Direct Inhibitory Effects of Lenalidomide

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Direct Inhibitory Effects of Lenalidomide on the Proliferation and VEGF

Production of Non-Hodgkin Lymphoma Cells Are Associated with Increased SPARC

Expression

http://ash.confex.com/ash/2008/webprogram/Paper10294.html

Lenalidomide is an oral anti-angiogenic, anti-proliferative and immunomodulatory

drug approved for the treatment of Low- or Intermediate-risk myelodysplastic

syndrome associated with a del(5q) cytogenetic abnormality, and in combination

with dexamethasone for previously treated multiple myeloma.

Early clinical results suggest potential clinical efficacy in B-cell non-Hodgkin

lymphoma (NHL). In this study, we investigated lenalidomide-mediated inhibition

of cell proliferation and angiogenic factors in the following NHL subtypes:

mantle cell lymphoma (MCL),

diffuse large-B-cell lymphoma, and

follicular lymphoma (FL).

The effect of lenalidomide on these tumor cells was determined after 1-3 days of

treatment by 3H-thymidine incorporation, Luminex-based microbead array, and

real-time qRT-PCR.

We also assessed the expression of tumor suppressor genes such as p21cip1 and

secreted protein acidic and rich in cysteine (SPARC).

We found that lenalidomide induced direct anti-proliferative effects on each NHL

subtype, with MCL cells being the most sensitive.

Pro-angiogenic factors such as vascular endothelial growth factor (VEGF) were

expressed at a high level in all lymphoma cell lines.

Lenalidomide inhibited VEGF production at much lower concentrations than

required for anti-proliferative effects, particularly in MCL and FL cell lines.

Addition of recombinant human VEGF or neutralizing anti-VEGF antibody had no

effect on MCL cell proliferation, suggesting that these effects are independent.

Mechanistic studies indicated that lenalidomide strongly increased the gene

expression of the tumor suppressor genes p21cip1 and SPARC to varying degrees.

Elevation of SPARC mRNA significantly correlated with both the

anti-proliferative and the VEGF-suppressive effects of lenalidomide on MCL cells

(p < 0.05). Transfection of tumor cells with SPARC siRNA led to significant

resistance to lenalidomide suggesting that this effect is mediated at least in

part through the up-regulation of SPARC. In conclusion, lenalidomide

demonstrates anti-proliferative activity against multiple NHL cell subtypes with

greatest potency against MCL. The potent anti-VEGF activity of lenalidomide

supports the anti-angiogenic potential of the drug. Thus, lenalidomide-induced

up-regulation of SPARC mRNA correlates with MCL sensitivity and may have

biomarker potential.

Disclosures: Zhang: Celgene Corporation: Employment. Schafer: Celgene

Corporation: Employment. Muller: Celgene Corporation: Employment. Stirling:

Celgene Corporation: Employment. Bartlett: Celgene Corporation: Employment.

Sunday, December 7, 2008

Hall A (Moscone Center)

Poster Board II-706

Ling-Hua Zhang*, H Schafer*, Muller*, Stirling* and Blake

Bartlett*

Celgene Corporation, Summit, NJ

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All the best,

Karl

Patients Against Lymphoma

www.Lymphomation.org