Antisense oligonucleotides inhibiting human bcl-2 gene expression

DETAILED DESCRIPTION The invention provides oligodeoxynucleotides and methods for inhibiting growth of lymphoma or leukemia cells, that are types of lymphocytes.
An antisense oligodeoxynucleotide complementary to at least an effective portion of the mRNA sense strand to the human bcl-2 gene is provided and cells are then contacted with the antisense oligodeoxynucleotide in a concentration sufficient to inhibit proliferation of the cells.
The methods of the invention are suitable for inhibiting proliferation of lymphoma/leukemia cells that express the human bcl-2 gene and have a t (14; 18) chromosomal translocation as well as those that express the bcl-2 gene but do not have a t (14; 18) chromosomal translocation.
In accordance with preferred embodiments, the oligodeoxynucleotide is substantially complementary to a strategic site in the mRNA sense strand.
A preferred strategic site is the translation-initiation site of the mRNA coding strand.
Alternative strategic sites include coding sites for splicing, transport or degradation.
The subject antisense oligodeoxynucleotide either in its "native", unmodified form or as a derivative, is brought into contact with the target lymphoma or leukemia cells.
For in vivo therapeutic use, a derivative of the "native" oligodeoxynucleotide, such as the phosphorothioate form is preferred since it is believed that these forms are more resistant to degradation, notwithstanding the fact that response times to some analogues, such as the phosphorothioate analogs, has been found to be somewhat slower than to the "native" form of the oligodeoxynucleotide.
A preferred antisense oligodeoxynucleotide, denominated herein the TI-AS (translation initiation antisense) nucleotide straddles the translation-initiation site of the mRNA coding strand of the human bcl-2 gene and is complementary to this region.
More preferably, this nucleotide comprises a TAC portion which is complementary to the ATG initiation sequence of the coding strand for the bcl-2 gene, and preferably further comprises flanking portions of two to about one hundred bases, more preferably from about five to about twenty bases, which are complementary to portions of the bcl-2 gene coding strand flanking said initiation sequence