dynamic properties of angiogenic and immunomodulatory factors in murine erythroleukaemogenesis.
Published: 2005
Language: eng
Number of pages: 175
Description: The impact of VEGF as a single factor on the progression of erythroleukaemia  in vivo was also investigated. Challenging a murine model hypermorphic for VEGF (VEGFhi/+), with Friend Disease, lead to a significant deceleration in the disease process. It is postulated that the combined erythroid lineage potentiation along with enhanced killing capacity of cytotoxic T cells is responsible for the reduced tumour burden and extended survival seen in erythroleukaemic VEGFhi/+ mice. Thus, the aforementioned findings suggest that dynamic physiological processes of inflammation and immunity, in addition to induced angiogenesis, function in parallel to promote erythroleukaemogenesis.Tumour angiogenesis has become a well-characterized concept through solid tumour studies. Presented herein is an investigation using a murine model of erythroleukaemia induced by Friend Virus in an effort to gain a better understanding of the angiogenesis response mechanism in the progression of aggressive haematological malignancies in man. As a hallmark of Friend Disease, splenomegaly was initially addressed. Splenectomized mice exhibited extended survival over age-matched, sham controls with a delay of thirty days for the loss of >50% (P &lt; 0.05). Splenocytes derived from erythroleukaemic mice secreted overproduced pro-inflammatory and pro-angiogenesis mediators, such as IL-6, VEGF and MCP-5. As well, overgrowth of primary malignant blasts was enhanced in medium preconditioned with such cells. In addition to splenic involvement in disease progression, therefore, localized dynamic responses involving both inflammation and angiogenesis are indeed indicated. A parallel response would be immunosuppression by promoting non-protective, Th2-type immunity. As such, to modify these dynamics in favour of a protective Th1-mediated response, while simultaneously inhibiting angiogenesis and inflammation, an in vivo efficacy study involving the targeting the cyclooxygenase-2 (COX-2) enzyme was conducted using celecoxib. Only in combination with a previously-established anti-angiogenesis dosing regimen of the cytotoxic agent vinblastine could a significant survival benefit be observed for erythroleukaemic mice (P &lt; 0.05).  In vitro, celecoxib did have a significant impact on murine erythroleukaemia cell lines, partly by interfering with signalling pathways downstream of the Epo and c-kit receptors. In either system, therefore, additive effects can be mediated against the tumour when combined with anti-angiogenesis modalities, but alone cannot be sufficient to achieve stable disease.
Notes: Thesis (Ph.D.)--University of Toronto, 2005.

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Source: Dissertation Abstracts International, Volume: 66-06, Section: B, page: 3006.