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Lymphoblastic T-cell lymphoma in mice is unaffected by Celecoxib as single agent or in combination with cyclophosphamide
Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik. Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
Department of Medicine, Rheumatology Unit and Karolinska Biomics Centre, Karolinska Institutet, Stockholm, Sweden.
Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
Department of Medicine, Rheumatology Unit and Karolinska Biomics Centre, Karolinska Institutet, Stockholm, Sweden.
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2009 (Engelska)Ingår i: Leukemia and Lymphoma, ISSN 1042-8194, E-ISSN 1029-2403, Vol. 50, nr 7, s. 1198-1203Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Celecoxib, an inhibitor of cyclooxygenase-2, is a promising novel antitumor agent with pleitropic mechanisms of action. Whereas this drug induces growth arrest and apoptosis of B-lymphoma cells, its effect against aggressive T-cell neoplasms remains to be studied. We therefore evaluated Celecoxib therapy of immunocompetent mice transplanted with lymphoblastic T-cell lymphomas. Oral Celecoxib in clinically relevant and non-toxic doses did not affect the degree of hypersplenism or the number of viable lymphoma cells. The clinical deterioration of Celecoxib-treated mice was not different from untreated controls. The impact of adding Celecoxib (60 mg/kg) to cyclophosphamide (200 mg/kg x 1, i.p.) was assessed but showed no benefit compared to cyclophosphamide alone. Thus, Celecoxib lacks effect against lymphoblastic T-cell lymphoma in mice.

Ort, förlag, år, upplaga, sidor
2009. Vol. 50, nr 7, s. 1198-1203
Nyckelord [en]
T-cell lymphoma, mouse, prostaglandins, Celecoxib, chemotherapy
Nationell ämneskategori
Cancer och onkologi
Forskningsämne
onkologi
Identifikatorer
URN: urn:nbn:se:umu:diva-35016DOI: 10.1080/10428190902946930PubMedID: 19557641OAI: oai:DiVA.org:umu-35016DiVA, id: diva2:328256
Tillgänglig från: 2010-07-02 Skapad: 2010-07-02 Senast uppdaterad: 2018-06-08Bibliografiskt granskad
Ingår i avhandling
1. Establishment and characterization of a murine T-cell lymphoma/leukemia model
Öppna denna publikation i ny flik eller fönster >>Establishment and characterization of a murine T-cell lymphoma/leukemia model
2010 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

Mouse models of human disease are valuable tools for studying pathogenesis and for evaluating novel therapies. T-cell lymphoma is a relatively rare disease in humans, affecting 100-150 persons yearly in Sweden. It exists in both aggressive and more indolent forms. We have established a mouse model for an aggressive T-cell lymphoma, the T-cell lymphoma/leukemia (TLL) mouse. In the present thesis, the TLL mouse model was characterized and used for experimental therapeutic and primary prevention studies.

The TLL mouse was established unintentionally in our laboratory during work on VH-gene replacement in a “knock-in” mouse experimental setting. The generated chimeras all developed aggressive T-cell lymphomas affecting the lymphoid organs, lungs, kidneys and liver. The lymphoma phenotype segregated from the targeted locus and we could demonstrate the presence of Moloney murine leukemia virus (MMLV) in the germline of the affected mice. MMLV is a retrovirus known to induce T-cell lymphomas when inoculated in newborn mice.  We further characterized two TLL substrains; TLL-2 and TLL-14 carrying the proviral integrations on chromosomes 2 and 14 respectively. Significant differences were found between the substrains regarding lymphoma frequency and immunophenotype, the TLL-14 substrain developing tumors with higher frequency than TLL-2 and with a more mature immunophenotype.

A transfer model was developed in which TLL cells could be readily transferred intravenously to syngenic recipients causing aggressive lymphomas. The transfer model was used in a therapeutic study where the selective COX-2 inhibitor celecoxib was evaluated as a single agent and in combination with the established anti-tumor agent cyclophosphamide. The study was based on results from other tumor types that have indicated celecoxib, originally an anti-inflammatory and analgetic drug, to have possible anti-tumor effects. In our TLL model, however, we could not demonstrate any benefit of celecoxib monotherapy or any additive effect to cyclophosphamide.

Dietary fatty acids, in particular omega-3 fatty acids, have been a focus of public and scientific interest due to observed effects on the prevention of cardiovascular disease, cancer and inflammatory conditions. In addition, omega-3 fatty acids inhibit T-cell proliferation in vitro. We supplemented the diet of TLL mice with omega-3 and omega-6 fatty acids respectively and could demonstrate a significant delay in lymphoma onset between 5-8 months of age in the group receiving an omega-3 rich diet.

Ort, förlag, år, upplaga, sidor
Umeå: Umeå universitet, 2010. s. 66
Serie
Umeå University medical dissertations, ISSN 0346-6612 ; 1348
Nyckelord
Mouse model, T-cell lymphoma, Moloney murine leukemia virus, proviral integration, lymphomagenesis, COX-2, omega 3
Nationell ämneskategori
Cancer och onkologi
Forskningsämne
onkologi
Identifikatorer
urn:nbn:se:umu:diva-35195 (URN)978-91-7264-992-7 (ISBN)
Disputation
2010-10-01, Sal B, 9tr, by 1D, Norrlands universitetssjukhus, Umeå, 09:00 (Engelska)
Opponent
Handledare
Tillgänglig från: 2010-09-08 Skapad: 2010-08-09 Senast uppdaterad: 2018-06-08Bibliografiskt granskad

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Johansson, Ann-SofieLarefalk, ÅsaHolmberg, Dan

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