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Small cell lung cancer therapeutic agent containing oligonucleotide

An oligonucleotide and nucleic acid technology, applied in the field of small cell lung cancer therapeutic drugs containing oligonucleotides, can solve the problems of inability to use by patients and high incidence of diarrhea

Pending Publication Date: 2021-03-16
OSAKA UNIV +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, both have the problem of a high incidence of side effects such as diarrhea
Moreover, irinotecan also has the limitation that it cannot be used in patients with interstitial pneumonia
In addition, SCLC develops resistance to chemotherapy in case of relapse after treatment with chemotherapy

Method used

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  • Small cell lung cancer therapeutic agent containing oligonucleotide
  • Small cell lung cancer therapeutic agent containing oligonucleotide
  • Small cell lung cancer therapeutic agent containing oligonucleotide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0449] (Example 1: Oligonucleotide Synthesis)

[0450] The oligonucleotides related to the present invention were synthesized by the methods described in Tetrahedron Letters 22, 1859-1862 (1981), International Publication No. 2011 / 052436 and the like.

[0451] Specifically, GeneDesign Co., Ltd. was requested to synthesize an oligonucleotide comprising 2',4'-BNA / LNA represented by the formula (a).

[0452]

[0453] (In the formula, Base is 5-methylcytosine, thymine, adenine or guanine.)

[0454] The oligonucleotide containing amide BNA (AmNA) represented by the formula (b) was synthesized by referring to the method described in International Publication No. 2011 / 052436.

[0455]

[0456] (In the formula, Base is 5-methylcytosine, thymine, adenine or guanine, and Me is methyl.)

[0457] An oligonucleotide of 15 to 19 bases (mer) comprising 2′,4′-BNA / LNA represented by formula (a) or amide BNA (AmNA) represented by formula (b) uses an automatic nucleic acid synthesizer (...

Embodiment 2

[0459] (Example 2: Design of antisense oligonucleotides)

[0460] Antisense oligonucleotides were designed to target the mRNA of human nSR100 (hnSR100) (GenBank: NM_194286.3 (SEQ ID NO: 1)).

[0461] In order to select the target region, reverse sequences (CG, GGA, GCA) of CG, TCC, and TGC that exhibit toxicity when antisense are removed. Then, based on the secondary structure prediction using mfold (mfold: http: / / unafold.rna.albany.edu / ?q=mfold), regions that are easily accessible to antisense oligonucleotides such as circular structures were selected. Next, using Blast (BLAST: https: / / blast.ncbi.nlm.nih.gov / Blast.cgi?PAGE_TYPE=BlastSearch), the nSR100 gene was centered on the region with high identity between human mRNA and mouse mRNA Selected so that the results obtained based on the evaluation in mice can be applied to humans. Thus, 22 candidate sequences were selected.

[0462] An oligonucleotide having a base sequence complementary to the candidate sequence selected a...

Embodiment 3

[0472] (Example 3: Inhibition of mRNA expression of nSR100 in vitro in human SCLC cells)

[0473] (3-1: Analysis of mRNA expression inhibition by various antisense oligonucleotides)

[0474] For the antisense oligonucleotides prepared in Example 2, mRNA expression suppression of nSR100 in human SCLC cells in vitro was investigated. As human SCLC cells, NCI-H82 cells (American Type Culture Collection: ATCC), STC-1 cells (ATCC) and NCI-N417 cells (ATCC) were used. Cells without oligonucleotide addition served as controls. In addition, as a comparison, an N26 oligonucleotide was used (base sequence: 5'-TGAacaaaataaTAc-3': in this example, bases in capital letters are 2', 4'-BNA / LNA, and bases in lowercase letters The base is DNA, S-oligonucleotide: sequence number 100).

[0475] Each antisense oligonucleotide was passed through the CEM method (using "Ca 2+ "enrichment for medium" method of calcium ion-rich medium: Nucleic Acids Research, 2015, Vol.43, e128) into human SCLC ce...

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Abstract

Disclosed is an oligonucleotide, or a pharmacologically acceptable salt thereof, that contains at least one prescribed nucleoside structure, is capable of binding with a human nSR100 gene, and has activity to suppress the expression of the human nSR100 gene. The length of this oligonucleotide is 12-20 bases, and the oligonucleotide is complementary to a prescribed target region. Also disclosed isan nSR100-gene-expression-suppressing agent and a cancer therapeutic agent that contain the oligonucleotide or a pharmacologically acceptable salt thereof. This cancer therapeutic agent can be used inthe treatment of small cell lung cancer, prostate cancer, or breast cancer.

Description

technical field [0001] The present invention relates to an oligonucleotide having nSR100 gene expression inhibitory activity and a therapeutic agent for cancer (for example, small cell lung cancer (SCLC)) containing such an oligonucleotide. Background technique [0002] Lung cancer, the leading cause of cancer-related death, is divided into two types: small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). Generally speaking, SCLC has a high degree of malignancy, rapid growth and metastasis of cancer cells, and it is often difficult to perform surgical resection. Furthermore, although cytotoxic antitumor drugs are effective at the beginning of treatment, small cell lung cancer often relapses, and once relapsed, resistance to existing antitumor drugs often becomes a problem, and the prognosis is poor. On the other hand, molecular target therapeutic drugs have been developed for NSCLC, and a certain therapeutic effect has been confirmed, but some patients may un...

Claims

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Application Information

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IPC IPC(8): C07H21/04A61K31/7125A61K48/00A61P11/00A61P13/08A61P15/00A61P35/00A61P43/00C12N15/113
CPCA61P11/00A61P13/08A61P15/00A61P35/00A61P43/00C12N15/113C12N2310/3231C12N2310/341C12N2310/346C12N2310/11
Inventor 下条正仁小比贺聪笠原勇矢铃木高尾山上正辉梅本忠士
Owner OSAKA UNIV
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