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Method of preventing or treating treatment-induced gastrointestinal injury

A gastrointestinal, colonic technology, used in oncology and cancer therapy, medical field, can solve the problem of prevention or treatment of GI damage or complications, etc.

Pending Publication Date: 2021-10-12
余健 +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

There are currently no FDA-approved agents for the prevention or treatment of CPT-11-induced GI injury or complications

Method used

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  • Method of preventing or treating treatment-induced gastrointestinal injury
  • Method of preventing or treating treatment-induced gastrointestinal injury
  • Method of preventing or treating treatment-induced gastrointestinal injury

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0074] Example 1. Materials and methods

[0075] Compound Screening and Preparation

[0076] In silico screening using the ZINC 8.0 database and in silico ADME / toxicity profiles as previously described (Mustata G. et al. "Curr Top Med Chem" (2011) 11:281-290, incorporated by reference incorporated herein) to identify candidate PUMA inhibitor structures and analogs. Compounds related to PUMAi were obtained from commercial suppliers.

[0077] Research design

[0078] The goals of this study were to determine whether PUMA and p53-dependent apoptosis mediate chemotherapy-induced intestinal stem cell loss and enteropathy, and whether their genetic and pharmacological inhibition confers intestinal chemoprotection. Non-tumor-bearing and tumor-bearing mice, p53 and Puma KO mice, small molecule PUMAi, and in vitro mouse and human colon organoids were used to measure the effect of PUMA inhibition on intestinal injury and regeneration, and tumor response following chemotherapy. Sampl...

Embodiment 2

[0134] Example 2. PUMA mediates chemotherapy-induced crypt apoptosis and lethality

[0135] To investigate the potential role of p53-dependent apoptosis in chemotherapy-induced acute intestinal injury, the inventors treated wild-type (WT), p53 knockout ( KO) and Puma KO mice. CPT-11 induces robust crypt apoptosis in WT mice as measured by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling (TUNEL) and active caspase-3 staining , which peaked at 6 hours and gradually decreased through 48 hours. Apoptosis was observed in both stem cells at the base of the crypt (CBCs in positions 1 to 3 relative to the bottom of the crypt) and +4 to 9 cells (relative to the bottom of the crypt), but not in p53 KO and Puma KO mice ( Figure 1A with 1B ,as well as Figures 8A-8D ). CPT-11 treatment induced p53 and its targets PUMA and p21 within 6 hours in the intestinal mucosa of WT but not p53 KO mice ( Figure 1C with Figure 8E ). Puma KO did not...

Embodiment 3

[0136] Example 3. Small molecule PUMAi protects against chemotherapy-induced crypt apoptosis and lethality

[0137] The inventors used pharmacophore modeling of key interactions of the PUMA BH3 domain with BCL-2 family proteins, in silico compound screening, and apoptosis analysis to identify a variety of potential PUMAi. It was confirmed that one of these compounds (PUMAi) inhibited the PUMA / BCL-xL but not the BIM / MCL-1 interaction ( Figures 10A-10C ). In colon cancer cell lines with different p53 or PUMA genotypes, including p53 WT (HCT 116), null (p53 KO), mutants (HT29, SW480, and DLD1) or PUMA null (PUMA KO), PUMAi did not reduce hi CPT-induced apoptosis ( Figure 10D ). PUMA was induced by CPT treatment only in p53 WTHCT116 cells, but not any p53-deficient cell line ( Figure 10E ). and mouse intestinal mucosa ( Figure 1C with 1D ) and very low or undetectable expression in normal human small intestine and colon, the basal amount of PUMA in HCT 116 cells was muc...

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PUM

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Abstract

The present invention provides compositions and methods for preventing or treating gastrointestinal injury induced by chemotherapy or radiotherapy.

Description

[0001] Cross References to Related Applications [0002] This application claims priority to U.S. Provisional Application No. 62 / 801,185, filed February 5, 2019, the disclosure of which is incorporated herein by reference. [0003] A statement about federally funded research [0004] This invention was made with government support under U19-A1068021 awarded by NIH. The government has certain rights in this invention. [0005] field of invention [0006] The present disclosure relates generally to the fields of medicine, oncology and cancer therapy. More specifically, the present disclosure relates to compounds, compositions and methods for preventing or treating gastrointestinal injury induced by chemotherapy or radiotherapy. Background technique [0007] Gastrointestinal (GI) side effects are a major dose limiting factor in chemotherapy and abdominal radiation therapy and can cause long-term complications in cancer survivors. For example, 5-fluorouracil (5-FU), common...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/045A61K31/496A61P1/00A61P39/02
CPCA61P39/02A61P1/00A61K31/495A61K31/513A61K31/496A61K31/165A61K31/5375A61K31/63A61K31/275A61K31/341A61K31/4406A61K31/36A61P35/00A61K31/4745A61K2300/00A61K31/16A61K31/4985A61K31/506
Inventor 余健张林B·莱博维茨
Owner 余健
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