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最后登录2025-3-11
  
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发表于 2015-12-17 14:27:18
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来自: 中国北京
Metformin enhances the activity of rituximab in B-cell lymphoma pre-clinical models.
Subcategory:
Lymphoma
Category:
Lymphoma and Plasma Cell Disorders
Meeting:
2015 ASCO Annual Meeting
Session Type and Session Title:
This abstract will not be presented at the 2015 ASCO Annual Meeting but has been published in conjunction with the meeting.
Abstract Number:
e19513
Citation:
J Clin Oncol 33, 2015 (suppl; abstr e19513)
Author(s):
Priyank P. Patel, Juan J Gu, Cory Mavis, Myron Stefan Czuczman, Francisco J. Hernandez-Ilizaliturri; Roswell Park Cancer Institute, Buffalo, NY
Abstract Disclosures
Abstract:
Background: The Warburg effect is primarily observed in rapidly growing tumors including aggressive B-cell lymphomas and is thought to be a consequence of the progression to cancer rather than the cause of it and altering the glucose metabolism in cancer cells appears to be an attractive strategy in cancer medicine. Retrospective studies have shown survival benefit in solid tumors and diffuse large B-cell lymphoma cohorts who were on metformin for type-2 diabetes. In an attempt to characterize the mechanism by which metformin affects the biology of B-cell lymphoma, we studied its effect on rituximab activity. Methods: A panel of B-cell lymphoma cells was exposed to metformin +/- rituximab or isotype control, changes in cell cycle distribution or induction of apoptosis was determined by flow cytometry. Antibody-dependent cellular cytotoxicity (ADCC) and complement mediated cytotoxicity (CMC) assays were performed to demonstrate changes in sensitivity to rituximab following metformin exposure. For in vivo studies, SCID mice were inoculated via tail vein injection (iv) with Raji cells (day 0) and assigned to observation, rituximab (at 10mg/kg/dose on days +3,7,10 and 14), metformin (at 2mg/ml in drinking water) or metformin and rituximab. Differences in survival (measured at the time for limb paralysis development) were evaluated by log-rank test between treatment arms. Results: In vitro exposure to metformin resulted in S/G1 cell cycle arrest and induction of apoptosis in a dose-dependent manner. Metformin enhanced the anti-proliferative effects of mAbs targeting CD20. Moreover, pre-incubation of lymphoma cells enhanced rituximab-mediated CMC. In vivo, significant improvement in survival was observed in metformin + rituximab arm (mean survival not reached at 69+/- 5.3 days) compared to rituximab (mean survival 57.1 +/- 4.2 days) (p = 0.05). Conclusions: Our data suggests that metformin inhibits the proliferation of B-cell lymphoma cell lines and enhances the anti-tumor activity of rituximab. Our finding highlights a potential role for metformin in the treatment of B-cell malignancies. |
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