oblimersen and Lymphoma

An increasing number of unique active new chemotherapeutic and biologic agents are currently available for clinical research studies. Nucleoside analogs in development for non-Hodgkin's lymphoma (NHL) include clofarabine, troxacitabine, and bendamustine, a hybrid of an alkylating nitrogen mustard group and a purine-like benzimidazole, with demonstrated activity in NHL. Drugs directed at the cell cycle include flavopiridol and UCN-01. The proteasome plays a pivotal role in cellular protein regulation and activation of NFkappaB, which maintains cell viability through the transcription of inhibitors of apoptosis. PS-341 is a specific, selective inhibitor of the 26S proteasome which induces apoptosis and has activity in cell types characterized by overexpression of Bcl-2. Response rates of 50%, including complete remissions, have been reported using this agent in patients with refractory multiple myeloma. Studies are ongoing in NHL and chronic lymphocytic leukemia. G3139, an antisense oligonucleotide, has shown promise in early studies. Rituximab has revolutionized the treatment of NHL. However, other active antibodies are now available, including alemtuzumab, epratuzumab, and Hu1D10. The radioimmunoconjugates (90)Y-ibritumomab tiuxetan and (131)I-tositumomab may also play an important role in the management of NHL. Future therapeutic strategies should involve rational combinations of new chemotherapy drugs, biologic agents, and antisense compounds to increase the cure rate in patients with lymphoma.

Topics: Adenine Nucleotides; Alemtuzumab; Alkaloids; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal, Murine-Derived; Antibodies, Neoplasm; Antineoplastic Agents; Apoptosis; Arabinonucleosides; Bendamustine Hydrochloride; Boronic Acids; Bortezomib; Cell Cycle; Cell Survival; Clofarabine; Cytosine; Dioxolanes; Flavonoids; Hematologic Neoplasms; Humans; Immunoconjugates; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma; Lymphoma, Non-Hodgkin; Multiple Myeloma; NF-kappa B; Nitrogen Mustard Compounds; Oligonucleotides, Antisense; Peptide Hydrolases; Piperidines; Protease Inhibitors; Proteasome Endopeptidase Complex; Pyrazines; Remission Induction; Rituximab; Staurosporine; Thionucleotides

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