BCL-2 antisense oligonucleotide genasense is active against imatinib-resistant BCR-ABL-positive cells.
OBJECTIVE
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.


METHODS
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-beta-D-arabinofuranosylcytosine, or etoposide. G3139 pretreatment resulted in enhanced induction of apoptosis by all of the agents.


CONCLUSIONS
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.
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001549:Benzamides; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D016044:Fusion Proteins, bcr-abl / Q000235:genetics*; D006801:Humans; D000068877:Imatinib Mesylate; D020014:K562 Cells; D007951:Leukemia, Myeloid / Q000188:drug therapy / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D016376:Oligonucleotides, Antisense / Q000627:therapeutic use*; D010879:Piperazines / Q000627:therapeutic use*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors / Q000235:genetics; D011743:Pyrimidines / Q000627:therapeutic use*; D016019:Survival Analysis; D013873:Thionucleotides / Q000627:therapeutic use*; D013997:Time Factors; D014183:Transplantation, Heterologous
D000970:Antineoplastic Agents; D001549:Benzamides; D016376:Oligonucleotides, Antisense; D010879:Piperazines; D019253:Proto-Oncogene Proteins c-bcl-2; D011743:Pyrimidines; D013873:Thionucleotides; C408162:oblimersen; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl