Compounds, compositions and methods for treating oxidative DNA damage disorders

Abstract

Compounds, compositions, and formulations, and accompanying methods useful for treating disorders arising from oxidative DNA damage, including oxidative DNA damage resulting from ionizing radiation or other therapy are described herein.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application claims priority under 35 U.S.C. §119(e) to U.S. Provisional Application Ser. No. 61 / 493,169 filed Jun. 3, 2011. The disclosure of which is incorporated herein by reference.TECHNICAL FIELD[0002]The present invention relates to compounds, compositions and formulations useful for treating disorders arising from oxidative DNA damage, including oxidative DNA damage resulting from ionizing radiation or other therapy.BACKGROUND AND SUMMARY OF THE INVENTION[0003]Evidence in patients and in animal models demonstrates that cancer therapies are often accompanied by neurological side effects. Two major neurological side effects are cognitive dysfunction, also referred to as “chemobrain,” and chemotherapy-induced peripheral neuropathy (CIPN). Two such therapies that cause neurological side effects include ionizing radiation and drugs that act through mechanisms causing DNA damage, such as platinum-containing drugs, taxanes, and the li...

AI Technical Summary

Benefits of technology

[0005]Although many IR neurotoxicity studies focus on the CNS, such radiation therapy may also cause significant toxicity to peripheral neurons (autonomic, motor, or sensory neurons). For example, in the GI tract and bladder, it has been reported that IR alters levels of substance P and calcitonin gene-related peptide (CGRP), two neuropeptides found in small-diameter sensory neurons [9-11]. Reduced capsaicin-evoked CGRP release from sensory neurons has been attributed to indicate reduced sensory neuron functioning. It has also been reported that these peptides modulate intestinal injury after radiation. In particular, CGRP is protective of the tissue, whereas SP contributes to the pathophysiology [12] in the gut, and worsens early-onset radiation-induced toxicity [12].

[0006]Using cultured neurons isolated from the central nervous system, several investigators have reported that IR exposure increases production of reactive oxygen species (ROS) [13], produces DNA damage [13, 14], and often causes apoptosis [13, 15], all in a dose-dependent manner. However, the mechanisms by which IR produces neurotoxicity remain undetermined. Without being bound by theory, it is believed herein that radiation might directly affect sensory neurons, exacerbating radiation-induced injury in various organs. Further, but without being bound by theory, it is believed herein that, in situ, radiation-induced oxidative damage to DNA may subsequently alter neuronal function and cause cell death. There is a need for protecting patients from and / or treating patients with neuronal damage, which may heighten the quality of life, especially of cancer survivors [6, 23, 24].

[0007]It has been discovered herein that modulating the expression of APE1 alters many forms of neurotoxicity, including IR-induced neurotoxicity. It has been observed herein that modulation of DNA repair mechanisms may reverse the undesired neurotoxic effects arising from a number of sources, including a number of anticancer drugs. Without being bound by theory it is believed herein that enhancing the base excision repair pathway may attenuate neuronal damage, such as by chemotherapeutic agents both during and after cancer therapy.

[0008]In one embodiment, compounds, compositions, methods, and uses are described herein for treating neurotoxicity. It is demonstrated herein that APE1 is involved in protecting neuronal cells, such as dorsal root ganglion (DRG) cells and hippocampal cells, from toxicity and / or neuronal dysfunction induced by chemotherapy, such as IR and cancer drugs, including platinum-containing drugs, taxanes, and the like. In another embodiment, compounds, compositions, methods, and uses are described herein that include inhibitors of APE1, including small-molecule inhibitors. In one aspect, the inhibitors selectively modulate the redox function of APE1. It has been unexpectedly discovered that negative modulation of the redox function of APE1, irrespective of the modulation of the DNA repair function, enhances neuroprotective activity and is an efficacious therapy for preventing, treating, and / or reversing neuronal damage.

Problems solved by technology

Evidence in patients and in animal models demonstrates that cancer therapies are often accompanied by neurological side effects.

Furthermore, there are no standard and effective treatments available to prevent or reverse such therapy-induced neurotoxicity.

It has also been reported that IR can produce significant neurotoxicity, especially upon direct exposure to central nervous system tissues [6, 7].

Although many IR neurotoxicity studies focus on the CNS, such radiation therapy may also cause significant toxicity to peripheral neurons (autonomic, motor, or sensory neurons).

However, the mechanisms by which IR produces neurotoxicity remain undetermined.

Further, but without being bound by theory, it is believed herein that, in situ, radiation-induced oxidative damage to DNA may subsequently alter neuronal function and cause cell death.

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