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Methods and compositions for the treatment of cancer using benzopyrone-type PARP inhibitors

A cancer and compound technology, applied in drug combinations, active ingredients of heterocyclic compounds, medical preparations containing active ingredients, etc., can solve problems such as necrosis, ATP consumption, and cell dysfunction

Inactive Publication Date: 2010-12-01
BIPAR SCI INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Oxidative stress-induced hyperactivation of PARP depletes NAD+ and thus ATP, ultimately resulting in cellular dysfunction or necrosis

Method used

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  • Methods and compositions for the treatment of cancer using benzopyrone-type PARP inhibitors
  • Methods and compositions for the treatment of cancer using benzopyrone-type PARP inhibitors
  • Methods and compositions for the treatment of cancer using benzopyrone-type PARP inhibitors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0578] In Vitro Efficacy of Compound of Formula IIIg (5-iodo-6-nitrocoumarin)

[0579] Materials and methods

[0580] Test Drugs - Cells were plated with vehicle or test drugs at concentrations of 0.1 μM, 0.3 μM, 1 μM, 3 μM, 10 μM, 30 μM and 100 μM and treated for 24 hours (day 1).

[0581] Tumor Cell Lines—Tumor cell lines (Table 1) were obtained from the American Type Cell Collection (ATCC, Rockville, MD) or the NCI-DCTD Tumor Repository (Bethesda, MD) and were stored in media supplemented with 10% fetal bovine serum (FBS, NovaTech). Store it in a specific growth medium. Cells were propagated at 37°C in a humidified atmosphere containing 5% carbon dioxide.

[0582] Cell Proliferation Assay - Cell proliferation was determined using the BrdU chemiluminescent assay, which measures the incorporation of 5-bromo-2'-deoxyuridine (BrdU) into the genomic DNA of proliferating cells. Briefly, cells and BrdU are added for 4 hours, during which time it is incorporated into the DN...

Embodiment 2

[0602] Example 2: Evaluation of IIIg on human cancer xenograft implants in nude mice.

[0603] Methods and materials

[0604] mouse

[0605]Female athymic nude mice (nu / nu, Harlan) were 9-10 weeks old and had a body weight (BW) range of 18.1-27.0 g on study day 1 . Let animals drink water (reverse osmosis water, 1ppm Cl) freely and eat (NIH 31 Modified and Irradiated Lab Diet Containing 18.0% crude protein, 5.0% crude fat and 5.0% crude fiber). ALPHA-dri irradiated in static microisolation chambers in mice bed-o-cobs The experimental animals were raised on beds, and the lights were turned on for 12 hours, the temperature was 21-22°C (70-72°F), and the humidity was 40-60%. The PRC explicitly follows the recommendations of the "Guide for Care and Use of Laboratory Animals" regarding confinement, husbandry, surgical procedures, dietary adjustments, and veterinary care. PRC's animal program is accredited by AAALAC International to ensure compliance with generally accepted...

Embodiment 3

[0649] Example 3: Efficacy of IIIg on pancreatic cancer cell lines

[0650] Pancreatic cancer cell lines and culture conditions

[0651] Human pancreatic cancer cell lines were maintained in minimal essential medium supplemented with 10% fetal bovine serum (FBS), sodium pyruvate, non-essential amino acids, l-glutamine, double vitamin solution (Life Technologies, Grand Island, NY ) and penicillin-streptomycin mixture (Flow Laboratories, Rockville, MD). Cultures were free of mycoplasma and the following pathogenic murine viruses: reovirus type 3, pneumovirus, K virus, Theiler encephalitis virus, Sendai virus, parvovirus, mouse adenovirus, mouse hepatitis virus, lymphocytic choriomeninges Influenza virus, pox virus and lactate dehydrogenase virus (analyzed by Science Applications International Corp. Frederick, MD).

[0652] Orthotopic Transplantation of Animal and Tumor Cells

[0653] Male athymic nude mice (NCI-nu) were purchased from the Animal Production Area of ​​the Natio...

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Abstract

The present invention provides compositions of matter, kits and methods for their use in the treatment of cancer. In particular, the invention provides compositions and methods for treating cancer in a subject by inhibiting a poly-ADP-ribose polymerase, as well as providing formulations and modes of administering such compositions.

Description

[0001] cross reference [0002] This application claims U.S. Provisional Application 60 / 981,436 (Attorney Docket No. 28825-745.101), filed October 19, 2007, entitled "Treatment of Cancer Using Benzopyrone-Type PARP Inhibitors" and filed September 11, 2008 Claim to U.S. Provisional Application 61 / 096,282 (Attorney Docket 28825-745.102), entitled "Methods and Compositions for Treating Cancer Using Benzopyrone PARP Inhibitors," both of which are hereby incorporated in their entirety Reference. Background of the invention [0003] Cancer is a serious threat to modern society. Due to their unique characteristics, the growth of malignant tumors poses a serious challenge to modern medicine. Their hallmarks include uncontrolled cell proliferation leading to unchecked growth of malignant tissue, ability to invade local and distant tissues, lack of differentiation, lack of detectable symptoms, and most importantly, lack of effective treatment and prevention methods. [0004] Cancer c...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/35A61K33/243
CPCA61K31/37A61K38/21A61K31/496A61K31/7068A61K33/24A61K31/282A61K31/555A61K31/453A61K31/4025A61K31/4433A61K31/4178A61K45/06A61P1/18A61P35/00A61P35/02A61P43/00A61K33/243A61K2300/00
Inventor 瓦莱里娅·S·奥索夫斯卡亚巴里·M·舍曼
Owner BIPAR SCI INC
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