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 Tauchi, T. Articles by Ohyashiki, K. Search for Related Content PubMed PubMed Citation Articles by Tauchi, T. Articles by Ohyashiki, K.

BCL-2 Antisense Oligonucleotide Genasense Is Active against Imatinib-resistant BCR-ABL-positive Cells¹

First Department of Internal Medicine, Tokyo Medical University, Shinjuku-ku, Tokyo 160-0023, Japan

Purpose: The near-universal emergence of imatinib resistance in patients with acute forms of Philadelphia chromosome-positive leukemia highlights the need for additional therapy to control this disease. G3139 (Genasense, oblimersen; Genta Inc.), a Bcl-2 antisense oligonucleotide, has been shown to down-regulate the Bcl-2 protein and induce apoptosis in myeloid leukemia cells from treated patients. We tested G3139 for its ability to inhibit BCR-ABL-mediated transformation in mice.

Experimental Design: Nude mice (n = 5/group) were transplanted s.c. with imatinib-resistant BCR-ABL-transformed TF-1 cells (BCR-ABL-TF-1-R cells). Mice with established tumors (0.1 g) were treated for 14 days with G3139 (7 mg/kg/day i.p.), or with the reverse-sequence control oligonucleotide G3622 (7 mg/kg/day i.p.) or with imatinib (50 mg/kg/day i.p.).

Results: Mice treated with G3622 or imatinib died within 10–12 weeks. Nearly all of the mice treated with G3139 survived for >6 months and had reduced tumor volume. Three of the 5 mice showed complete tumor regression. A transient decrease in Bcl-2 protein was observed that correlated with histological evidence of apoptosis. In addition, we harvested BCR-ABL-TF-1-R tumor cells from mice treated with G3139 or control G3622 (7 mg/kg/day i.p., 7 days). Cells were then cultured with the antileukemic agents imatinib, daunorubicin, 1-ß-D-arabinofuranosylcytosine, or etoposide. G3139 pretreatment resulted in enhanced induction of apoptosis by all of the agents.

Conclusion: These results suggest that G3139 is a promising candidate for treatment of patients with imatinib-resistant Ph-positive leukemia, and that combination of G3139 and imatinib may be useful to circumvent clinically acquired imatinib resistance.

This article has been cited by other articles:

				C. Bartholomeusz, H. Itamochi, L. X.H. Yuan, F. J. Esteva, C. G. Wood, N. Terakawa, M.-C. Hung, and N. T. Ueno Bcl-2 Antisense Oligonucleotide Overcomes Resistance to E1A Gene Therapy in a Low HER2-Expressing Ovarian Cancer Xenograft Model Cancer Res., September 15, 2005; 65(18): 8406 - 8413. [Abstract] [Full Text] [PDF]

				Y. Dai, M. Rahmani, S. J. Corey, P. Dent, and S. Grant A Bcr/Abl-independent, Lyn-dependent Form of Imatinib Mesylate (STI-571) Resistance Is Associated with Altered Expression of Bcl-2 J. Biol. Chem., August 13, 2004; 279(33): 34227 - 34239. [Abstract] [Full Text] [PDF]