Combination Antiangiogenic and Immunomodulatory Gene Therapy for Breast Cancer PDF Download
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Languages : en
Pages : 0
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Inhibition of angiogenesis has been shown to be an effective strategy in cancer therapy in mice. We constructed a recombinant adenovirus that expresses endostatin, which resulted in a significant delay of tumor progression of JC breast and Lewis lung carcinoma, and more importantly, in complete prevention of lung metastases formation in Lewis lung carcinoma. The inability to control pre-established tumors may be due to insufficient circulating endostatin levels or to inadequate local endostatin concentrations, both of which have been shown to be important for the anti-tumor effect of endostatin. Thus, we constructed a recombinant adenovirus expressing a murine Ig-endostatin fusion protein resulting in significantly higher circulating endostatin levels with improved anti-tumor activity. Furthermore, a tumor-targeted version of endostatin was made using homing peptides to activated endothelial cells (RGD, NGR) to increase directly endostatin concentrations in the tumor. Finally, conditionally replicating adenovirus (CRAD) targeted to the activated endothelium was very efficacious in selectively destroying 3-D capillary networks. In conclusion the present study clearly demonstrates the potential of vector-mediated antiangiogenic gene therapy in cancer. Changes in vector design resulting in higher transgene expression levels, tumor-targeted delivery of endostatin, or endothelial selective replication of adenovirus may prove to be an effective anti-cancer therapy.
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Languages : en
Pages : 0
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Inhibition of angiogenesis has been shown to be an effective strategy in cancer therapy in mice. We constructed a recombinant adenovirus that expresses endostatin, which resulted in a significant delay of tumor progression of JC breast and Lewis lung carcinoma, and more importantly, in complete prevention of lung metastases formation in Lewis lung carcinoma. The inability to control pre-established tumors may be due to insufficient circulating endostatin levels or to inadequate local endostatin concentrations, both of which have been shown to be important for the anti-tumor effect of endostatin. Thus, we constructed a recombinant adenovirus expressing a murine Ig-endostatin fusion protein resulting in significantly higher circulating endostatin levels with improved anti-tumor activity. Furthermore, a tumor-targeted version of endostatin was made using homing peptides to activated endothelial cells (RGD, NGR) to increase directly endostatin concentrations in the tumor. Finally, conditionally replicating adenovirus (CRAD) targeted to the activated endothelium was very efficacious in selectively destroying 3-D capillary networks. In conclusion the present study clearly demonstrates the potential of vector-mediated antiangiogenic gene therapy in cancer. Changes in vector design resulting in higher transgene expression levels, tumor-targeted delivery of endostatin, or endothelial selective replication of adenovirus may prove to be an effective anti-cancer therapy.
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Languages : en
Pages : 23
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Inhibition of angiogenesis has been shown to be an effective strategy in cancer therapy in mice. However, its widespread application has been hampered by difficulties in the large-scale production of the antiangiogenic proteins. This limitation may he resolved by in vivo delivery and expression of the antiangiogenic genes. We have constructed a recombinant adenovirus that expresses murine endostatin that is biologically active both in vitro as determined in endothelial cell proliferation assays as well as in vivo by suppression of angiogenesis induced by VEGF165. %Persistent high serum levels of endostatin (605- 1740 ng/ml; mean 936 ng/ml) was achieved after systemic administration of the vector to nude mice which resulted in significant reduction of the growth rates and the volumes of JC breast carcinoma and Lewis lung carcinoma (p
Author: Darren W. Davis
Publisher: CRC Press
ISBN: 1420004298
Category : Medical
Languages : en
Pages : 878
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Book Description
Top Investigators Explore the Complexities of Angiogenesis Cancer Research The targeting of tumor angiogenesis has evolved into one of the most widely pursued therapeutic strategies. However, as of yet, no antiangiogenic agent used as a monotherapy has demonstrated a survival benefit in a randomized Phase III trial. The combination of bev
Author: Beverly A. Teicher
Publisher: Springer Science & Business Media
ISBN: 1597451843
Category : Medical
Languages : en
Pages : 585
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Book Description
This volume represents a compendium of scientific findings and approaches to the study of angiogenesis in cancer. The second edition of Antiangiogenic Agents in Cancer Therapy is intended to give a current perspective on the state-of-the-art of angiogenensis and therapy directed at this process. Antiangiogenesis is a dynamic and evolving field in oncology. New therapeutic targets continue to emerge followed by the rapid development of new therapeutic agents to be investigated in clinical trials. Optimizing the therapeutic potential of antiangiogenic agents in combination with the other therapies in the armamentarium to fight cancer will be an on-going challenge.
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Languages : en
Pages : 77
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During the last three years of support of the career development award, we sought to develop and evaluate recombinant adeno-associated virus vectors encoding anti- angiogenic factors. We have completed the work with significant outcome, and also initiated new studies that will allow us to test novel possibilities for breast cancer treatment. The outcome of the present studies strongly indicated that sustained expression of anti-angiogenic factors not only provide significant growth inhibition of localized cancer in mouse model but also exerted tumor-free survival in combination with chemotherapy. We have also identified that the effect of anti-angiogenic therapy with rAAV in combination with chemotherapy, was independent of surviving pathway. Histopathological analysis of major visceral organs and liver enzyme analysis also revealed no toxicity because of combination therapy.
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Languages : en
Pages : 52
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Cancer growth and spread depends on the orchestrated proliferation of tumor-associated blood supply. Cancer cells release signals that instruct the body to build new blood vessels, angiogenesis, required to feed the tumor as it increases in size. Pharmacological agents, i.e. proteins and derivatives, that interfere with angiogenesis, in cancer bearing mice, stop cancer growth and lead to its regression. Animal modeling has revealed that repeated administration of large amounts of such antiangiogenic proteins is required for anti- cancer effect. This may be logistically difficult to achieve in larger beings such as humans. A remedy to this problem would involve a combined cell and gene therapy approach. We propose that normal tissue such as marrow stromal cells (MSCs) can be harvested from patients, genetically engineered, and subsequently returned to the patient as an implant releasing on a continuous basis therapeutic proteins that interfere with cancer growth and spread. We have already developed and published most of the key components required to develop this novel therapeutic modality, such as vectors, MSCs, and matrices. Also thus far, we have shown significant decrease in tumor progression over time with Interleukin-l2-secreting MSCs in the 4T1 mouse model of breast cancer and ascertained reproducibility of these results.
Author: Jie Ma
Publisher:
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Category :
Languages : en
Pages : 524
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Abstract: Angiogenesis, the formation of new blood vessels from pre-existing ones, has been extensively examined as a therapeutic target for cancer treatment. Different approaches have been investigated for the inhibition of tumor angiogenesis, with promising results reported from preclinical and clinical studies. Anti-angiogenesis reagents are usually cytostatic rather than cytoreductive, which makes combination of this class of drugs with conventional therapies not only desirable but necessary. Metronomic chemotherapy involves the intermittent administration of cytotoxic chemotherapeutics, such as cyclophosphamide, where tumor-associated endothelial cells become a primary target of the treatment. In 9L rat gliosarcoma grown in immune-deficient scid mice, intratumoral expression of cyclophosphamide-activating cytochrome P450 genes enhanced the antitumor activity of metronomic cyclophosphamide treatment, which was accompanied by increased apoptosis of tumor cells and a -70% loss of the tumor endothelial cell population. Similar anti-angiogenic responses were observed in 9L and 9L/P450 tumors, suggesting that metronomic cyclophosphamide regresses P450-expressing tumors by independent but complementary mechanisms: increased tumor cell killing via intratumoral P450-catalyzed prodrug activation, coupled with strong anti-angiogenic activity primarily associated with hepatic prodrug activation. Axitinib, a small-molecule receptor tyrosine kinase inhibitor, induced strong anti-angiogenic responses in highly vascularized 9L tumors, but only transiently delayed tumor growth. Combination of axitinib with metronomic cyclophosphamide arrested 9L and 9L/P450 tumor growth upon the initiation of drug treatment, but failed to regress the tumors. Further analysis revealed that axitinib reduced tumor uptake of 4-OH-CPA, the activated metabolite of cyclophosphamide, by 30-40%, and completely blocked metronomic cyclophosphamide-induced endogenous angiogenesis inhibitor thrombospondin-1 expression in host cells. In contrast, poorly vascularized PC-3 human prostate tumors underwent growth stasis following axitinib monotherapy, accompanied by near complete inhibition of tumor vascular patency. Despite up to a 70% decrease in tumor 4-OH-CPA uptake, combinations of axitinib with metronomic or maximum tolerated dose cyclophosphamide treatment significantly increased overall antitumor activity, indicating that axitinib-induced anti-angiogenesis dominates the anti-PC-3 tumor responses in the combination treatment. Thus, in combination therapies where angiogenesis inhibition adversely affects chemotherapeutics, overall antitumor activity can be enhanced by increasing intratumoral cytotoxicity and more effective suppression of tumor vascular patency, for which optimization is required to maximize therapeutic response.
Author: Guido Bocci
Publisher: Springer
ISBN: 3662436043
Category : Medical
Languages : en
Pages : 302
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Book Description
This book analyzes all aspects of metronomic chemotherapy, a new approach involving low-dose, long-term, and frequently administered therapy that has preclinical and clinical activity in various tumors. After an opening section on the pharmacological bases of metronomic chemotherapy, including its antiangiogenic effects and impact on immunity, preclinical studies on various classes of drug are discussed. Clinical applications of metronomic chemotherapy in a wide variety of tumors are then addressed in detail, with description of the results of all published studies. The clinical pharmacology of metronomic chemotherapy is also considered in depth, encompassing pharmacokinetics, pharmacogenetics, pharmacoeconomics, and adverse drug reactions. The book closes by describing the role of this therapy in the veterinarian clinic.
Author: Jonathan Fisher
Publisher: Frontiers Media SA
ISBN: 2832548423
Category : Medical
Languages : en
Pages : 228
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Book Description
Author: Yi Lu
Publisher: Springer Science & Business Media
ISBN: 1441901310
Category : Medical
Languages : en
Pages : 695
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Book Description
Pharmaceutical Perspectives of Cancer Therapeutics covers a wide variety of therapeutic approaches including gene therapy, immunological therapy; cancer vaccines; strategy for solid tumors as well as for hematological cancers; methods to suppress tumor angiogenesis and metastasis; development and utilization of relevant animal models; introduction of new concepts such as cancer stem cells and new technologies, such as DNA and tissue microarrays; and RNA interference. In addition, clinical application, the development of DNA diagnosis biomarkers and cancer prevention, as well as the utilization of imaging in cancer therapy are also discussed. The use of synthetic carriers, such as lipids, polymers, and peptides for delivery and targeting of small molecules, proteins, and nucleic acids to cancer cells in vivo are discussed. Pharmaceutical Perspectives of Cancer Therapeutics also includes cancer therapy modality in surgery, chemotherapy, and radiotherapy, as well as in combination or multi-modality, giving our book a more focused view of cancer therapy.
