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At least 91 records · Page 5Linked to original sources
PubMed1983

Patient with 13 chromosome deletion: evidence that the retinoblastoma gene is a recessive cancer gene.

Although a constitutional chromosomal deletion including 13q14 has been found to date in all retinoblastoma patients whose esterase D activity is 50 percent of normal, one female patient has been found who has 50 percent esterase D activity in all normal cells examined but no deletion of 13q14 at the 550-band level. Therefore, she has the smallest constitutional chromosomal deletion within 13q14 that is associated with susceptibility to retinoblastoma. Two stem lines were identified in a retinoblastoma from this patient, and each one had a missing 13 chromosome. No detectable esterase D activity was found in the tumor, indicating that the normal nondeleted 13 chromosome was lost in both stem lines. Thus the data from this patient not only show that there is a total loss of genetic information at the location of the retinoblastoma gene within the tumor, but also imply that recessive genes may play an important role in the development of certain human tumors including retinoblastoma.

Child, Preschool↗
PubMed2005

WWOX--the FRA16D cancer gene: expression correlation with breast cancer progression and prognosis.

AIMS: WWOX is a tumour suppressor gene involved in various tumours including breast cancer. High chromosomal abnormalities in a genomic region spanned by WWOX are associated with the fact that this gene covers approximately 1 million base pairs of the second most affected among common chromosomal fragile sites FRA16D. We evaluated WWOX expression levels in breast cancer samples in association with diagnostics-prognostics markers. METHODS: We performed quantitative real-time RT-PCR to analyse levels of expression of WWOX in 132 cases of breast cancer. We evaluated the relationship between WWOX mRNA levels, clinico-pathological factors, expression of aberrant WWOXDelta6-8 mRNA and other cancer related genes. RESULTS: Expression of WWOX was higher in patients younger than 50 years old, in ER and PR positive tumours vs negative for those receptors and tumours without lymph node metastasis vs LN+. WWOX mRNA levels were also higher in tumours with higher apoptotic index (Bcl2/Bax ratio). Negative associations were found between WWOX expression and cytokeratins 5/6 and 17 (P<0.05). High level expression of WWOX was also associated with better disease free survival. Presence of WWOXDelta6-8 transcripts were accompanied with lower WWOX wild type mRNA level. CONCLUSIONS: Reduced WWOX expression commonly observed in various neoplasias in cases of breast cancer is associated with markers of bad prognosis. Our findings reveal additional evidence that WWOX may be involved in steroid (estrogens) metabolism and signaling pathways. WWOX can be considered as a new target for gene therapy development due to the association of high WWOX expression with improved disease free survival.

Adult↗
PubMed2024

SJPedPanel: A Pan-Cancer Gene Panel for Childhood Malignancies to Enhance Cancer Monitoring and Early Detection.

PURPOSE: The purpose of the study was to design a pan-cancer gene panel for childhood malignancies and validate it using clinically characterized patient samples. EXPERIMENTAL DESIGN: In addition to 5,275 coding exons, SJPedPanel also covers 297 introns for fusions/structural variations and 7,590 polymorphic sites for copy-number alterations. Capture uniformity and limit of detection are determined by targeted sequencing of cell lines using dilution experiment. We validate its coverage by in silico analysis of an established real-time clinical genomics (RTCG) cohort of 253 patients. We further validate its performance by targeted resequencing of 113 patient samples from the RTCG cohort. We demonstrate its power in analyzing low tumor burden specimens using morphologic remission and monitoring samples. RESULTS: Among the 485 pathogenic variants reported in RTCG cohort, SJPedPanel covered 86% of variants, including 82% of 90 rearrangements responsible for fusion oncoproteins. In our targeted resequencing cohort, 91% of 389 pathogenic variants are detected. The gene panel enabled us to detect &#x223c;95% of variants at allele fraction (AF) 0.5%, whereas the detection rate is &#x223c;80% at AF 0.2%. The panel detected low-frequency driver alterations from morphologic leukemia remission samples and relapse-enriched alterations from monitoring samples, demonstrating its power for cancer monitoring and early detection. CONCLUSIONS: SJPedPanel enables the cost-effective detection of clinically relevant genetic alterations including rearrangements responsible for subtype-defining fusions by targeted sequencing of &#x223c;0.15% of human genome for childhood malignancies. It will enhance the analysis of specimens with low tumor burdens for cancer monitoring and early detection.

Humans↗
PubMed1996

Adenovirus-mediated gene transfer to human breast tumor cells: an approach for cancer gene therapy and bone marrow purging.

To examine the potential use of adenovirus vectors in cancer gene therapy as a mechanism for purging bone marrow cells of possible breast cancer contaminants, we compared the infection efficiency of adenovirus and the transfection efficiency of plasmid DNA in the presence of adenovirus in human breast cancer and bone marrow cells. Following infection of breast cancer cells with an adenovirus expressing beta-galactosidase gene, high levels of beta-galactoside activity were observed. No beta-galactosidase activity was observed in low-density human bone marrow cells. A replication-deficient adenovirus mutant dl312 enhanced the transfection efficiency of a plasmid DNA-expressing beta-galactosidase gene into breast cancer cells, and addition of a liposome, lipofectamine, further enhanced the transfection efficiency. In contrast, human bone marrow cells treated under the same conditions expressed very low levels of transfected beta-galactosidase DNA. Transfection of cells with plasmid DNA expressing a truncated but fully active Pseudomonas exotoxin gene in the presence of dl312 and lipofectamine resulted in marked breast cancer cell killing, whereas colony-forming unit granulocyte-macrophage (CFU-GM) were relatively resistant to these treatments. A recombinant adenovirus expressing human wild-type p53 protein (AdWTp53) was also highly cytotoxic to breast tumor cells. Infection of breast cancer cells with AdWTp53 (100 plaque-forming units/cell) resulted in 100% loss of the clonogenicity of breast tumor cells. However, colony formation from CFU-GM was relatively resistant to the cytotoxic effects of AdWTp53 alone or in the presence of pULI100 plasmid and lipofectamine. On the basis of these results, it is proposed that human adenoviruses are potentially useful for cancer gene therapy and bone marrow purging.

ADP Ribose Transferases↗
PubMed2003

Cancer gene therapy: an awkward adolescence.

At the Eleventh International Conference on Gene Therapy of Cancer (December 12-14, 2002, San Diego, CA) progress on using gene transfer technology to treat cancer was presented. Although there is as yet no cancer gene therapy being marketed, considerable progress has been made in defining likely strategies and likely targets for gene therapy of cancer. These strategies, including viral and non-viral delivery systems, and potential targets in cancer cells linked to our developing knowledge of cancer cell biology, are reviewed in this paper. Use of gene therapy to sensitize tumors to radiation and chemotherapy is one promising area of investigation. Some of the ancillary benefits of research on cancer gene therapy, including the development of public-private partnerships, recruitment of laboratory scientists into clinical research, and credentialing of potential cancer cell targets for therapies other than gene therapy, are noted.

Clinical Trials as Topic↗
PubMed2005

Recombinant polymers for cancer gene therapy: a minireview.

A major challenge for successful cancer gene therapy is the development of safe and effective gene delivery vectors. Gene delivery vectors can be viral or nonviral. Among nonviral vectors various polymeric vectors have shown potential in gene delivery. However, much work needs to be done in order to correlate polymer structure with gene release at the target site and transfection efficiency. This article is a brief introduction into cancer gene therapy, barriers and methods for gene transfer with emphasis on the applications of recombinant polymers for cancer gene therapy.

Amino Acid Sequence↗
PubMed2002

The genus Bifidobacterium for cancer gene therapy.

A fundamental obstacle in cancer gene therapy is the specific targeting of therapy to solid tumor; as yet, no systemic delivery system exists. Bifidobacterium longum, a strain of domestic bacteria that is non-pathogenic and anaerobic, selectively localized to and proliferated in solid tumors after systemic application. We propose a novel approach to cancer gene therapy in which anaerobic bacteria of the genus B longum are used to achieve tumor-specific gene delivery and enzyme-prodrug therapy.

Animals↗
PubMed2005

Hopping around the tumor genome: transposons for cancer gene discovery.

Retroviruses are powerful insertional somatic mutagens that have been used for many landmark discoveries of cancer genes in model organisms. However, their use as a cancer gene discovery tool has been limited to only a few tissues, mainly the hematopoietic system and mammary gland. Recently, the Sleeping Beauty (SB) transposon system was shown to be useful for random somatic cell mutagenesis in mice, allowing the induction or acceleration of tumor formation both in the hematopoietic system and in sarcomas. In these tumors, SB transposons repeatedly "tagged" specific genes, both known and new cancer genes. These results indicate that the SB system has great potential both for generating specific mouse models of human cancer and for cancer gene discovery in a wide variety of tissues.

Animals↗
PubMed2004

Preclinical evaluation of a class of infectivity-enhanced adenoviral vectors in ovarian cancer gene therapy.

Ovarian carcinoma cells are often infected inefficiently by adenoviruses (Ad) due to low expression of coxsackie-adenovirus receptors (CAR), hindering the application of adenovirus-mediated gene therapy in ovarian cancer. In this study, we explored a class of infectivity-enhanced Ad vectors, which contain CAR-independent targeting motifs RGD (Ad5.RGD), polylysine (Ad5.pK7), or both (Ad5.RGD.pK7), for their utility in ovarian cancer gene therapy using in vitro and in vivo model systems. We found that these vectors infected established ovarian carcinoma cell lines and primary ovarian cancer cells with significantly enhanced infectivity. Among them, Ad5.RGD.pK7 appeared to be most efficient. Further, we evaluated their gene delivery efficiency using two different ovarian cancer mouse models--subcutaneous and intraperitoneal human ovarian cancer xenografts. All of the modified vectors appeared to be more efficient than the unmodified Ad5 vector in both models, although some of the differences are not statistically significant. Of these, Ad5.RGD.pK7 exhibited the highest efficacy in the subcutaneous tumor model, while Ad5.pK7 worked most efficiently in the intraperitoneal tumor model. These preclinical results suggest that Ad5.RGD.pK7 and Ad5.pK7 may be very useful in ovarian cancer gene therapy.

Adenoviridae↗
PubMedDate not supplied

Copy number of cancer genes predict tumor grade and survival of pancreatic cancer patients.

Pancreatic cancer is on the increase. While means of early diagnosis are being sought, it continues to present late. Prognostication is based on patient and tumor characteristics, including expression or mutation of cancer-related genes. Few studies have examined the impact of the amplification of these genes on the outcome of pancreatic cancer. We have now used a non-radioisotopic slot-blot technique to relate gene copy numbers of p53, c-myc and K-ras to tumor grade and survival. Outcomes were corrected for patient characteristics, tumor location and TNM staging. The Kaplan-Meier test for likelihood of survival showed that increase in copy number of the two oncogenes and loss of p53 were associated with non-significant reduction in survival. When these variations in cancer gene copy numbers were, however, examined by logistic regression analysis in the context of patient and tumor characteristics, survival was negatively related to K-ras amplification (p = 0.0291). Tumor grade, but not survival was positively related to loss of p53 gene copy (p = 0.0131) as well as c-myc amplification (p = 0.0248). Thus using a simple non-radioisotopic technique for the detection of cancer gene copy number in association with patients and disease characteristics, we could predict survival on the one hand and tumor behavior on the other. Such information could be used to plan initial and follow-up therapy.

Adult↗
PubMed2006

The insulinoma-associated 1: a novel promoter for targeted cancer gene therapy for small-cell lung cancer.

The insulinoma-associated 1 (INSM1) gene is expressed exclusively during early embryonal development, but has been found re-expressed at high levels in neuroendocrine tumors. The regulatory region of the INSM1 gene is therefore a potential candidate for regulating expression of a therapeutic gene in transcriptionally targeted cancer gene therapy against neuroendocrine tumors. We analyzed expression of a reporter gene from a 1.7 kb region of the INSM1 promoter in a large number of small-cell lung cancer (SCLC) cell lines. This INSM1 promoter region showed very high levels of expression in most of the SCLC cell lines and expression was absent in cell lines of non-neuroendocrine origin. Inclusion of the general transcriptional enhancer from SV40 compromised the specificity of the promoter and did not enhance transcription in most of the SCLC cell lines. For comparison, the region of the gastrin releasing peptide (GRP) previously suggested for SCLC gene therapy was analyzed in a similar manner. High expression was observed for a number of cell lines, but unlike for the INSM1 promoter, reporter gene expression from the GRP promoter did not correlate to the relative GRP mRNA levels, demonstrating that this region may not contain all necessary regulatory elements. Expression of the suicide gene herpes simplex virus thymidine kinase (HSV-TK) from the INSM1 promoter in combination with treatment with the prodrug ganciclovir (GCV) caused a significant increase in GCV sensitivity specifically in INSM1-expressing cell lines. The INSM1 promoter is therefore a potential novel tool for transcriptionally targeted gene therapy for neuroendocrine tumors.

Antiviral Agents↗
PubMed2003

p53, deleted in colorectal cancer gene, and thymidylate synthase as predictors of histopathologic response and survival in low, locally advanced rectal cancer treated with preoperative adjuvant therapy.

PURPOSE: Adjuvant therapy, either preoperatively or postoperatively, and modifications of surgery have been used to try to improve outcome of surgery for rectal cancer in regard to both local recurrence and survival. Assessment of prognosis in patients after resection is currently primarily based on clinicopathologic factors. These predict the subsequent behavior of the tumor only imperfectly. The aim of this study was to evaluate three potential molecular genetic markers of prognosis (p53, deleted in colorectal cancer gene, and thymidylate synthase) in Dukes Stage B and C low rectal tumors treated with adjuvant therapy and to determine whether they correlate with survival, local recurrence, or the pathologic response to adjuvant therapy (assessed by extent of tumor regression and tumor down-staging). METHODS: Sixty locally advanced low rectal tumors resected after preoperative chemoradiotherapy or radiotherapy alone were studied by immunohistochemical staining for p53, deleted in colorectal cancer gene, and thymidylate synthase. In addition, p53 gene mutations were sought by polymerase chain reaction-single-strand conformation polymorphism analysis. These results were correlated with survival, local recurrence, and pathologic response to adjuvant therapy. RESULTS: Lack of thymidylate synthase staining by immunohistochemistry was associated with tumor down-staging after preoperative chemoradiotherapy but not after radiotherapy or for these two combined groups. There was no correlation between p53, deleted in colorectal cancer gene, or thymidylate synthase immunohistochemical staining or between p53 polymerase chain reaction-single-strand conformation polymorphism and local recurrence or survival in locally advanced low rectal cancers treated with preoperative adjuvant therapies. CONCLUSION: Prediction of prognosis in patients with locally advanced low rectal cancers treated with preoperative adjuvant therapies continues to be problematic. Thymidylate synthase immunohistochemistry appears to be the most promising factor of those assessed in predicting tumor down-staging after preoperative chemoradiotherapy for locally advanced low rectal cancers.

Adenocarcinoma↗
PubMed2005

Calcium phosphate nanoparticles as a novel nonviral vector for efficient transfection of DNA in cancer gene therapy.

To explore an efficient gene vector in cancer gene therapy, a novel nonviral vector calcium phosphate nanoparticle (CPNP) was developed. Transmission electromicroscopy and Zeta potential demonstrated that CPNP was 23.5-34.5 nm diameters and had +16.8 mV positive surface charges. The analysis of the CPNPDNA complex showed CPNP could transfer foreign DNA into targeted cells with high transfection efficiency, as well as its DNA-binding property and protection of DNA from degradation. Furthermore, the CPNP-DNA complex had no obvious cytotoxicity for CNE-2 cells, while the liposome-DNA complex had certain cytotoxicity. When the CPNP combined with suicide genes yCDglyTK for nasopharyngeal carcinoma (NPC) therapy in vitro, just 24.76% of cells survived when the wild-type CNE-2 cells were treated with the CPNP-yCDglyTK complex plus the prodrug, 5-FC (200 mg/mL). Otherwise, the expression of yCDglyTK was detected in implanted CNE-2 tumors by reverse transcription-polymerase chain reaction (RT-PCR) analysis when the CNE-2 tumor was treated with an intratumoral injection of the CPNPyCDglyTK complex. Our results showed that the CPNP might be a potential vector for gene therapy.

Animals↗
PubMed2003

1-Mb resolution array-based comparative genomic hybridization using a BAC clone set optimized for cancer gene analysis.

Array-based comparative genomic hybridization (aCGH) is a recently developed tool for genome-wide determination of DNA copy number alterations. This technology has tremendous potential for disease-gene discovery in cancer and developmental disorders as well as numerous other applications. However, widespread utilization of a CGH has been limited by the lack of well characterized, high-resolution clone sets optimized for consistent performance in aCGH assays and specifically designed analytic software. We have assembled a set of approximately 4100 publicly available human bacterial artificial chromosome (BAC) clones evenly spaced at approximately 1-Mb resolution across the genome, which includes direct coverage of approximately 400 known cancer genes. This aCGH-optimized clone set was compiled from five existing sets, experimentally refined, and supplemented for higher resolution and enhancing mapping capabilities. This clone set is associated with a public online resource containing detailed clone mapping data, protocols for the construction and use of arrays, and a suite of analytical software tools designed specifically for aCGH analysis. These resources should greatly facilitate the use of aCGH in gene discovery.

Cell Line, Tumor↗
PubMed1995

What does it mean to be a cancer gene carrier? Problems in establishing causality from the molecular genetics of cancer.

This article addresses the following question: What does it mean to be a cancer gene carrier? The existence of families prone to cancer has prompted an intense search for predisposing heritable gene mutations. Genes that impart susceptibility to colorectal, breast, and ovarian cancers have been recently identified. It is doubtful, however, that the action of a single mutant gene totally accounts for the development of malignant disease. The mutant gene likely causes cancer in these family members only in conjunction with other genes, environmental factors, or both. Furthermore, although an individual carrier of a mutant gene within a cancer-prone family has an increased risk of malignancy, nutritional, pharmacologic, or other interventions may still confer protection. Extrapolations from cancer-prone families to the general population are even more problematic. The excess risk of malignancy among carriers of mutant genes who are not members of cancer-prone families is unknown. Large-scale epidemiologic studies are needed to determine the magnitude (or even the existence) of such excess risk.

Environmental Exposure↗
PubMed2005

Viral vectors for cancer gene therapy: viral dissemination and tumor targeting.

Cancer gene therapy is the most promising and active field in gene therapy treatment. Although previous experimental and clinical trials have brought forward some exciting cases, in general, the clinical benefits have been limited. A major difference between virus-mediated gene therapy and other therapies is the poor physical diffusibility of viral vectors, which is also one of the major obstacles in cancer gene therapy. As safety is a prerequisite to enhanced viral dissemination, tumor-specific targeting becomes crucial. The present review focuses on questions related to efficient viral dissemination in tumor masses and how to sustain a high level of oncolytic virus targeting of tumor cells only. We will first consider two common reasons for limited virus spread in tumor masses and then discuss strategies for improving the tumor-specific oncolysis of currently used viral vectors and to comment on their advantages and potential problems.

Animals↗
PubMed1993

The search for the familial breast/ovarian cancer gene.

Familial breast cancer is a very common autosomal dominant disorder in women. A predisposing gene for breast and ovarian cancer (BRCA1) has been mapped by linkage analysis to the long arm of chromosome 17. In almost all families with breast and ovarian cancer and half of those with only breast cancer, the disease is linked to this gene. The BRCA1 gene, which is also believed to be involved in sporadic breast and ovarian cancer, should soon be identified.

Breast Neoplasms↗