Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Patent
1997-12-15
1999-12-21
Fredman, Jeffrey
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
536 231, 536 243, 536 2431, 536 2433, 514 44, 435 6, 435 911, 435 912, C07H 2104, C07H 2102, A61K 4800, C12Q 168
Patent
active
060050950
DESCRIPTION:
BRIEF SUMMARY
This invention relates to an antisense transcript expressed in some kind of tumor cells and to synthetic oligodeoxynucleotides (ODN) useful in the diagnosis and treatment of said tumor cells.
More particularly, the present invention relates to an endogenous antisense transcript that complements the pre-mRNA (immature RNA) of the hybrid gene carrying the chromosome translocation t(14;18) that promotes the overexpression of BCL-2 protein, thus causing neoplastic transformation. The present invention relates also to oligodeoxynucleotides which inhibit the action of said transcript.
It is well known that the synthetic oligodeoxynucleotides are short single strand DNA chains. The nucleotide sequence is ordered in a specular fashion (antisense) to complement a nucleotide sequence within the mRNA to be inhibited. By that modality they are capable to regulate gene expression in a specific way.
It is important that the oligodeoxynucleotides have a proper length suitable to optimally hybridize the target mRNA. In general, the minimum length is of 10 bases and the maximum length is of about 100 bases. Preferably, the length is of 15-30 bases; still preferably it is of 18 bases since the statistical analysis teaches that every sequence having this length is unique within the human genome.
The oligodeoxynucleotides can act at different steps of the mRNA metabolic pathway, either at the nuclear or at the cytoplasmic level. It is moreover likely that oligodeoxynucleotides act at the ribosome level, or straight to the DNA level both in the nucleus and in the mitochondria. The nucleotide length of the oligodeoxynucleotides may be selected also in view of the basic knowledge of the person skilled in the art concerning the efficacy in the cellular membranes (Locke S. L. et al.: Mechanism of oligonucleotide uptake by cells: involvement of specific receptors? Proc. Natl. Acad. Sci. USA 86: 3474, 1989. Yakubov L. A. et al.: Characterization of oligonucleotide transport into living cells. Proc. Natl. Acad. Sci. USA 86: 6454, 1989).
It is also known that discrete regions within specific genes may be transcribed in both directions. More commonly, a single strand (positive) from the double strand is transcribed into mRNA and then translated into protein. In some circumstances, however, the negative strand may also be transcribed (endogenous antisense RNA), playing a regulatory role in the functions of the regular transcript. The antisense transcripts may regulate the synthesis, maturation, stability and translation of the messenger RNA (Green P. J. et al.: The role of antisense RNA in gene regulation, Ann. Rev. Biochem. 55: 569, 1990; Krystal G. W. et al.: N-myc mRNA forms RNA--RNA duplex with endogenous antisense transcripts. Mol. Cell Biol. 10: 4180, 1990; Taylor E. R. et al.: Identification of antisense transcripts of the chicken insulin-like growth factor-II gene. J. Mol. Endocrinol. 7: 145, 1991).
Finally, it is also known that in most follicular B cell lymphomas, positives for t(14-18) translocation, the early events truncate the 3' end of bcl-2 gene in chromosome 18 and join it to the truncated 5' end of the IgH locus in chromosome 14, originating the chimeric gene bcl-2/IgH responsible for BCL-2 overexpression (Nunez G. et al.: Deregulated bcl-2 gene expression selectively prolongs survival of growth factor--deprived haemopoietic cell lines. J Immunol 144: 3602, 1990. Cleary M. L. et al.: Cloning and structural analysis of cDNAs for Bcl-2 and a hybrid Bcl-2/immunoglobulin transcript resulting from the t(14;18) translocation. Cell 47: 19, 1986). Protein BCL-2 has been shown to inhibit programmed cell death in certain circumstances, providing a cell survival advantage.
The bcl-2 sequence is known (Cleary M. L. et al.: Cloning and structural analysis of cDNAs for Bcl-2 and a hybrid Bcl-2/immunoglobulin transcript resulting from the t(14;18) translocation. Cell 47: 19, 1986). It is also known that its breakpoints are mainly in the 3'UTR. More particularly, about 60% of breakpoints in the chromosome 18 occurs in a segment betwee
REFERENCES:
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Capaccioli Sergio
Morelli Susanna
Nicolin Angelo
Consiglio Nazionale Delle Ricerche
Fredman Jeffrey
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