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Targeting the mammalian target of Rapamycin to inhibit VEGF and cytokines for the treatment of primary effusion lymphoma.

Abstract：

:Primary effusion lymphoma (PEL) is a fatal malignancy, which typically presents as a lymphomatous effusion that later disseminates. Rapamycin (Rapa), which targets mTOR (mammalian target of Rapa), is currently evaluated as a treatment for PEL, but the recent development of PEL in Rapa-treated post-transplant recipients questions the drug's use in PEL. Here, we used a murine model of PEL effusion that mimics the human disease to investigate the anti-PEL activity of Rapa. We found that Rapa reduces ascites accumulation and extends mouse survival. Initially, Rapa reduced PEL load compared with control mice, but most mice rapidly showed PEL progression. Levels of VEGF, which promotes vascular permeability contributing to effusion formation, were significantly reduced in ascites of Rapa-treated mice compared with controls. Expression of IL-10, the principal autocrine growth factor for PEL, was initially reduced in PEL from Rapa-treated mice but rapidly increased despite treatment. We found that the hypoxic environment of ascites and Rapa cooperate in stimulating IL-10 expression in PEL, which likely contributes to the emergence of drug resistance. These results identify Rapa an effective drug to reduce PEL effusions but illustrate the rapid development of drug resistance, which likely limits the efficacy of Rapa in PEL.

journal_name

Leukemia

journal_title

Leukemia

authors

Gasperini P,Tosato G

doi

10.1038/leu.2009.117

subject

Has Abstract

pub_date

2009-10-01 00:00:00

pages

1867-74

issue

10

eissn

0887-6924

issn

1476-5551

pii

leu2009117

journal_volume

23

pub_type

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