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Kuopio, Finland

Turunen M.P.,Ark Therapeutics | Yla-Herttuala S.,University of Eastern Finland | Yla-Herttuala S.,Kuopio University Hospital
Cardiovascular Research | Year: 2011

The role of small RNAs in epigenetic regulation is an emerging field. This research may also open novel treatment strategies based on manipulation of the epigenetic status of the target tissues. Our objective is to review epigenetic regulation of key vascular genes and growth factors. Vascular endothelial growth factor A (VEGF-A) is one of the key players in regulating and maintaining cardiovascular functions and pathology. Although its epigenetic regulation is still not completely understood, expression of the VEGF gene can be manipulated by epigenetic mechanisms using small RNAs that are targeted to the gene promoter which results in the alteration of histone code. VEGF exerts its effects mostly through two receptors, VEGFR1 and VEGFR2, and their expression is also regulated by promoter DNA methylation in various cancer cells. These findings suggest the importance of epigenetic mechanisms in the regulation of vascular functions. © The Author 2011. Source

Samaranayake H.,Ark Therapeutics | Samaranayake H.,University of Eastern Finland | Maatta A.-M.,Ark Therapeutics | Pikkarainen J.,Ark Therapeutics | And 3 more authors.
Human Gene Therapy | Year: 2010

In 1971 Judah Folkman proposed the concept of antiangiogenesis as a therapeutic target for cancer. More than 30 years later, concept became reality with the approval of the antivascular endothelial growth factor (VEGF) monoclonal antibody bevacizumab as a first-line treatment for metastatic colorectal cancer. Monoclonal antibodies and small molecular drugs are the most widely applied methods for inhibition of angiogenesis. The efficacy of these antiangiogenic modalities has been proven, in both preclinical and clinical settings. Although angiogenesis plays a major role in wound healing, hypoxia, and in the female reproductive cycle, inhibition of angiogenesis seems to be a relatively safe therapeutic option against cancers, and has therefore become a logical arena for a wide range of experimentation. The twentieth century has shown the boom of gene therapy and thus it has been applied also in the antiangiogenic setting. This review summarizes methods to induce antiangiogenic responses with gene therapy and discusses the obstacles and future prospects of antiangiogenic cancer gene therapy. © 2010, Mary Ann Liebert, Inc. 2010. Source

Lehtinen J.,University of Helsinki | Raki M.,University of Helsinki | Bergstrom K.A.,University of Helsinki | Uutela P.,University of Helsinki | And 11 more authors.
PLoS ONE | Year: 2012

Background: Epidermal growth factor receptor (EGFR) is overexpressed in many solid tumor types, such as ovarian carcinoma. Immunoliposome based drug targeting has shown promising results in drug delivery to the tumors. However, the ratio of tumor-to-normal tissue concentrations should be increased to minimize the adverse effects of cytostatic drugs. Methodology/Principal Findings: We studied the EGFR-targeted doxorubicin immunoliposomes using pre-targeting and local intraperitoneal (i.p.) administration of the liposomes. This approach was used to increase drug delivery to tumors as compared to direct intravenous (i.v.) administration of liposomes. EGFR antibodies were attached on the surface of PEG coated liposomes using biotin-neutravidin binding. Receptor mediated cellular uptake and cytotoxic efficacy of EGFR-targeted liposomes were investigated in human ovarian adenocarcinoma (SKOV-3 and SKOV3.ip1) cells. In vivo distribution of the liposomes in mice was explored using direct and pre-targeting approaches and SPECT/CT imaging. Targeted liposomes showed efficient and specific receptor-mediated binding to ovarian carcinoma cells in vitro, but the difference in cytotoxicity between targeted and non-targeted liposomes remained small. The relatively low cytotoxic efficacy is probably due to insufficient doxorubicin release from the liposomes rather than lack of target binding. Tumor uptake of targeted liposomes in vivo was comparable to that of non-targeted liposomes after both direct and pre-targeting administration. For both EGFR-targeted and non-targeted liposomes, the i.p. administration increased liposome accumulation to the tumors compared to i.v. injections. Conclusions/Significance: Intraperitoneal administration of liposomes may be a beneficial approach to treat the tumors in the abdominal cavity. The i.p. pre-targeting method warrants further studies as a potential approach in cancer therapy. © 2012 Lehtinen et al. Source

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