Mature vascular endothelium can give rise to smooth muscle cells via endothelial-mesenchymal transdifferentiation: in vitro analysis.

Though in the past believed to be a rare phenomenon, endothelial-mesenchymal transdifferentiation has been described with increasing frequency in recent years. It is believed to be important in embryonic vascular development, yet less is known regarding its role in the adult vasculature. Using FACS and immunomagnetic (Dynabeads) purification techniques (based on uptake of DiI-acetylated low-density lipoproteins and/or PECAM-1 expression) and double-label indirect immunostaining (for endothelial and smooth muscle [SM] markers), we demonstrate that mature bovine vascular endothelium contains cells of an endothelial phenotype (defined by VE-cadherin, von Willebrand factor, PECAM-1, and elevated uptake of acetylated low-density lipoproteins) that can undergo endothelial-mesenchymal transdifferentiation and further differentiate into SM cells (as defined by expression of alpha-SM-actin, SM22alpha, calponin, and SM-myosin). "Transitional" cells, coexpressing both endothelial markers and alpha-SM-actin, were consistently observed. The percentage of cells capable of endothelial-mesenchymal transdifferentiation within primary endothelial cultures was estimated as 0.01% to 0.03%. Acquisition of a SM phenotype occurred even in the absence of proliferation, in gamma-irradiated (30 Gy) and/or mitomycin C-treated primary cell cultures. Initiation of transdifferentiation correlated with disruption of cell-cell contacts (marked by loss of VE-cadherin expression) within endothelial monolayers, as well as with the action of transforming growth factor-beta(1). In conclusion, our in vitro data show that mature bovine systemic and pulmonary endothelium contains cells that can acquire a SM phenotype via a transdifferentiation process that is transforming growth factor-beta(1)- and cell-cell contact-dependent, but proliferation-independent.

Phase II pilot study of oral dasatinib in patients with higher-risk myelodysplastic syndrome (MDS) who failed conventional therapy.

Given evidence for the role of Src family kinases, especially Lyn kinase, in myeloblast proliferation and the in vitro inhibitory activity of dasatinib on Src and Lyn, we conducted a phase II study to assess overall response to 100mg/day dasatinib in patients with higher-risk myelodysplastic syndrome (MDS), chronic myelomonocytic leukemia, or acute myeloid leukemia arising from MDS and who had failed prior treatment with azanucleoside analogs. Among 18 patients treated, 3 responded, 4 had stable disease, and 10 experienced disease progression. Toxicities were limited and consistent with previous reports. Dasatinib appears to be safe but with limited efficacy.

The role of lenalidomide in the treatment of patients with chromosome 5q deletion and other myelodysplastic syndromes.

PURPOSE OF REVIEW: The aim of this article is to discuss the relevant pathobiologic effects of lenalidomide and the most recent clinical evidence to support its use in patients with myelodysplastic syndrome. RECENT FINDINGS: Lenalidomide is an immunomodulatory agent with biological activity in several hematologic malignancies, including myelodysplastic syndrome. The precise mechanism yielding benefit in patients with myelodysplastic syndrome and 5q- syndrome is not clear, but various molecular and pathogenic targets have been identified. Enhancement of cellular immunity through T-cell and NK-cell activation and suppression of inflammatory cytokines and pro-angiogenic peptides upon lenalidomide treatment has been demonstrated in in-vitro models of myelodysplastic syndrome. Furthermore, lenalidomide induces a direct cytotoxic effect against 5q- clones in leukemia cell lines and enhances ligand-induced erythropoietin receptor signaling in erythroid progenitors. Clinical trials with lenalidomide in myelodysplastic syndrome have supported the in-vitro evidence of karyotype-dependent activity by demonstration of a high frequency of cytogenetic and pathologic responses in patients with myelodysplastic syndrome and deletion of chromosome 5q. Lenalidomide was approved for the treatment of transfusion-dependent patients with low to intermediate risk myelodysplastic syndrome and chromosome 5q deletion. SUMMARY: Lenalidomide is an active immunomodulatory agent for the treatment of myelodysplastic syndrome with encouraging erythropoetic and cytogenetic remitting activity that is karyotype dependent.

Immunomodulatory drugs (IMiDs): a new treatment option for myelodysplastic syndromes.

The IMiDs represent a new proprietary class of thalidomide analogues that possess greater potency and less toxicity than the parent compound. As a group, these agents share the pharmacologic property of modulating cellular response to ligand activation, the precise biologic effect of which is cell lineage and stimulant-dependent. Lenalidomide (CC-5013; Revlimid), a second generation IMiD, has shown significant erythropoietic activity in patients with lower risk MDS that have failed or are not candidates for recombinant erythropoietin treatment. Unlike cytokine therapy, lenalidomide suppresses select MDS clones and enhances erythropoietin receptor signaling to restore erythropoiesis. Activity is greatest in patients with interstitial deletions involving chromosome 5q31.1. A multicenter phase II study reported a 76 % overall transfusion response rate in transfusion-dependent patients with deletion 5q, with 67 % achieving transfusion independence after a median interval of 4.6 weeks of treatment. Cytogenetic responses were observed in 73% of patients with complete cytogenetic remission in 45% patients. Both transfusion response and cytogenetic response frequency were independent of karyotype complexity, raising excitement that this new treatment strategy might favorably alter the natural history of disease in higher risk patients with deletion 5q. Lenalidomide was approved by the U.S. Food and Drug Administration on December 27, 2005, for the treatment of IPSS Low and intermediate-1 risk MDS patients with del(5q) abnormality. A phase III Intergroup trial (ECOG 2905) will test the capacity to potentiate erythropoietin response by comparing response to lenalidomide monotherapy to the combination of darbepoetin and lenalidomide in non-deletion 5q MDS patients.