Re-Establishment of a Normal Apoptotic Process as a Therapeutic Approach in B-CLL

Author(s): Jean-Pierre Kolb, Catherine Kern, Claire Quiney, Viviana Roman, Christian Billard.

Journal Name:Current Drug Targets - Cardiovascular & Hematological Disorders

Volume 3 , Issue 4 , 2003

Abstract:

Even though the capacity of B-CLL leukemic cells to proliferate has been underestimated until recently, the accumulation of tumor cells in patients mostly results from a defect in the apoptotic program. Several mechanisms can account for this deficient cell death pathway. These include overexpression of antiapoptotic molecules such as members of the Bcl-2 family, which control the opening of the mitochondrial transition permeability pore, and of the IAP (inhibitors of apoptosis) family, which inhibit the activity of caspases. The latter is also suppressed by nitric oxide (NO) released through an inducible NO synthase present in the leukemic cells. The activity of the receptors with a death domain (Fas, TRAIL) is impaired, thus contributing to the resistance to spontaneous and / or drug-induced apoptosis. Interferons as well as several cytokines and angiogenic factors are also involved in the failure of programmed cell death, either by providing efficient signals for survival (BAFF) or by counteracting the apoptotic process. A better knowledge of the mechanisms of survival and escape from apoptosis of B-CLL cells has led to the proposal of new drugs that selectively interfere at the different steps of these cascades. Their study is complicated by the lack of suitable cell lines and pre-clinical models. Nevertheless, some of these chemotherapeutic agents appear to be promising, provided they are correctly targeted to the leukemic cells.

Keywords: b-cll, apoptosis, caspases, cytokines, nitric oxide, tnf, chemotherapy

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Article Details

VOLUME: 3
ISSUE: 4
Year: 2003
Page: [261 - 286]
Pages: 26
DOI: 10.2174/1568006033481384
Price: $58