oblimersen and Leukemia

Bcl-2 is an apoptosis regulating protein, overexpression of which is associated with chemotherapy resistant disease, aggressive clinical course, and poor survival in patients with B-cell lymphoproliferative disorders. Overexpression of Bcl-2 protein results in an aberrant intrinsic apoptotic pathway that confers a protective effect on malignant cells against a death signal (e.g., chemotherapy or radiotherapy). Downregulation of this oncoprotein, thus, represents a possible new way to target clinically aggressive disease. Preclinical studies have shown that this oncoprotein can be effectively decreased by Bcl-2 antisense in malignant lymphoid cells and can reverse chemotherapy resistance, as well as enhance the anti-apoptotic potential of both chemotherapeutic and biologic agents. Ongoing clinical trials are exploring the role of Bcl-2 downregulation with oblimersen (Bcl-2 antisense) in patients with non-Hodgkin's lymphoma, chronic lymphocytic leukemia and multiple myeloma. Early results from these studies are promising and support the proof of the principle. As these studies are completed and mature data emerges, the role of Bcl-2 antisense therapy in the treatment of B-cell malignancies will become clearer.

Topics: Antineoplastic Agents; Drug Resistance, Neoplasm; Humans; Leukemia; Lymphoma, B-Cell; Multiple Myeloma; Oligonucleotides, Antisense; Proto-Oncogene Proteins c-bcl-2; Thionucleotides

Overexpression of Bcl-2 is a potential mechanism for chemoresistance in acute leukemia and has been associated with unfavorable clinical outcome. We hypothesized that down-regulation of Bcl-2 would restore chemosensitivity in leukemic cells. To test this hypothesis, we performed a phase 1 study of G3139 (Genasense, Genta, Berkeley Heights, NJ), an 18-mer phosphorothioate Bcl-2 antisense, with fludarabine (FL), cytarabine (ARA-C), and granulocyte colony-stimulating factor (G-CSF) (FLAG) salvage chemotherapy in patients with refractory or relapsed acute leukemia. Twenty patients with refractory or relapsed acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL) were enrolled. G3139 was delivered by continuous infusion on days 1 to 10. FLAG chemotherapy was administered on days 5 to 10. Common side effects of this combination included fever, nausea, emesis, electrolyte imbalance, and fluid retention that were not dose limiting. Plasma pharmacokinetics of G3139 demonstrated steady-state concentration (Css) within 24 hours. Of the 20 patients, 9 (45%) had disease response, 6 (5 AML, 1 ALL) with complete remission (CR) and 3 (2 AML and 1 ALL) with no evidence of disease but failure to recover normal neutrophil and/or platelet counts or to remain in remission for at least 30 days (incomplete remission). Bcl-2 mRNA levels were down-regulated in 9 of the 12 (75%) evaluable patients. This study demonstrates that G3139 can be administered safely with FLAG chemotherapy and down-regulate its target, Bcl-2. The encouraging clinical and laboratory results justify the current plans for a phase 3 study in previously untreated high-risk AML (ie, age at least 60 years).

Topics: Acute Disease; Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Down-Regulation; Female; Genes, bcl-2; Granulocyte Colony-Stimulating Factor; Humans; Leukemia; Male; Middle Aged; Oligonucleotides, Antisense; Remission Induction; Salvage Therapy; Thionucleotides; Vidarabine

An 18-mer phosphorothioate bcl-2 antisense oligonucleotide (ASO) inhibited colony formation of three B-cell leukemia/lymphoma cell lines in a dose dependent manner in the range of 0.125-0.5 micromol/l. The scrambled cogener had no detectable effect. A decrease in BCL-2 protein and apoptotic DNA fragmentation was detected in the studied cell lines and primary blast cells of two children with acute lymphoblastic leukemia. Neither BCL-2 protein level, nor DNA integrity was affected by the scrambled control indicating the specific effect ASO. As far as we know, this is the first report on the effects of bcl-2 ASO on childhood leukemia/lymphoma cell samples.

Topics: B-Lymphocytes; Cell Line, Tumor; Cell Proliferation; Child; Child, Preschool; DNA Fragmentation; Dose-Response Relationship, Drug; Female; Humans; Leukemia; Lymphoma; Male; Proto-Oncogene Proteins c-bcl-2; RNA, Messenger; Thionucleotides

Topics: Clinical Trials as Topic; Cytarabine; Drug Combinations; Gossypol; Humans; Leukemia; Mastocytosis, Systemic; Molecular Structure; Pyrimidines; Pyrrolidines; Thionucleotides; Thymine; Trifluridine; Uracil

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