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Novel compositions and uses of anti-hypertension agents for cancer therapy

A technology for cancer treatment and anti-hypertension, applied in drug combinations, antibodies, anti-tumor drugs, etc., can solve the problems of limited methods and low efficacy

Inactive Publication Date: 2014-02-05
THE GENERAL HOSPITAL CORP +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

These barriers limit the amount of drug that reaches the target cancer cells, resulting in low efficacy
[0007] Currently, there are limited approaches aimed at overcoming these delivery barriers for nanotherapeutics and low molecular weight drugs

Method used

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  • Novel compositions and uses of anti-hypertension agents for cancer therapy
  • Novel compositions and uses of anti-hypertension agents for cancer therapy
  • Novel compositions and uses of anti-hypertension agents for cancer therapy

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0503] Example 1: Losartan inhibits the effect of cancer-associated fibroblasts (CAF) on collagen I synthesis

[0504] The effects of Losartan on the production of collagen I and the expression and activation of TGF-β1 by breast CAF were tested ( figure 1 ). Losartan reduces TGF-β1 activation and collagen I production in cancer-associated fibroblasts in vitro. The cells were treated with 10 μmol / L Losartan for 24 hours. Losartan reduced the level of activated TGF-β1 by 90%, while the total TGF-β1 level was not affected. There is a corresponding 27% reduction in collagen I levels. The decrease in activated TGF-β1 and collagen I was statistically significant (Student's t-test p<0.05). Since most of the collagen in the tumor is produced by CAF, the effect of Losartan on the collagen content in the tumor was examined.

Embodiment 2

[0505] Example 2: Losartan reduces collagen I in tumors in a dose-dependent manner

[0506] In order to determine the dose response of losartan in intratumoral collagen levels, intraperitoneal (ip) injections of 10mg / kg / day, 20mg / kg / day and 60mg / kg / day of losartan were performed, and then the back skin folds The fibrous collagen of HSTS26T tumor in dorsal skin fold chambers was subjected to second harmonic generation (SHG) imaging ( Figure 2A-Figure 2B ), and perform collagen I immunostaining on tumor sections ( image 3 A- image 3 D). Although the SHG signal intensity can include the signal contributed by collagen I and other fibril-forming collagens (for example, collagen III or collagen V), collagen I is usually the main collagen type in most soft tissues (Gelse K et al., (2003) Adv Drug Deliv Rev 55: 1531-1546), so it is the main source of SHG signal. In addition, in human pancreatic tumors, collagen I is the main fibrous collagen, while the level of collagen V is signifi...

Embodiment 3

[0507] Example 3: Losartan reduces the expression of TSP-1 in tumors

[0508] TSP-1 is a key regulator of TGF-β1 activation, and it has been reported that Losartan can reduce TSP-1 expression and TGF-β1 activation in mouse models of Marfan’s syndrome and muscular dystrophy (Dietz HC (2010) ) J Clin Invest 120: 403-407). As shown in this article, the measurement of protein levels in homogenized HSTS26T tumors showed that Losartan did not affect total TGF-β1 levels, but significantly reduced TSP-1, activated TGF-β1, and collagen I level ( Image 6 ). Losartan also reduced TSP-1 immunostaining in HSTS26T (73%, p Figure 7A-Figure 7B ). In both Mu89 and HSTS26T tumors, the immunostaining pattern of TSP-1 ( Figure 7A-Figure 7B ) And the immunostaining pattern of collagen I ( Figure 5C-Figure 5D ) Are highly consistent. The inventors detected high levels of TSP-1 and collagen I at the tumor border, while Losartan induced a significant decrease in the levels of TSP-1 and collagen I...

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Abstract

Methods and compositions for improving the delivery and / or efficacy of cancer therapeutics are disclosed. Methods and compositions for treating or preventing a cancer (e.g., a solid tumor such as a desmoplastic tumor) by administering to a subject an antihypertensive agent, as a single agent or combining the antihypertensive agent with a cancer therapeutic agent (for example, a therapeutic agent ranging in size from a large nanotherapeutic to a low molecular weight chemotherapeutics and / or oxygen radical) are disclosed.

Description

[0001] Cross references to related applications [0002] According to 35U.SC§119(e), this application requires priority of the U.S. Provisional Application Serial No. 61 / 415,192 filed on November 18, 2010 and the U.S. Provisional Application Serial No. 61 / 438,240 filed on January 31, 2011. Right, the content of each is incorporated into this article by reference. [0003] governmental support [0004] The present invention was completed under federal funding under grant number PO1-CA-80124-03 granted by the National Institutes of Health. The US government has certain rights in this invention. Background technique [0005] The progress of biomedical research has led to the introduction of several novel molecular agents and nano therapeutic agents for systemic administration in both preclinical and clinical settings (Jones, D. (2007) Nat Rev Drug Discov 6, 174-175; Moghimi, SM et al. (2005) Faseb J19, 311-330). Although these new agents act on unique targets (providing higher specifi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K9/14A61K39/395
CPCA61K39/395A61K9/1273A61K45/06A61K9/127A61P9/00A61P11/00A61P11/06A61P13/12A61P17/00A61P19/02A61P21/00A61P35/00A61P35/04A61P37/06A61P43/00A61K2300/00
Inventor 雷克什·库马尔·哈因伊夫·鲍彻维科什·帕尔·辛格·肖汉本杰明·迪奥普-弗里庞斯蒂芬·克兰艾伦·L·克兰罗伯特·塞缪尔·兰格
Owner THE GENERAL HOSPITAL CORP
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