oblimersen and Leukemia--Myelogenous--Chronic--BCR-ABL-Positive

Topics: Animals; Benzamides; Chromosome Aberrations; Drug Resistance, Neoplasm; Fusion Proteins, bcr-abl; Hematopoietic Stem Cell Transplantation; Humans; Imatinib Mesylate; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Piperazines; Piperidines; Pyridines; Pyrimidines; Quinolones; Randomized Controlled Trials as Topic; Thionucleotides

The CALGB studied the feasibility and effectiveness of adding oblimersen (G3139; Genasense) to imatinib mesylate (IM) in imatinib-resistant chronic phase chronic myeloid leukemia (CML) patients. We hypothesised that IM resistant CML cells are no longer being driven to proliferate by Bcr/Abl activity alone. Instead, the anti-apoptotic protein Bcl-2 would regulate one of the pathways controlling growth and/or viability. Thus, blocking both Bcr/Abl and Bcl-2 simultaneously would result in hematologic and cytogenetic improvement. Oblimersen was administered via continuous intravenous infusion over 10 days every 21 days, along with daily IM. Doses of both drugs were escalated in 3 cohorts; the initial dose of IM was 600 mg/day. Response was defined as a decrease by >30% in the percentage of t(9;22) metaphase cells. Twelve patients had primary and nine had secondary imatinib resistance. Ten patients received 4 mg/kg/day oblimersen/600 mg IM, six patients received 7 mg/kg/day oblimersen/600 mg IM and five patients received 7 mg/kg/day oblimersen/800 mg IM. Only two (9.5%) patients achieved a decrease by >30% in the percentage of t(9;22) metaphase cells. Although the combination of oblimersen and IM is safe and feasible, we did not observe clinical benefit in these patients with imatinib-resistant CML using these doses and schedule.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Drug Resistance, Neoplasm; Feasibility Studies; Female; Fusion Proteins, bcr-abl; Humans; Imatinib Mesylate; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Male; Middle Aged; Piperazines; Proto-Oncogene Proteins c-bcl-2; Pyrimidines; Thionucleotides; Treatment Failure

Topics: Clinical Trials as Topic; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Maximum Tolerated Dose; Oligonucleotides, Antisense; Proto-Oncogene Proteins c-bcl-2; Thionucleotides; Treatment Outcome

To explore whether the oligonucleotide uptake in hematological tumor cells is related to cellular species and proliferation.. Intracellular mean fluorescence intensity was measured by flow cytometry.. After treatment with FITC-labeled G3139 at the concentration of 0.60 mumol.L-1 for 4 h, the G3139 uptake into peripheral blood mononuclear cell and bone marrow mononuclear cell in hematological tumor patients was significantly higher than that in normal control. There was different uptake of G3139 among the malignant hematological tumor cell strains, and the uptake in cells derived from monocyte, B lymphocyte and myeloid cell was much higher than that in cells derived from T lymphocyte. After treatment with all-trans retinoic acid (ATRA), HL60 cell proliferation was markedly inhibited and the uptake of G3139 decreased significantly.. Hematological tumor cells were capable of taking up oligonucleotide, and the oligonucleotide uptake in hematological tumor cells is related to its cellular species and its activation.

Topics: Biological Transport; Cell Division; Genes, bcl-2; HL-60 Cells; Humans; Leukemia; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Promyelocytic, Acute; Leukocytes, Mononuclear; Lymphoma, Non-Hodgkin; Oligonucleotides, Antisense; Thionucleotides; Tretinoin; Tumor Cells, Cultured