminoacid and type of aminoacid change; and presence/absence of microsatellite instability (MSI) in tumour DNA. Overall, nine variants did not fulfil > or = 2 pathogenicity criteria. MSI was investigated in tumour samples from carriers of nine different missense mutations. Only 3/9 variants were associated with MSI in tumour DNA. In addition, four variants were not present in affected pedigree members, and five variants were observed in the control population. Based upon these results, we conclude that most MLH1 and MSH2 missense changes are unlikely to act as major causative factors in colorectal cancer susceptibility and development.

Adaptor Proteins, Signal Transducing↗
PubMed2004

ApcMin/+ mouse model of colon cancer: gene expression profiling in tumors.

The Apc(Min/+) mouse is a popular animal model for studies of human colon cancer, but the molecular changes associated with neoplasia in this system have only been partially characterized. Our aim was to identify novel genes involved in tumorigenesis in this model. RNA from intestinal adenomas and from pre-neoplastic small intestine were prepared from six Apc(Min/+) mice. The tumor transcriptomes were analyzed with high-density oligonucleotide microarrays representing approximately 12,000 probe sets; we compared their profiles with those of matched pre-neoplastic intestine. Stringent analysis revealed reproducible changes for 98 probe sets representing 90 genes, including novel observations regarding 50 genes whose involvement in this mouse model has never been reported. In addition to the expected changes in growth regulatory genes, the altered gene products could be assigned to four functional groupings that should enhance tumorigenesis: metabolic changes that would result in a high rate of glycolysis, alterations in enzymes involved in reactive oxygen species or carcinogen metabolism, cytoskeletal elements, and proteins involved in tumor invasion or angiogenesis. A fifth group consisted of expression changes that might restrict tumor progression, suggesting that the adenomatous state reflects a balance of pro- and anti-tumorigenic factors. Since many of the altered genes had not previously been reported to be involved in any tumorigenic processes, our observations provide a host of new candidates for potential modulation to prevent or treat intestinal neoplasia.

Adenomatous Polyposis Coli Protein↗
PubMed1995

Cloning of the mouse homologue of the deleted in colorectal cancer gene (mDCC) and its expression in the developing mouse embryo.

Loss of DCC gene expression has now been demonstrated in a wide variety of metastatic cancers. Here we present the nucleotide sequence and predicted amino acid sequence of mouse DCC. Mouse and human DCC share 96% identity at the amino acid level. Analysis of DCC mRNA expression throughout the mid and late stages of gestation in the mouse, demonstrated that DCC mRNA is expressed at significantly higher levels in the developing mouse embryo than in any adult tissue. In addition, we show that an embryo-specific, alternatively spliced, form of DCC is expressed in day 9.5 through day 18.5 embryos. The expression of both alternatively spliced forms of DCC is developmentally regulated such that the embryonic form of DCC predominates in day 9.5 and 10.5 embryos. In the later stage embryos the expression of this alternatively spliced form of DCC is down-regulated with respect to that of the adult form. Whole-mount in situ hybridization of day 11.5 mouse embryos revealed that DCC mRNA is expressed at high levels in the developing brain and the neural tube. However, no DCC mRNA could be detected in any other embryonic tissue at this stage of development. These observations suggest that during embryogenesis DCC may play a pivotal role in the development of the central nervous system.

Alternative Splicing↗
PubMed1992

The colorectal cancer gene hunt: current findings.

Identification of four genes, each with its own clinical significance, promises probes for early diagnosis of colorectal cancer in the near future. It also suggests possibilities for new forms of chemotherapy to offset the effects of mutated or lost genes. Given the "moving target" of metastasis, this is likely to be a more fruitful approach than gene replacement--and a more immediate one.

Adenomatous Polyposis Coli↗
PubMed2000

[Recombinant adenovirus expressing wild-type p53 is antiagiogenic--implication for lung cancer gene therapy].

Angiogenesis is required for the growth and progression of malignancies. Recent studies have demonstrated that genetic alterations may accompany acquisition of the angiogenic phenotype. Here we demonstrate that the recombinant adenovirus-mediated transfer of the wild-type p53 gene into a mutant p53-expressing human non-small cell lung cancer cell line markedly inhibited the expression of an angiogenic factor, vascular endothelial growth factor (VEGF), and increased the expression of a novel antiangiogenic factor, brain-specific angiogenesis inhibitor 1 (BAI 1), resulting in reduced neovascularization in vivo. These results may explain in part the mechanism of the bystander effect induced by wild-type p53 gene transfer of adjacent tumor cells.

Adenoviridae↗
PubMed2003

Coupled two-way clustering analysis of breast cancer and colon cancer gene expression data.

UNLABELLED: We present and review coupled two-way clustering, a method designed to mine gene expression data. The method identifies submatrices of the total expression matrix, whose clustering analysis reveals partitions of samples (and genes) into biologically relevant classes. We demonstrate, on data from colon and breast cancer, that we are able to identify partitions that elude standard clustering analysis. AVAILABILITY: Free, at http://ctwc.weizmann.ac.il.. SUPPLEMENTARY INFORMATION: http://www.weizmann.ac.il/physics/complex/compphys/bioinfo2/

Algorithms↗
PubMed2002

Prostate cancer gene therapy.

Numerous gene therapy trials in the United States and throughout the world using various strategies are in progress for the treatment of locally advanced and metastatic prostate cancer. Although vector technology advances at a rapid pace, progress in elucidating the molecular pathways critical for the development and progression of prostate cancer has been slower and more deliberate. Thus far, prostate gene therapy appears to be safe and well tolerated. Through these early clinical trials, the safety and efficacy of gene therapy alone or in combination with more conventional therapy as a basis for the treatment of prostate cancer will ultimately be determined.

Adenoviridae↗
PubMed1997

Cancer gene therapy using a novel adeno-associated virus vector expressing human wild-type p53.

Previous studies have indicated that transfer of wild-type (wt) p53 cDNA into cancer cells can suppress the tumor phenotype in vitro and in vivo. In this study we examined the effects of wt p53 transduction in the human cancer cell line H-358 (that bears a homozygous deletion of p53) using a novel recombinant adeno-associated viral vector engineered to express wt p53 (rAAVp53). Western blot analysis demonstrated the expression of wt p53 in H-358 cells following infection with rAAVp53. Furthermore, rAAVp53 inhibited the growth of the neoplastic cells and also mediated cytotoxicity. Cell cycle analysis of rAAVp53-infected cells showed a significant increase in the percentage of cells arrested at the G1-S checkpoint. H-358 cells infected with rAAVp53 underwent apoptosis as demonstrated by the morphological appearance of DAPI-stained nuclei. Direct injection of rAAVp53 into H-358 tumors implanted subcutaneously in immunodeficient nu/nu mice inhibited tumor growth completely in three of the five animals tested. Mock-infected and rAAV control treated tumors showed no growth inhibition. In situ staining in nu/nu mice detected the presence of wild-type p53 protein in residual tumor cells following rAAVp53 administration. The impressive in vivo efficacy of the rAAVp53 suggests a bystander effect. We conclude that rAAV may be effective as a gene transfer vector in the delivery of p53 to cancer cells.

Animals↗
PubMed2001

Systemic administration of a matrix-targeted retroviral vector is efficacious for cancer gene therapy in mice.

Targeting cytocidal vectors to tumors and associated vasculature in vivo is a long-standing goal of human gene therapy. In the present study, we demonstrated that intravenous infusion of a matrix (i.e., collagen)-targeted retroviral vector provided efficacious gene delivery of a cytocidal mutant cyclin G1 construct (designated Mx-dnG1) in human cancer xenografts in nude mice. A nontargeted CAE-dnG1 vector (p = 0.014), a control matrix-targeted vector bearing a marker gene (Mx-nBg; p = 0.004), and PBS served as controls (p = 0.001). Enhanced vector penetration and transduction of tumor nodules (35.7 +/- 1.4%, mean +/- SD) correlated with therapeutic efficacy without associated toxicity. Kaplan-Meier survival studies were conducted in mice treated with PBS placebo, the nontargeted CAE-dnG1 vector, and the matrix-targeted Mx-dnG1 vector. Using the Tarone log-rank test, the overall p value for comparing all three groups simultaneously was 0.003, with a trend that was significant to a level of 0.004, indicating that the probability of long-term control of tumor growth was significantly greater with the matrix-targeted Mx-dnG1 vector than with the nontargeted CAE-dnG1 vector or PBS placebo. The present study demonstrates that a matrix-targeted retroviral vector deployed by peripheral vein injection (1) accumulated in angiogenic tumor vasculature within 1 hr, (2) transduced tumor cells with high-level efficiency, and (3) enhanced therapeutic gene delivery and long-term efficacy without eliciting appreciable toxicity.

Animals↗
PubMed2004

Adeno-associated virus 2-mediated antiangiogenic cancer gene therapy: long-term efficacy of a vector encoding angiostatin and endostatin over vectors encoding a single factor.

Angiogenesis is characteristic of solid tumor growth and a surrogate marker for metastasis in many human cancers. Inhibition of tumor angiogenesis using antiangiogenic drugs and gene transfer approaches has suggested the potential of this form of therapy in controlling tumor growth. However, for long-term tumor-free survival by antiangiogenic therapy, the factors controlling tumor neovasculature need to be systemically maintained at stable therapeutic levels. Here we show sustained expression of the antiangiogenic factors angiostatin and endostatin as secretory proteins by recombinant adeno-associated virus 2 (rAAV)-mediated gene transfer. Both vectors provided significant protective efficacy in a mouse tumor xenograft model. Stable transgene persistence and systemic levels of both angiostatin and endostatin were confirmed by in situ hybridization of the vector-injected tissues and by serum ELISA measurements, respectively. Whereas treatment with rAAV containing either endostatin or angiostatin alone resulted in moderate to significant protection, the combination of endostatin and angiostatin gene transfer from a single vector resulted in a complete protection. These data suggest that AAV-mediated long-term expression of both endostatin and angiostatin may have clinical utility against recurrence of cancers after primary therapies and may represent rational adjuvant therapies in combination with radiation or chemotherapy.

Angiogenesis Inhibitors↗