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Query: UMLS:C0006142 (breast cancer)
 160,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Gene therapy with Herpes Simplex Virus thymidine kinase gene (HSV-tk) is effective in various tumor models in vitro and in vivo. We compared the efficacy of the HSV-tk gene therapy in vitro and in vivo in MCF-7 and MCF7-ras cells which form tumor in athymic mice. After viral infection, cells were treated with GCV (Ganciclovir) and live cells were counted. The in vitro treatment significantly inhibited cell growth but did not induce early and late apoptosis, measured, respectively, by annexin or by propidium iodide staining and a significant cell death. The HSV-tk/GCV treatment of MCF7-ras tumor in athymic mice showed a significant inhibition of tumor development until 60 days post-treatment. Some mice showed a complete tumor eradication without tumor regrowth after the end of treatment. In conclusion, we demonstrated that the HSV-tk/GCV system is not very efficient in vitro, but very efficient in vivo in our animal breast cancer model.
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PMID:"Suicide" gene therapy of breast cancer cells is only cytostatic in vitro but anti-tumoral in vivo on breast MCF7-ras tumor. 1564 26

Oncolytic herpes simplex virus vectors are a promising strategy for cancer therapy, as direct cytotoxic agents, inducers of antitumor immune responses, and as expressers of anticancer genes. Progress is dependent upon representative preclinical models to evaluate therapy. In this study, two families of oncolytic herpes simplex virus vectors (G207 and NV1020 series) that have been in clinical trials were examined for the treatment of breast cancer, using the C3(1)/T-Ag transgenic mouse model. Female mice spontaneously develop mammary carcinomas, and the C3(1)/T-Ag-derived tumor cell line M6c forms implantable tumors. Both in vitro and in vivo, G47Delta, derived from G207 by deletion of ICP47 and the US11 promoter, was more efficacious than G207. Whereas NV1023, derived from NV1020 by deletion of ICP47 and insertion of LacZ, was as cytotoxic to M6c cells in vitro as G47Delta, it did not inhibit the growth of s.c. M6c tumors but did extend the survival of intracerebral tumor bearing mice. In contrast, NV1042, NV1023 expressing interleukin 12, inhibited s.c. M6c tumor growth to a similar extent as G47Delta, but was less effective than NV1023 in intracerebral tumors. In the spontaneously arising mammary tumor model, when only the first arising tumor per mouse was treated, G47Delta inhibited the growth of a subset of tumors, and when all tumors were treated, G47Delta significantly delayed tumor progression. When the first mammary tumor was treated and the remaining mammary glands removed, NV1042 was more efficacious than G47Delta at inhibiting the growth and progression of injected tumors.
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PMID:Oncolytic herpes simplex virus vector therapy of breast cancer in C3(1)/SV40 T-antigen transgenic mice. 1573 42

Replication-selective oncolytic herpes simplex virus (HSV) has shown considerable promise as an antitumor agent. Although the current oncolytic HSVs were exclusively constructed from HSV-1, HSV-2 has several unique features that could be exploited to convert the virus to an oncolytic agent. The N-terminus of the HSV-2 ICP10 gene product contains a well-defined serine/threonine protein kinase (PK) domain, which can activate the Ras/MEK/MAPK mitogenic pathway and thus facilitate efficient HSV-2 replication. Because the Ras signaling pathway is a key regulator of normal cell growth and malignant transformation, it is aberrantly activated in many human tumors. Here we report that a mutant HSV-2 (FusOn-H2), constructed by replacing the PK domain of ICP10 with the gene encoding the green fluorescent protein, can selectively replicate in and thus lyse tumor cells. Moreover, infection of FusOn-H2 led to syncytia formation in tumor cells, providing an additional tumor-destroying mechanism. A single moderate-dose injection of FusOn-H2 into established breast cancer xenografts completely eradicated the tumors in more than 80% of the animals, leading to their long-term survival. We conclude that this HSV-2 mutant is a safe and potent oncolytic agent useful for the treatment of malignant solid tumors such as breast cancer.
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PMID:A mutant type 2 herpes simplex virus deleted for the protein kinase domain of the ICP10 gene is a potent oncolytic virus. 1656 13

Oncolytic herpes simplex virus-1 (HSV-1) mutants selectively replicate in and lyse tumor cells. Viral replication is dependent on the cellular proliferative mechanism. Estrogen increases cellular proliferation and decreases apoptosis in estrogen receptor-positive (ER+) human breast cancer cells. We hypothesize that the cellular changes produced by estrogen may enhance oncolytic viral replication and improve the treatment of ER+ breast cancer cells. Estrogen increased proliferation and replication of the HSV-1 mutant, NV1066, in ER+ breast cancer cells. Additionally, cells grown with estrogen had lower rates of apoptosis and higher bcl-2 levels at baseline and after infection. Estrogen enhanced the oncolytic effect of NV1066, with cell kills of 95% and 97% at MOIs of 0.1 and 0.5, compared to 53 and 87% respectively without estrogen (p<0.001). Therapy of ER+ human breast cancer cells with a replication-competent HSV-1 mutant is improved in the presence of estrogen, in contrast to more standard therapies, such as chemotherapy and radiation, which demonstrate decreased efficacy in similar conditions. These data provide the mechanistic basis for the use of oncolytic HSV-1 in patients with hormone receptor-positive breast cancer, particularly if the disease progresses with conventional therapies.
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PMID:Estrogen enhances the efficacy of an oncolytic HSV-1 mutant in the treatment of estrogen receptor-positive breast cancer. 1668 45

The human epidermal growth factor receptor 2/neuregulin (HER2/neu) receptor is overexpressed in highly malignant mammary and ovarian tumors and correlates with a poor prognosis. It is a target for therapy; humanized monoclonal antibodies to HER2 have led to increased survival of patients with HER2/neu-positive breast cancer. As a first step in the design of an oncolytic herpes simplex virus able to selectively infect HER2/neu-positive cells, we constructed two recombinants, R-LM11 and R-LM11L, that carry a single-chain antibody (scFv) against HER2 inserted at residue 24 of gD. The inserts were 247 or 256 amino acids long, and the size of the gD ectodomain was almost doubled by the insertion. We report the following. R-LM11 and R-LM11L infected derivatives of receptor-negative J or CHO cells that expressed HER2/neu as the sole receptor. Entry was dependent on HER2/neu, since it was inhibited in a dose-dependent manner by monoclonal antibodies to HER2/neu and by a soluble form of the receptor. The scFv insertion in gD disrupted the ability of the virus to enter cells through HVEM but maintained the ability to enter through nectin1. This report provides proof of principle that gD can tolerate fusion to a heterologous protein almost as large as the gD ectodomain itself without loss of profusion activity. Because the number of scFv's to a variety of receptors is continually increasing, this report makes possible the specific targeting of herpes simplex virus to a large collection of cell surface molecules for both oncolytic activity and visualization of tumor cells.
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PMID:A herpes simplex virus recombinant that exhibits a single-chain antibody to HER2/neu enters cells through the mammary tumor receptor, independently of the gD receptors. 1669 34

Hypoxia is a common tumor condition associated with metastases, therapeutic resistance, and poor patient survival. Forty percent of breast cancers are hypoxic, with a median oxygen concentration of 3.9%, and a third of tumors have regions less than 0.3%. Normal breast tissue is reported to have oxygen concentrations greater than 9%. This tumor hypoxia in breast cancer confers resistance to conventional radiation therapy and chemotherapy, as well as making estrogen-receptor-positive tumors less sensitive to hormonal therapy. Novel treatment modalities are needed to target hypoxic tumor cells. Lower tumor oxygen levels compared with surrounding normal tissues may be utilized to target and enhance herpes oncolytic viral therapy in breast cancer. Attenuated oncolytic herpes simplex viruses offer a unique cancer treatment by specifically infecting, replicating within, and lysing tumor cells. They carry genetically engineered mutations to reduce their virulence and attenuate their ability to infect normal tissues. Studies have shown the safety and efficacy of oncolytic herpes simplex viruses in treating breast cancer both in humans and in preclinical models. The placement of essential viral genes under the control of a hypoxia-responsive enhancer, which is upregulated selectively in hypoxic tissue, represents a promising strategy to target oncolytic viruses precisely to hypoxic cancer cells. In this review we describe strategies to harness hypoxia as a trigger for oncolytic viral gene expression in breast cancer, thereby increasing the specificity of viral infection, replication, and cytotoxicity to hypoxic areas of tumor. Such a targeted approach will increase efficacy in the therapy of hypoxic tumors while achieving a reduction in total dose of viral therapy.
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PMID:Employing tumor hypoxia for oncolytic therapy in breast cancer. 1682 62

A 45-year-old woman with breast cancer was admitted to our hospital because of several episodes of disturbed consciousness and generalized convulsions. While these symptoms resolved quickly, dysphagia and bilateral blepharoptosis persisted. Neurological findings were improved by steroid therapy. MRI on the first hospital day showed T2/FLAIR high intensity lesions in both occipital lobes, but these lesions diminished on the 8th day, indicating reversible posterior leukoencephalopathy syndrome. A new lesion appeared in the left temporal lobe on the 8th day. A diagnosis of Hashimoto's encephalopathy (HE) was made due to the following features: 1) encephalitis not due to herpes simplex virus, 2) high titers of antithyroid antibodies in serum, 3) marked effectiveness of steroid therapy, and 4) antibodies against the amino terminal of alpha-enolase, a specific antigen for HE.
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PMID:[Reversible posterior leukoencephalopathy syndrome in Hashimoto's encephalopathy: a case report]. 1715 34

A new oncolytic and fusogenic herpes simplex virus type 1 (HSV-1) was constructed on the basis of the wildtype HSV-1(F) strain. To provide for safety and tumor selectivity, the virus carried a large deletion including one of the two alpha4, gamma(1)34.5, alpha0 genes and the latency-associated transcript region. The gamma(1)34.5 gene, a major neurovirulence factor, was replaced by a gene cassette constitutively expressing the red fluorescent protein gene. Homologous recombination was used to transfer the fusogenic gBsyn3 mutation to the viral genome to produce the OncSyn virus. OncSyn causes extensive virus-induced cell fusion (syncytia) and replicates to higher titers than the parental Onc and HSV-1(F) strains in breast cancer cells. Biochemical analysis revealed that the OncSyn virus retains a stable genome and expresses all major viral glycoproteins. A xenograft mouse model system using MDA-MB-435S-luc (MM4L) human breast cancer cells constitutively expressing the luciferase gene implanted within the interscapular region of animals was used to test the ability of the virus to inactivate breast tumor cells in vivo. Seventy-two mice bearing MM4L breast cancer xenografts were randomly divided into three groups and given two rounds of three consecutive intratumoral injections of OncSyn, inactivated OncSyn, or phosphate-buffered saline 3 days apart. A single round of virus injections resulted in a drastic reduction of tumor sizes (p <or= 0.0001) and diminution of chemiluminescence emitted by the cancer cells (p <or= 0.0002). This effect was enhanced by a second round of virus injections into the tumors 3 days after the first round (p <or= 0.0001). Systematic necropsy and pathological evaluation of the primary tumors revealed that the single round of injections resulted in extensive necrosis of tumor cells (p <or= 0.0001), which was enhanced by the second round of injections (p <or= 0.0002). Internal organs were not affected by virus inoculation. Mouse weights were not significantly impacted by any treatment during the course of the entire study (p = 0.46). These results show that the attenuated, fusogenic, and oncolytic HSV-1(F) virus strain OncSyn may effectively treat human breast tumors in vivo.
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PMID:Effective treatment of human breast tumor in a mouse xenograft model with herpes simplex virus type 1 specifying the NV1020 genomic deletion and the gBsyn3 syncytial mutation enabling high viral replication and spread in breast cancer cells. 1753 76

Gene therapy with adenoviral vectors is a promising new approach for the treatment of refractory advanced breast cancer. Strategies to restrict adenoviral-mediated therapeutic gene expression are important to avoid harming normal cells. Fatty acid synthase (FAS) is overexpressed in several human cancers. FAS is highly expressed in infiltrating breast cancer tissue, and always associated with malignant phenotypes and poor prognosis. In this study, expression of the FAS was evaluated in three breast cancer cell lines. A 680 bp-FAS promoter was cloned and its transcriptional activity was analyzed in breast cancer cell lines. We made a recombinant adenovirus construct carrying herpes simplex virus thymidine kinase (HSV-TK) driven by human FAS promoter (Ad-FAS-TK) and analyzed its target cytotoxicity in vitro and in vivo against human breast cancer cells combined with prodrug ganciclovir (GCV). The results show that the expression of FAS varies in the three breast cancer cell lines examined (respectively, SK-Br3>MCF-7>MDA-MB-231), but FAS promoter can initiate relative high transcriptional activities in all three kinds of cancer cells while little in normal fibroblast cells. Furthermore, FAS promoter can drive the therapeutic gene in a wider range of human breast cancers than cerbB2 promoter and exhibit a stronger activity than midkine (MK) promoter. Combination of Ad-FAS-TK and GCV treatment exhibited strong-targeted cytotoxic effect on breast cancer cells but showed little activity in normal fibroblast cells. The tumorigenic capability of breast cancer cells treated with Ad-FAS-TK/GCV was completely inhibited in vitro and in vivo assays. In conclusion, adenoviral-mediated suicide gene therapy controlled by tumor associated-FAS promoter can induce specific cytotoxic effect on human breast cancer cells in vitro and in vivo. So it is a promising target for the development of gene therapy against breast cancers.
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PMID:A new targeting approach for breast cancer gene therapy using the human fatty acid synthase promoter. 1765

Investigation of the chemical constituents of the fruits of Knema glauca (Myristicaceae) yielded a new acyclic diterpene acid, named glaucaic acid 4, together with four acylphenols, including 1-(2,6-dihydroxyphenyl) tetradecan-1-one 1, malabaricone A 6, dodecanoylphloroglucinol 7 and 1-(2,4,6-trihydroxyphenyl)-9-phenylnonan-1-one 8, two lignans sesamin 2 and asarinin 3, and a flavan, myristinin D 5. In addition, myristinin A 9 and (+/-)-7,4'-dihydroxy-3'-methoxyflavan 10 were isolated from its leaves and stems, respectively. When tested against small-cell lung cancer (NCI-H187), epidermoid carcinoma (KB) and breast cancer (BC) cell lines, compounds 1, 6-8 and 10 displayed weak to moderate cytotoxicity. The acylphenols 6-8 displayed antituberculosis activity against the microbe Mycobacterium tuberculosis with MIC values of 25, 50 and 100 microg/mL, respectively, and antiviral activity against herpes simplex virus type 1, with 7 as the most active compound (IC(50) = 3.05 microg/mL). Malabaricone A 6 was also active against the malarial parasite Plasmodium falciparum with an IC(50) value of 2.78 microg/mL.
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PMID:A new acyclic diterpene acid and bioactive compounds from Knema glauca. 1947 82


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