This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Schimmer, A. D. Articles by Reed, J. C. Search for Related Content PubMed PubMed Citation Articles by Schimmer, A. D. Articles by Reed, J. C.

Functional Blocks in Caspase Activation Pathways Are Common in Leukemia and Predict Patient Response to Induction Chemotherapy¹

The Burnham Institute, La Jolla, California 92037 [A. D. S., I. M. P., S. K., E. E-D., Y. K., W. S. S., J. C. R.]; Princess Margaret Hospital, Toronto, Ontario, Canada M5G 2M9 [M. D. M., R. P., K. M.]; and M. D. Anderson Cancer Center, Houston, Texas 77030 [M. A.]

Defects in apoptosis mechanisms contribute to chemoresistance in malignancy. However, correlations of apoptosis-regulating proteins with clinical outcome in cancer patients are variable, presumably reflecting the difficulty of using static tests of gene expression in a scenario influenced by a dynamic interplay of multiple pro- and antiapoptotic molecules. Therefore, we assessed the functional integrity of apoptosis pathways in intact primary leukemia cells and correlated the functional status of these pathways with clinical outcome. Active apoptogenic proteins were introduced into primary leukemia cells by electroporation followed by measurement of active caspases by flow cytometric techniques. Cytochrome c was introduced to activate the intrinsic (mitochondrial) pathway, whereas caspase-8 was introduced to activate the extrinsic (death receptor) pathway. In a series of 24 patients with acute myeloid leukemia, 79% had a block in at least one pathway, indicating that defects in caspase activation mechanisms are common in patients with leukemia. Simultaneous blocks in both pathways correlated with chemoresistant disease (92% of patients with chemoresistant disease versus 33% of patients with chemosensitive disease; P = 0.005) and decreased overall patient survival (35% versus 89% 1-year survival; P = 0.02). Simultaneous blockage of the intrinsic and extrinsic pathways could be explained by a defect located at a point of convergence of the two pathways, probably related to overexpression of endogenous inhibitors of the effector-caspases, rather than decreased levels of these proteases. This study supports the importance of apoptosis pathways in determining response to chemotherapy and suggests that functional defects in caspase activation are prognostic in patients with leukemia.

This article has been cited by other articles:

				L. H. Meyer, L. Karawajew, M. Schrappe, W.-D. Ludwig, K.-M. Debatin, and K. Stahnke Cytochrome c-related caspase-3 activation determines treatment response and relapse in childhood precursor B-cell ALL Blood, June 1, 2006; 107(11): 4524 - 4531. [Abstract] [Full Text] [PDF]

				E. C. LACASSE, E. R. KANDIMALLA, P. WINOCOUR, T. SULLIVAN, S. AGRAWAL, J. W. GILLARD, and J. DURKIN Application of XIAP Antisense to Cancer and Other Proliferative Disorders: Development of AEG35156/ GEM(R)640 Ann. N.Y. Acad. Sci., November 1, 2005; 1058(1): 215 - 234. [Abstract] [Full Text] [PDF]

				B. Z. Carter, M. Gronda, Z. Wang, K. Welsh, C. Pinilla, M. Andreeff, W. D. Schober, A. Nefzi, G. R. Pond, I. A. Mawji, et al. Small-molecule XIAP inhibitors derepress downstream effector caspases and induce apoptosis of acute myeloid leukemia cells Blood, May 15, 2005; 105(10): 4043 - 4050. [Abstract] [Full Text] [PDF]

				R. Contractor, I. J. Samudio, Z. Estrov, D. Harris, J. A. McCubrey, S. H. Safe, M. Andreeff, and M. Konopleva A Novel Ring-Substituted Diindolylmethane,1,1-Bis[3'-(5-Methoxyindolyl)]-1-(p-t-Butylphenyl) Methane, Inhibits Extracellular Signal-Regulated Kinase Activation and Induces Apoptosis in Acute Myelogenous Leukemia Cancer Res., April 1, 2005; 65(7): 2890 - 2898. [Abstract] [Full Text] [PDF]

				O. Berezovskaya, A. D. Schimmer, A. B. Glinskii, C. Pinilla, R. M. Hoffman, J. C. Reed, and G. V. Glinsky Increased Expression of Apoptosis Inhibitor Protein XIAP Contributes to Anoikis Resistance of Circulating Human Prostate Cancer Metastasis Precursor Cells Cancer Res., March 15, 2005; 65(6): 2378 - 2386. [Abstract] [Full Text] [PDF]

				M. Konopleva, T. Tsao, Z. Estrov, R.-m. Lee, R.-Y. Wang, C. E. Jackson, T. McQueen, G. Monaco, M. Munsell, J. Belmont, et al. The Synthetic Triterpenoid 2-Cyano-3,12-dioxooleana-1,9-dien-28-oic Acid Induces Caspase-Dependent and -Independent Apoptosis in Acute Myelogenous Leukemia Cancer Res., November 1, 2004; 64(21): 7927 - 7935. [Abstract] [Full Text] [PDF]

				L. Tourneur, S. Delluc, V. Levy, F. Valensi, I. Radford-Weiss, O. Legrand, J. Vargaftig, C. Boix, E. A. Macintyre, B. Varet, et al. Absence or Low Expression of Fas-Associated Protein with Death Domain in Acute Myeloid Leukemia Cells Predicts Resistance to Chemotherapy and Poor Outcome Cancer Res., November 1, 2004; 64(21): 8101 - 8108. [Abstract] [Full Text] [PDF]

				P. A. Nguewa, M. A. Fuertes, C. Alonso, and J. M. Perez Pharmacological Modulation of Poly(ADP-ribose) Polymerase-Mediated Cell Death: Exploitation in Cancer Chemotherapy Mol. Pharmacol., November 1, 2003; 64(5): 1007 - 1014. [Full Text] [PDF]