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B cell chronic lymphocytic leukemia response to nutlin-3 should be studied

07-26-2006

The clinical applications of nutlin-3 to treat B-cell chronic lymphocytic leukemia (B-CLL) should be studied.

"Deletions and/or mutations of p53 are relatively rare and late events in the natural history of B-CLL. However, it is unknown whether p53 signaling is functional in B-CLL and if targeted nongenotoxic activation of the p53 pathway by using nutlin-3, a small molecule inhibitor of the p53/MDM2 interaction, is sufficient to kill B-CLL cells," scientists in Italy reported.

"In vitro treatment with nutlin-3 induced a significant cytotoxicity on primary CD19+ B-CLL cells, but not on normal CD19+ B lymphocytes, peripheral-blood mononuclear cells, or bone marrow hematopoietic progenitors," explained P. Secchiero and colleagues, University of Ferrara. "Among 29 B-CLL samples examined, only 1 was resistant to nutlin-3-mediated cytotoxicity. The induction of p53 by nutlin-3 in B-CLL samples was accompanied by alterations of the mitochondrial potential and activation of the caspase-dependent apoptotic pathway.

"Among several genes related to the p53 pathway, nutlin-3 up-regulated the steady-state mRNA levels of PCNA, CDKN1A/p21, GDF15, TNFRSF10B/TRAIL-R2, TP5313/PIG3, and GADD45. This profile of gene activation showed a partial overlapping with that induced by the genotoxic drug fludarabine. Moreover, nutlin-3 synergized with both fludarabine and chlorambucil in inducing B-CLL apoptosis."

The researchers concluded, "Our data strongly suggest that nutlin-3 should be further investigated for clinical applications in the treatment of B-CLL."

Secchiero and colleagues published their study in Blood (Functional integrity of the p53-mediated apoptotic pathway induced by the nongenotoxic agent nutlin-3 in B-cell chronic lymphocytic leukemia (B-CLL). Blood, 2006;107(10):4122-4129).

For more information, contact P. Secchiero, University of Ferrara, Dept. Morphology & Embryology, Human Anatomy Sect, Via Fossato Mortara 66, I-44100 Ferrara, Italy.

Publisher contact information for the journal Blood is: American Society Hematology, 1900 M Street. NW Suite 200, Washington, DC 20036, USA.

Keywords: Ferrara, Italy, Apoptosis, Bone Marrow, Hematology, Hematopoietic, Leukemia, Peripheral Blood, Small Molecule Inhibitor Cancer Therapy, Cytotoxicity, B-CLL, Nutlin-3.

This article was prepared by Cancer Gene Therapy Week editors from staff and other reports. Copyright 2006, Cancer Gene Therapy Week via NewsRx.com.