ASH: Fludarabine, Apoptosis, and Drug Resistance

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[4833] Fludarabine-Induced Apoptosis in Chronic Lymphocytic Leukemia

Cells Is Not Affected by Inhibitor of Apoptosis Proteins (IAPS).

Session Type: Publication Only

Karina Lani Silva, Delfraro de a Castro, Deborah Vidal

Vasconcellos, Jolie Kiemlian Kwee, Arthur Coelho Moellman, Claudete

Esteves Klumb, Raquel Ciuvalschi Maia (Intr. by S. Pombo-de-

Oliveira). Laboratório de Hematologia Celular e Molecular, Instituto

Nacional de Cancer, Rio de Janeiro, Brazil; Programa de Pos-Graduacao

em Ciencias Morfologicas, Universidade Federal do Rio de Janeiro, Rio

de Janeiro, Brazil; Programa de Pos-Graduacao em Biologia Celular e

Molecular, Fundacao Oswaldo Cruz, Rio de Janeiro, Brazil; Serviço de

Hematologia, Instituto Nacional de Cancer, Rio de Janeiro, Brazil

B-cell chronic lymphocytic leukemia (B-CLL) is characterized by the

accumulation of mature lymphocytes due to defective apoptosis.

Inhibition of apoptosis also contributes to chemoresistance, mainly

in patients in advanced clinical stages.

Fludarabine is a potent chemotherapeutic drug used for patients with

B-CLL. Despite good initial clinical responses, some patients acquire

resistance to this drug. One of the mechanisms through which

malignant cells are believed to acquire resistance to apoptosis is by

overexpression of inhibitor of apoptosis proteins (IAPs).

IAPs are a family of proteins able to block apoptosis either by

binding and inhibiting caspases or through caspases-independent

mechanisms.

To date, overexpression of IAPs has been detected in many types of

malignant diseases, including B-CLL. As fludarabine can induce

apoptosis trough caspases activation and this proteases could be

inhibited by IAPs, we evaluated in this current study, the expression

of three members of IAP family (c-IAP1, c-IAP2 and XIAP) by

immunocitochemistry in 30 peripheral blood B-CLL specimens and

correlated it to fludarabine-induced apoptosis.

In parallel, we also evaluated the expression of these IAPs before

and after in vitro fludarabine treatment. B-CLL cells were incubated

with fludarabine25 m M for 12 hours and the induction of apoptosis

were measured by annexin-V assay. The apoptosis index by fludarabine

was extremely significant (p < 0.001). Different levels of c-IAP1, c-

IAP2 and XIAP expression were commonly found in circulating B-CLL

cells. High levels of c-IAP1, c-IAP2 and XIAP expression were

observed in 20%, 60,7% and 60% of samples, respectively. However, the

overexpression of these IAPs was not correlated with an in vitro

fludarabine apoptosis-resistance. Besides, fludarabine was not able

to change the levels of IAPs expression as described for other drugs

in literature.

These results suggest that fludarabine might cause apoptosis by a

caspase-independent manner.

Abstract #4833 appears in Blood, Volume 103, issue 12, November 16,

2004

Keywords: B cell chronic lymphocytic leukemia|Fludarabine

phosphate|Apoptosis