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PubMed1997

How cancer gene testing can benefit patients.

A revolution has taken place in the past few decades in our understanding of the genetic origins of human cancer. In particular, genes implicated in inherited susceptibility to forms of cancer are increasingly being identified and their mutations characterized. Many of these genes are also involved in sporadic tumours of the same type, as well as additional tumour types. Understanding of these genes will therefore affect an even greater number of patients.

Bioethics↗

PubMed1996

Strategies for cancer gene therapy using adenoviral vectors.

Modification of tumor cells using gene transfer either to enhance host immunity or to act directly on tumor cells is being intensively studied in animal models. Remarkable results have yielded to approved clinical protocols in the treatment of cancer patients using this approach. Several methods of gene delivery have been developed. This article is particularly devoted to the interest of the use of adenoviral vectors in the different strategies of cancer gene therapy.

Adenoviridae↗

PubMedDate not supplied

Effect of confluence state and passaging on global cancer gene expression pattern in oral carcinoma cell lines.

BACKGROUND: After establishment of a cell culture, inhomogenous growth and cell selection takes place at early passages. Reproducing the same confluence state among experiments might be difficult. MATERIALS AND METHODS: Here we used cDNA arrays to compare the global gene expression pattern of two oral cancer cell lines at 80%, 100% and super-confluence stages. Also, the stability of the global gene expression pattern during culture was assessed in two cell lines at passages 10 and 53 (early and late passage). An intraclass correlation coefficient test was used for comparisons. RESULTS: The consistency between the different confluence states was almost perfect (> 0.8) and substantial (0.6-0.8). Also the consistency between early and late passages was almost perfect in the cell lines used. CONCLUSION: Our results indicate that neither the state of confluence nor passage have significant effects on the global gene expression profile, despite the variability in expression levels of individual genes.

Carcinoma, Squamous Cell↗

PubMed1986

Cancer genes: their clinical potential.

The central problem in cancer therapy is the poor selectivity of current systemic agents against the common solid tumours. The demonstration that unique segments of DNA, constant in location and conserved in evolution, are involved in growth control opens new avenues for basic and clinical research. The functions of the products of these oncogenes need to be elucidated. Examples of growth control functions include homology to growth factors, surface receptors, protein kinases and cell cycle control proteins. From DNA sequence data peptides predicted to be exposed within intact molecules have been constructed and used to produce monoclonal antibodies to oncogene products. Such antibodies have demonstrated the intracellular localisation of oncogene products and their cell cycle regulatory role. A battery of antibodies against the different oncogene products can be used to aid diagnosis and prognosis. Immunohistology and other methods permit the geographical and quantitative analysis of oncoprotein function in normal and neoplastic tissues. New tumour marker systems have been uncovered. Furthermore, by purification and biochemical analysis the molecular basis for the action of these proteins can be elucidated. It is likely that by the end of the decade new drugs that inhibit oncoprotein function will be available for clinical trial.

Animals↗

PubMed2004

Comparing solid tumors with cell lines: implications for identifying drug resistance genes in cancer.

Gene expression arrays allow researchers to profile the differences between cell lines or tissues and they may identify genetic markers of development, organ maturation, or tumor progression. Although a primary tumor that grows in a host and a tumor-cell-line derived from that primary tumor and grown in vitro share similar gene expression profiles, there are, not unexpectedly, some important differences. In fact, Stein and colleagues have found that genes that are differentially expressed in primary tumors as compared to the specific genes expressed in their cell-line derivatives are more reliably predictive of tumor tractability. Thus, sensitivity in vitro might not reflect sensitivity in vivo. Because anti-tumor compounds are largely evaluated in cell culture assays, these compounds' therapeutic utility must be judged in light of genes described by Stein et al. that better predict tractability.

Antineoplastic Agents↗

PubMed2022

Reversal of cancer gene expression identifies repurposed drugs for diffuse intrinsic pontine glioma.

Diffuse intrinsic pontine glioma (DIPG) is an aggressive incurable brainstem tumor that targets young children. Complete resection is not possible, and chemotherapy and radiotherapy are currently only palliative. This study aimed to identify potential therapeutic agents using a computational pipeline to perform an in silico screen for novel drugs. We then tested the identified drugs against a panel of patient-derived DIPG cell lines. Using a systematic computational approach with publicly available databases of gene signature in DIPG patients and cancer cell lines treated with a library of clinically available drugs, we identified drug hits with the ability to reverse a DIPG gene signature to one that matches normal tissue background. The biological and molecular effects of drug treatment was analyzed by cell viability assay and RNA sequence. In vivo DIPG mouse model survival studies were also conducted. As a result, two of three identified drugs showed potency against the DIPG cell lines Triptolide and mycophenolate mofetil (MMF) demonstrated significant inhibition of cell viability in DIPG cell lines. Guanosine rescued reduced cell viability induced by MMF. In vivo, MMF treatment significantly inhibited tumor growth in subcutaneous xenograft mice models. In conclusion, we identified clinically available drugs with the ability to reverse DIPG gene signatures and anti-DIPG activity in vitro and in vivo. This novel approach can repurpose drugs and significantly decrease the cost and time normally required in drug discovery.

Humans↗

PubMed2006

Cancer gene therapy targeting angiogenesis: an updated review.

Since the relationship between angiogenesis and tumor growth was established by Folkman in 1971, scientists have made efforts exploring the possibilities in treating cancer by targeting angiogenesis. Inhibition of angiogenesis growth factors and administration of angiogenesis inhibitors are the basics of anti-angiogenesis therapy. Transfer of anti-angiogenesis genes has received attention recently not only because of the advancement of recombinant vectors, but also because of the localized and sustained expression of therapeutic gene product inside the tumor after gene transfer. This review provides the up-to-date information about the strategies and the vectors studied in the field of anti-angiogenesis cancer gene therapy.

Angiogenesis Inhibitors↗

PubMed1998

Loss of tumorigenicity of human pancreatic carcinoma cells engineered to produce interleukin-2 or interleukin-4 in nude mice: a potentiality for cancer gene therapy.

To examine the possibility of cytokine gene therapy in relation to pancreatic cancer, we evaluated the antitumor effect of human pancreatic carcinoma cells (AsPC-1) which were retrovirally-transduced with several kinds of cytokine genes. These cells were inoculated into BALB/c nude mice and their tumor volumes were assessed. The in vitro growth rate of the transduced cells was not different from that of a parental cell line. Among the transduced cells, human interleukin (IL)-6-transduced AsPC-1 and mouse granulocyte macrophage colony-stimulating factor-transduced AsPC-1 cells showed a significant retardation of tumor growth compared with a parental cell line. In the cases of AsPC-1 cells transduced with the human IL-2 or mouse IL-4 gene, small tumors were generated but thereafter they regressed completely. Histological examinations showed monocytic cell infiltration around the tumors of IL-2- or IL-4-producing cells. These data suggest that secretion of IL-2 or IL-4 from tumor cells can induce an antitumor effect even in the defective condition of mature T cells.

Animals↗

PubMed2006

Cancer gene therapy using a novel secretable trimeric TRAIL.

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), a member of the TNF family, is a type II transmembrane cytokine molecule. Soluble TRAIL has been shown to induce apoptosis in a wide variety of cancer cells in vitro and to suppress tumor growth specifically without damaging normal cells and tissues in vivo. In our previous report, we have demonstrated that an artificial gene encoding the polypeptide composed of the three functional elements (a secretion signal, a trimerization domain and an apoptosis-inducing moiety of TRAIL gene sequence) expresses and secretes highly apoptotic trimeric TRAIL into the culture supernatant. Here, as an approach to TRAIL-based cancer gene therapy, we developed an adenoviral vector delivering the gene that encodes our secretable trimeric TRAIL (stTRAIL). This adenovirus (Ad-stTRAIL) potently induced apoptosis in vitro in cancer cell lines such as HeLa, MDA-MB-231, A549, HCT116 and U-87MG. In an animal xenograft tumor model bearing a human glioma cell line U-87MG, intratumoral delivery of Ad-stTRAIL dramatically suppressed tumor growth without showing detectable adverse side effects. Histological analysis revealed that Ad-stTRAIL suppresses tumor growth by inducing apoptotic cell death. Contrary to the known rapid clearance of systemically delivered TRAIL protein from the blood circulation, stTRAIL expressed by Ad-stTRAIL in tumor tissues persisted for more than 4 days. In a comparison of tumor suppressor activity between Ad-stTRAIL and Ad-flTRAIL (delivering the full-length TRAIL gene) after mixing infected cells with uninfected cells and implanting these mixed cells in nude mice, Ad-stTRAIL showed higher tumor suppressor activity than that of Ad-flTRAIL. Our data reveal that a gene therapy using Ad-stTRAIL has a promising potential to treat human cancers including gliomas.

Adenoviridae↗

PubMed2005

Transcriptional targeting modalities in breast cancer gene therapy using adenovirus vectors controlled by alpha-lactalbumin promoter.

The breast-specific antigen alpha-lactalbumin is expressed in >60% of breast cancer tissues. To evaluate the effect of gene therapy for breast cancer by controlling adenovirus replication with human alpha-lactalbumin promoter, we investigated the activity of a 762-bp human alpha-lactalbumin promoter. Alpha-lactalbumin promoter showed significantly higher activity in MDA-MB-435S and T47D breast cancer cells than in normal breast cell lines or other tumor cell lines. We then developed two novel breast cancer-restricted replicative adenoviruses, AdALAE1a and AdE1aALAE1b. In AdALAE1a, expression of adenoviral E1a gene is under the control of alpha-lactalbumin promoter, and in AdE1aALAE1b, expression of both E1a and E1b genes is under the control of a single alpha-lactalbumin promoter. Both breast cancer-restricted replicative adenoviruses showed viral replication efficiency and tumor cell-killing capability similar to wild-type adenovirus in MDA-MB-435S and T47D cells. The replication efficiency and tumor cell-killing capability of both viruses were attenuated significantly in cells that did not support alpha-lactalbumin promoter. AdE1aALAE1b showed better breast cancer-restricted replication than AdALAE1a, suggesting that a transcriptional targeting modality with alpha-lactalbumin promoter controlling both E1a and E1b gene expression is superior to alpha-lactalbumin promoter controlling only E1a gene expression. Importantly, we found that AdE1aALAE1b could be used to target hormone-independent breast tumors in vivo by inhibiting the growth of MDA-MB-435S s.c. tumors. These data showed that alpha-lactalbumin promoter could regulate the replication of adenovirus to target hormone-independent breast cancers, suggesting that alpha-lactalbumin promoter can be used to develop a novel therapeutic modality for hormone-independent breast cancer.

Adenoviridae↗

PubMed2004

Strategies for cancer gene therapy.

Gene therapy offers new opportunities for cancer treatment and prevention through the use of targeted, relatively nontoxic treatments that can identify, disable, and destroy malignant cells. This article reviews the principles behind oncogene inactivation, tumor suppressor gene replacement, inhibition of angiogenesis, immunopotentiation, molecular chemotherapy, and addition of drug resistance genes. The adcantages and limitations of viral and nonviral vectors for delivery of the therapeutic genes are presented.

Adjuvants, Immunologic↗

PubMed2000

Bystander effect in herpes simplex virus-thymidine kinase/ganciclovir cancer gene therapy: role of gap-junctional intercellular communication.

Antitumor suicide gene therapy is one of the emerging strategies against cancer. It consists of the introduction into cancer cells of a gene capable of converting a nontoxic prodrug into a cytotoxic drug. Because this therapeutic gene cannot be easily introduced into the whole cell population of a tumor, the successful eradication of tumors depends on a phenomenon called the "bystander effect," by which the introduced gene can affect even cells in which it is not itself present. From a therapeutic point of view, it may be crucial to enhance this phenomenon through various means to achieve tumor eradication. One such suicide gene, the thymidine kinase gene from the herpes simplex virus, in combination with the prodrug ganciclovir, has been extensively and successfully used in some animal models exhibiting a strong bystander effect. Among the mechanisms involved in this phenomenon, gap junctional intercellular communication (GJIC) is directly involved in the transfer of the toxic metabolites of ganciclovir, which pass directly from herpes simplex virus thymidine kinase-expressing cells to surrounding cells that do not express it. Because GJIC appears to be a mediator of the bystander effect both in vitro and in vivo, here we review possible molecular strategies for enhancing the extent of tumor cell death by increasing the intratumoral GJIC capacity.

Animals↗

PubMed2001

Application of Cre-loxP system to the urinary tract and cancer gene therapy.

The bacteriophage P1-derived Cre-loxP system is a powerful and versatile tool for in vivo DNA recombination. It is widely used in gene targeting research. The combination of the Cre-loxP system and a specific promoter enables conditional "knockout" of a target gene in a particular tissue or cell type. It has also made it possible to delete genes in adult animals that are essential for embryogenesis. This system is also used to enhance tissue- or tumor-specific promoter activities that are useful for gene therapy of certain types of cancer. It is expected that this simple and effective system will be further utilized in various research applications.

Animals↗

PubMed2005

A new targeting approach for breast cancer gene therapy using the heparanase promoter.

Gene therapy with adenoviral (Ad) vectors is a promising new approach in the treatment of cancer. Strategies to restrict adenoviral-mediated transgene expression are important to avoid gene transfer into normal cells. Heparanase (HPR) is overexpressed in breast cancer but downregulated in differentiated normal tissue. Expression of the HPR gene was evaluated in breast cancer cells. Biodistribution and liver tropism was evaluated in a mouse model. HPR is highly expressed in breast cancer tissue. The HPR promoter retained its fidelity in an adenovirus context and was activated in breast cancer cells but showed low activity in normal breast cells and the murine liver. We conclude that the HPR pathway is a promising target for the development of breast cancer directed gene therapy strategies.

Adenoviridae↗

PubMed2001

Antiproliferative prostaglandins and the MRP/GS-X pump role in cancer immunosuppression and insight into new strategies in cancer gene therapy.

A dramatic complication in late-stage cancer patients is host immunosuppression. Cyclopentenone prostaglandins (CP-PGs) overproduced in cancer may impair the function of the immune system. These agents, if produced at high concentrations, are powerful cytostatic and cytotoxic compounds that may arrest cell proliferation and immune response in cancer. Lymphoid tissues of tumor-bearing animals accumulate large amounts of CP-PGs, whereas the tumor tissue does not. This may be because cancer cells are able to overexpress multidrug resistance-associated protein (Mg(2+)-dependent vanadate-sensitive GS-conjugate export ATPase, MRP/GS-X pump), which extrudes CP-PGs to the extracellular space as glutathione S-conjugates. In contrast, MRP/GS-X pump activity is disproportionately low in lymphocytes. This led us to propose the transfection of lymphocytes with multidrug resistance-associated protein genes (MRP) for further autologous transfusion or direct in vivo delivery to lymphocytes by using adenovirus-retrovirus chimeras in order to restore immune system function in cancer, at least partially. We are currently evaluating MRP-transfected lymphocyte (MTL) therapy, using Walker 256 tumor-bearing rats as a model.

Animals↗

PubMed2007

Entrapment of retroviral vector producer cells in three-dimensional alginate scaffolds for potential use in cancer gene therapy.

We explored the possibility of entrapping retroviral vector producing cells (VPC) within porous 3D matrix to induce a local and sustained release of viral particles to the malignant milieu. PA317/STK, which constantly shed retroviral vectors, was used to transduce cancer cells with the herpes simplex virus thymidine kinase (HSV-tk) gene. Once HSV-tk is expressed, it preferentially phosphorylates nucleoside analog prodrugs, such as ganciclovir (GCV) and N-methanocarbathymidine (N-MCT), to their active triphosphate metabolites, which when incorporated into cellular DNA cause cell death. PA317/STK cells were seeded within 3D alginate scaffold at two different cell densities via static seeding procedure. In vitro assays determined that PA317/STK seeded at high-cell density in scaffolds maintained constant cell number, low cell leakage, and spheroid morphology with viral vector transfection activity. Postcell-seeding viral vector activity was confirmed by transfection of murine colon cancer cells (MC38) with conditioned media originated from VPC-containing scaffolds and the subsequent ability to generate N-MCT triphosphate. Preliminary in vivo transplantation of VPC-containing scaffolds into the peritoneal cavity of mice bearing intraperitoneal MC38 tumors with 2 weeks subsequent GCV administration resulted in a significantly higher survival rate relative to control groups. Our results demonstrate the feasibility of employing alginate scaffolds to efficiently entrap and support PA317/STK cells for cancer gene therapy.

Alginates↗

PubMedDate not supplied

Psychological issues among children of hereditary breast cancer gene (BRCA1/2) testing participants.

Children growing up in hereditary breast cancer families may experience diminished psychological well-being. In addition to coping with having a cancer-affected parent or close relatives, these children may focus on their own health risks in light of shared genetic information. While knowledge of a parent's BRCA1/2 negative status may allay a subset of children's worries and fears about cancer, others could experience distressing thought patterns over positive test results. The purpose of this preliminary study is to explore conceptions of health, cancer risk, and psychological adjustment among children in families suggestive of carrying BRCA1/2 susceptibility genes. As part of a longitudinal investigation of the outcomes of BRCA1/2 testing in adults, 20 children of a highly select group of 15 mothers (80% previously affected by breast/ovarian cancer) completed a self-report survey of their beliefs and opinions regarding cancer and genetic testing, stress and worry about cancer, and anxiety, depression, and behavior problems. All information was completed at baseline, prior to the mother's receipt of her genetic test result. The data did not suggest unusually elevated cancer worries or psychological adjustment problems in these children at this point in the parental genetic testing process. However, children with more psychological distress symptoms did experience more frequent thoughts of becoming sick and greater cancer worries. To the extent that learning about a parent's positive test result could exacerbate these tendencies, recommendations to promote child psychological and family communications research that monitor such responses are offered.

Adolescent↗

PubMed1998

A population study of mutations and LOH at breast cancer gene loci in tumours from sister pairs: two recurrent mutations seem to account for all BRCA1/BRCA2 linked breast cancer in Iceland.

The majority of breast cancer in high risk families is believed to result from a mutation in either of two genes named BRCA1 and BRCA2. A germline defect in either gene is usually followed by chromosomal deletion of the normal allele in the tumour. In Iceland two recurrent mutations have been identified, 999del5 BRCA2 and G5193A BRCA1. In this study, randomly selected pairs of sisters diagnosed with breast cancer at the age of 60 years or younger were analysed to evaluate the proportion of breast cancer resulting from BRCA1 and BRCA2. Genotypes and allele loss in tumour tissue from 42 sister pairs were compared using markers within and around the BRCA1 and BRCA2 genes. Eleven sister pairs were highly suggestive of BRCA2 linkage, and no obvious BRCA1 linkage was seen. Screening for the G5193A BRCA1 and 999del5 BRCA2 mutations showed the 999del5 mutation in the 11 BRCA2 suggestive pairs plus three pairs less indicative of linkage, and the G5193A BRCA1 mutation in one pair. When known mutation carriers are removed from the group, no indication of further linkage to BRCA1 or BRCA2 is seen. The results of our studies suggest that a large proportion of familial breast cancer in Iceland is the result of the 999del5 BRCA2 mutation, and it is unlikely that BRCA1 and BRCA2 germline mutations other than 999del5 and G5193A play a significant role in hereditary breast cancer in Iceland. Furthermore it can be concluded that most families with BRCA1 or BRCA2 linkage are easily identified by studying LOH around the defective gene in as few as two affected relatives.

Age Factors↗