Modulation of line-1 reverse transcriptase

Abstract

A reverse transcriptase encoded by L-1 (LINE-1) has been identified as a target molecule for treating or preventing cancers induced or mediated by this molecule. Method of treating or preventing such cancers in patients involves administration of a therapeutically effective amount of a composition having an inhibitor or antagonist of the reverse transcriptase in cells of the patients. The inhibitor or antagonist blocks lengthening of telomeres in telomerase negative cells. Methods and kits for detecting pathologically proliferating cells expressing L1RT are also disclosed.

Description

[0001] This application claims the benefit of U.S. Provisional Application No. 60 / 440,988 filed Jan. 15, 2003, and the text of application No. 60 / 440,988 is incorporated by reference in its entirety herewith.FIELD OF THE INVENTION [0002] The present invention is directed to the field of cancer therapy. Specifically, target molecules have been identified modulation of which regulates elongation of telomeres in telomerase negative cancerous cells. More particularly, it relates to the use of various inhibitor compounds that interfere with human L1 (Line-1) retrotransposon encoded reverse transcriptase (L1RT) for treating or preventing L1RT induced cancers. The invention also relates to screening methods for identifying pharmacologically active compounds that may be useful for treating L1RT-mediated proliferative diseases. BACKGROUND OF THE INVENTION [0003] An asymmetry in the synthesis of leading and lagging DNA strands creates the “end problem” for replication of linear genomes8. To o...

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Benefits of technology

[0008] It has now been found that a product of L1 (Line-1) retrotransposon reverse transcriptase nucleic acid is associated with the lengthening and therefore maintenance of telomeres in certain cancer cells. Specifically, it has been found that interference with the expression of reverse transcriptase encoded by the L1 retrotransposon suppresses the elongation of telomeres in the cancer cells. More pecifically, it has been found that interference with the expression of the L1 reverse transcriptase in telomerase negative cells leads to phenotypic manifestations such as telomere shortening, cell cycle arrest and apoptosis or cell death. It is believed that the reverse transcriptase is involved in maintaining telomeres probably by “slippage” mechanism of telomeric DNA synthesis and/or telomere end targeted L1 transposon retrotransposition.

[0009] Still more specifically, it has been found that treatment of the telomerase negative cells (ALT cells) with reverse transcriptase inhibitor 3′-azido-2′,3′-dideoxythymidine (AZT) or suppression of L1 reverse transciptase (L1RT) using antisense strategy induces progressive telomere loss, G2 phase arrest, chromosomal abnormalities and eventual cell death.

[0010] Accordingly, in one embodiment of the invention, a method is provided for treating tumors characterized by expression of L1RT and/or absence of telomerase expression. Interference with L1RT expression or activity will either directly result in cell death or will potentiate the effects of chemotherapeutic agents that ultimately kill cells through apoptosis. In particular, the invention provides a method for inhibiting proliferation of L1RT expressing cells having potential for continuous increase in cell number by administering inhibitors and antagonists of L1RT. For example, L1RT expression can be suppressed or down regulated by obtaining a DNA molecule having a cDNA sequence operably linked to a promoter such that it will be expressed in antisense orientation, the cDNA having all or part of the sequence of L1RT, and transfecting, with the DNA molecule, the L1RT cells with potential for uncontrolled proliferation. The inhibitor or antagonist is optionally administered with a pharmaceutically acceptable carrier.

[0011] In another embodiment of the invention, a method for prevention of a cancer in a person (e.g. a human) in need thereof is provided. The cance

Problems solved by technology

An asymmetry in the synthesis of leading and lagging DNA strands creates the “end problem” for replication of linear genomes8.

At this stage, when most of telomeres are extremely short, end-to-end fusions and chromosomal breakage-fusion cause marked chromosomal abnormalities and apoptosis.

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