title: Antisense Oligonucleotides: Considerations for Lymphoma Therapy.
abstract: The majority of lymphomas are of B-cell lineage in origin. Translocations involving the q32 region of chromosome 14, the site of the immunoglobulin heavy chain gene (IGH), are most often observed. Rearrangement of one of the two alleles of this IGH gene is essential for development of the pre-B-cell into a functional B-cell and takes place normally under the influence of a DNA recombinase enzyme system. B-cell lymphomas predominantly involve the deregulation of proto-oncogenes following their juxtaposition to immunoglobulin genes. Their occurrence in part must be due to their obligate DNA breaks and rearrangement within the IG loci and probably involves a mistake mediated by the recombinase enzyme system responsible for normal IG rearrangement.(1,2) The overall result of these changes is a failure of the malignant cell to die in a programmed manner (apoptosis). Conventional treatments are not targeted to these molecular changes and often fail to effect a cure due to an inability to induce apoptosis. Antisense oligonucleotides (ASO) consisting of short sequences of DNA complementary to aberrantly expressed genes in tumours could potentially 'switch off' the inappropriate gene with a consequent antitumour effect by the induction of apoptosis. This represents the underlying basis of antisense therapy in malignant lymphoma. The binding of a sequence-specific oligonucleotide to a targeted length of mRNA occurs with a high level of specificity. Formation of an mRNA-DNA duplex should in theory suppress the translation of the targeted message into protein. If the production of that protein is essential for the survival, or malignant potential, of the cell, then blocking its production will negate the oncogenicity of the cell. Antisense oligonucleotides have been reported to inhibit gene expression as far back as 1978 with the inhibition of the Rous sarcoma virus in transfected chick embryo fibroblasts by a 13-mer oligonucleotide.(3).
authors.affiliation: a LRF Dept of Haematology and Oncology , Institute of Child Health , 30 Guilford Street, London WC1N 1EH , Tel, Fax, e mail: f.cotter@ich.bpmf.ac.uk.
authors.forename: F E
authors.initials: FE
authors.lastname: Cotter
keywords: Antisense; Apoptosis; BCL-2; Lymphoma