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Method to inhibit cell growth using oligonucleotides

a technology of oligonucleotides and oligonucleotide, which is applied in the directions of aerosol delivery, extracellular fluid disorder, peptide/protein ingredients, etc., can solve the problems of morbidity and mortality rates that have not significantly improved, and achieve the effects of reducing the occurrence of skin cancer, preventing spongiosis, blistering or dyskeratosis

Inactive Publication Date: 2006-03-09
TRUSTEES OF BOSTON UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0015] Also encompassed by the invention is a method for reducing the occurrences of skin cancer in a human, the method comprising applying to the skin an effective amount of a composition comprising an oligonucleotide having between 2 and 200 bases and having at least 33% but less than 100% identity with the sequence (TTAGGG)n, where n=1 or greater and when said oligonucleotide comprises the sequence RRRGGG (R=any oligonucleotide) has a guanine content of 50% or less.
[0027] The present invention is also directed to a method for preventing spongiosis, blistering or dyskeratosis in the skin of a mammal, following exposure to ultraviolet light, the method comprising applying to the skin an effective amount of a composition comprising one or more oligonucleotides.
[0029] In another aspect of the methods of the present invention to reduce the occurrence of skin cancer in a human is a method for reducing the occurrence of skin cancer in a human with xeroderma pigmentosum, or other genetically determined cancer predisposition, the method comprising applying to the skin an effective amount of a composition comprising one or more oligonucleotides according to the present invention.

Problems solved by technology

For some types of cancers and stages of disease at diagnosis, morbidity and mortality rates have not improved significantly in recent years in spite of extensive research.
Cancers are currently often treated with highly toxic therapies.

Method used

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  • Method to inhibit cell growth using oligonucleotides
  • Method to inhibit cell growth using oligonucleotides
  • Method to inhibit cell growth using oligonucleotides

Examples

Experimental program
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Effect test

example 1

[0123] Based on our observation that the oligonucleotides of the present invention have the same relative molar efficacy in causing pigmentation in melanocytes, apoptosis and cellular senescence in malignant cells, a retrospective comparison of activities of a number of oligonucleotides was made and the relative molar efficacy of the oligonucleotides with respect to one another was calculated with the results set out in Table 1. Based on these results, we have concluded that the following parameters are among those that are important in determining efficacy of the oligonucleotides of the present invention. [0124] 1) percent tolemere identity; [0125] 2) number of hydrolyzable linkages; [0126] 3) guanine content; [0127] 4) sequence motif

[0128] The comparisons also reveal that the presence of cytosine residues in the oligonucleotides can have a negative impact on molar efficiency.

TABLE 1Relative Molar Efficacy of Tested T-OligosSequenceActivity  T0* TT1  AA0  TTA1.5  TTAG2* GAGTATGA...

example 2

Sequence Parameters

[0129] In order to further examine the effect of various nucleotide sequence parameters on the relative efficacy of T-oligos to induce apoptosis in MM-AN melanoma several oligonucleotides were synthesized which had varying % identity with the telomere repeat and which were varied with respect to the number of bases, number of guanine bases, number of GT's, number of GGT's, and the number of GGTTs. Apoptosis studies were undertaken as described in PCT / US03 / 11393 incorporated herein by reference. (See e.g. Examples 13, 28) MM-An melanoma cells were exposed to each of the T-oligos shown in Table 3 at a concentration of 40 μM for 96 hours. After 96 hours the cells were stained with propidium iodide and the percent of DNA content in the sub GI portion of the cell cycle was determined by FACS analysis. Relative activity was determined by comparison to the relative activities shown in Table 1. The sequence parameters that were investigated include: % identity with the t...

example 3

Dose-Response Effects of T-Oligos on Apoptosis in MM-AN Cells

[0131] Experiments were conducted comparing the ability of different T-oligos at a range of concentrations to induce apoptosis in MM-AN melanoma cells. Apoptosis studies were undertaken as described in PCT / US03 / 11393 (See e.g. Examples 13 and 28) and treated once in triplicate with each T-oligo at each dose (1, 5 and 10 μM) and subjected to FACS analysis after 96 hours as described in PCT / US03 / 11393. The T-oligos used were pGTTAGGGTTAG (SEQ ID NO:5), p(GGTT)4 (SEQ ID NO:29) and p(GGTT)5 (SEQ ID NO:35). Results are shown in FIGS. 1 and 4. The results are compatible with earlier experiments and show that the standard (GTTAGGGTTAG) (SEQ ID NO:5) is less effective at inducing apoptosis than either the p(GGTT)4 SEQ ID NO:29 or p(GGTT)5 (SEQ ID NO:35), which were comparable in efficacy. In a separate experiment (GGTT)4 with and without 5′ phosphorylation were equally active in the MM-AN cell assay for apoptosis. Maximally effec...

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Abstract

Described are methods for treating hyperproliferative disorders, including cancers, by administering to the affected mammal (e.g., human) an effective amount of a composition comprising one or more oligonucleotides which share at least 33% but less than 100% nucleotide sequence identity with the human telomere overhang repeat. Methods of treatment or prevention of hyperproliferative diseases or pre-cancerous conditions affecting epithelial cells, such as psoriasis, atopic dermatitis, or hyperprolferative diseases of other epithelia and methods for reducing photoaging, or oxidative stress or for prophylaxis against or reduction in the likelihood of the development of skin cancer, are also disclosed. The compositions and methods are also useful to treating other cancers.

Description

RELATED APPLICATIONS [0001] This application is a continuation-in-part of application Ser. No. 10 / 122,630 filed Apr. 12, 2002, which is a continuation-in-part of International Application No. PCT / US01 / 10162, which designated the United States and was filed on Mar. 30, 2001, published in English, which is a continuation-in-part of application Ser. No. 09 / 540,843 filed Mar. 31, 2000, which is a continuation-in-part of application Ser. No. 09 / 048,927 filed Mar. 26, 1998, now U.S. Pat. No. 6,147,056, which is a continuation-in-part of the U.S. National stage of International Application No. PCT / US96 / 08386 filed Jun. 3, 1996, published in English, U.S. application Ser. No. 08 / 952,697, now abandoned, which is a continuation-in-part of application Ser. No. 08 / 467,012 filed Jun. 6, 1995, now U.S. Pat. No. 5,955,059. The entire teachings of the above applications and issued patents are incorporated herein by reference.BACKGROUND OF THE INVENTION [0002] Mammalian cells have a complex response...

Claims

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Application Information

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IPC IPC(8): A61K48/00A61K9/12C12N15/09A61K31/7088A61K38/00A61K41/00A61K47/10A61P1/18A61P7/00A61P15/00A61P17/00A61P19/00A61P21/00A61P35/00A61P35/02
CPCA61K31/7088A61K31/713A61K31/7125A61K31/711A61P1/18A61P15/00A61P17/00A61P19/00A61P21/00A61P35/00A61P35/02A61P43/00A61P7/00A61K48/00
Inventor GILCHREST, BARBARAELLER, MARK
Owner TRUSTEES OF BOSTON UNIV
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