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Protection of normal tissue in cancer treatment

A cancer and cancer cell technology, applied in drug combinations, medical preparations containing active ingredients, peptide sources, etc., can solve problems that have not been fully elucidated

Inactive Publication Date: 2020-08-14
THOMAS JEFFERSON UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, although the response of the small intestine to gamma radiation has been well examined at the pathomorphological level, the exact cause of GI lethality has not been fully elucidated

Method used

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  • Protection of normal tissue in cancer treatment
  • Protection of normal tissue in cancer treatment
  • Protection of normal tissue in cancer treatment

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Embodiment 1

[0232] Therapeutic radiation and genotoxic chemotherapy are part of the medical equipment for cancer treatment. These genotoxic agents are generally dose-limiting due to damage to normal tissues. We have found that the cell signaling molecule cyclic GMP can prevent genotoxic damage to cells through a p53-dependent mechanism. Here, we describe a method to improve the treatment of colorectal tumors by radiation or chemotherapy by identifying tumors that are GUCY2C-negative or harbor mutant p53. For these tumors, GUCY2C activators (e.g., ST, linaclotide (linaclotide) (SEQ ID NO:59, plecanatide (plecanatide) SEQ ID NO:60)) can be used to leave normal intestinal epithelium, Without affecting the therapeutic efficacy of genotoxic agents (eg radiation, chemotherapy). In this way, higher doses of genotoxic therapy can be administered to kill tumors without causing normal tissue damage. In addition, provided herein are agents that use genotoxic agents in conjunction with elevating c...

Embodiment 2

[0341] Long-lived pluripotent stem cells (ISCs) at the base of intestinal crypts modulate their phenotype for normal maintenance of the epithelium and regeneration after injury. Their long lifespan, lineage plasticity and proliferative potential underlie the necessity for tight homeostatic regulation of the ISC compartment. In this context, the guanylate cyclase C (GUCY2C) receptor and its paracrine ligands regulate intestinal epithelial homeostasis, including proliferation, lineage commitment and DNA damage repair. However, the role of this axis in maintaining the ISC remains unknown. Transgenic mice (Guey2c- / -) enabling analysis of ISCs (Lgr5-GFP) in the presence of GUCY2C depletion were combined with immunoassay techniques and drug treatments to define the role of the GUCY2C signaling axis in supporting ISCs . ISC was reduced in Gucy2c- / - mice, which correlated with loss of active Lgr5+ cells, but reciprocal increase in reserve Bmil+ cells. GUCY2C is expressed in crypt-b...

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Abstract

Methods of treating individuals who have cancer are disclosed. In some methods, the cancers may lack functional guanylyl cyclase C and / or p53. In some methods, the methods comprise protecting gastrointestinal cells from genotoxic damage by administering one or more compounds sufficient to elevate intracellular cGMP in the gastrointestinal cells, and then administering chemotherapy and / or radiationtherapy to kill cancer cells. In some methods, the method comprise administering one or more guanylyl cyclase C agonist compounds to intestinal stem cells in the individual an amount of sufficient toactivate guanylyl cyclase C of the intestinal stem cells and elevate intracellular cGMP in the intestinal stem cells, and then administering chemotherapy and / or radiation therapy to kill cancer cells.

Description

technical field [0001] The present invention relates to compositions and methods for protecting individuals from serious and potentially fatal side effects associated with cancer chemotherapy and radiation therapy. [0002] Background of the invention [0003] Cancer is the leading cause of death worldwide; since 2004 it has caused 7-8 million deaths per year (approximately 13% of all deaths). Worldwide deaths from cancer are projected to continue to rise, with an estimated 12 million deaths by 2030. Lung, stomach, liver, colon, and breast cancers account for the greatest number of cancer deaths each year. Cancer is the second leading cause of death in adults in the United States and is responsible for more than half a million deaths each year. Lung, prostate, breast, and colon cancers are the leading causes of cancer-related death. [0004] Chemotherapy and radiation therapy (the two most common types of cancer treatments) work by destroying fast-growing cells such as can...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K38/02A61P35/00C07K2/00C07K14/47
CPCA61K45/06A61K38/005A61K38/10A61K2300/00A61P35/00A61K9/0053
Inventor S·A·沃尔德曼
Owner THOMAS JEFFERSON UNIV
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