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Methods for treating cancer

A cancer, gastric cancer technology, applied in the field of desmoid fibroma, colorectal cancer, bladder cancer, gastric cancer and breast cancer, can solve the problem that the restoration of full-length APC protein has not yet been implemented, dose-limiting toxicity, etc.

Inactive Publication Date: 2009-10-28
RAMOT AT TEL AVIV UNIV LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, studies aimed at restoring full-length APC protein to cells lacking functional APC protein have not been performed so far
[0027] Aminoglycosides such as gentamicin have severe dose-limiting toxicities and require intravenous administration, thus making them unattractive long-term treatments for cancer

Method used

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  • Methods for treating cancer
  • Methods for treating cancer

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0137] Tylosin-induced mutant APC stop codon read-through

[0138] The tylosin used in the following experiments was commercial tylosin tartrate purchased from Sigma Chemicals, Israel (catalog number T6134); spiramycin was purchased from Sigma Chemicals, Israel (catalog number S-9132); and erythromycin The vegetable was purchased from Fluka, Switzerland (catalog number 45673). Elinomycin is available from Sigma Chemicals, Israel (catalog number T6514).

[0139]The dual luciferase reporter plasmid system was used to measure the effect of tylosin on the read-through of APC hotspot stop codon mutations in colorectal tissue culture cells. In this system, the Renilla luciferase reporter gene is located upstream of the hot spot in the APC wild-type or mutated sequence, and the firefly luciferase reporter gene is located downstream of the hot spot in the APC wild-type or mutated sequence, and both genes Under the transcriptional control of the APC promoter (Figure 2a). The Renilla lucife...

Embodiment 2

[0141] Tylosin causes down-regulation of β-catenin / Tcf signal transduction

[0142] Due to mutations that cause excessive activation of the Wnt signaling pathway, colorectal cell lines show high levels of β-catenin / Tcf-mediated transcription. In order to measure the effect of tylosin on β-chain protein / Tcf-mediated transcription levels, CX-1CRC cells containing a termination mutation at APC hotspot 1554 were transfected with pTOPFLASH, which is a widely used measurement A luciferase reporter plasmid for Tcf and β-chain protein transcription activity (pTOPFLASH contains a poly Tcf-binding site linked to a luciferase reporter gene). The data showed that treatment of CX-1 cells with 8μg / ml tylosin resulted in an approximately 50% reduction in β-catenin / Tcf / LEF transcriptional signal transduction ( image 3 ). Similar results were shown for SW1417 cells containing APC hotspot mutations at codon 1450 (results not shown).

Embodiment 3

[0144] Tylosin treatment inhibits cell tumorigenesis

[0145] APC truncation is associated with tumor formation (15). The inventor predicts that the restoration of functional full-length APC protein in cell lines containing only truncated APCs will result in a reduction in tumorigenesis. 1×10 7 Two HT-29CRC cells containing a hot spot mutation at APC codon 1554 were injected into 12 nude SCID mice. The treatment group of mice (6 mice) received a drinking water solution of 0.4 μg / ml tylosin. The growth of the tumor was monitored and a significant difference was observed in tumor size between control mice and tylosin-treated mice. The treated mice had a reduced tumor size compared to the control mice (Figure 4a). After receiving drinking water with or without tylosin for 14 days, the mice were sacrificed and tumors removed. The tumors were weighed and the tumor mass of tylosin-treated mice was on average about 40% lower than that of the control group (Figure 4b).

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Abstract

Use of a macrolide antibiotic for the manufacture of a medicament for the treatment or prevention of a cancer selected from colorectal cancer, Desmoid tumor, bladder cancer, gastric cancer, and breast cancer, the macrolide antibiotic being one or more of : tylosin, pharmaceutically acceptable salts thereof, and derivatives thereof; erythromycin, pharmaceutically acceptable salts thereof, and derivatives thereof; oleandomycin, pharmaceutically acceptable salts thereof, and derivatives thereof; and spiramycin, pharmaceutically acceptable salts thereof, and derivatives thereof. Also provided are pharmaceutical compositions and methods for the treatment or prevention of the above mentioned cancers and methods for treating or preventing, in a mammal, a cancer that expresses a mutated APC gene.

Description

Invention field [0001] The present invention relates to the treatment of cancer and more specifically to methods for the treatment of colorectal cancer, Desmoid tumor, bladder cancer, gastric cancer and breast cancer. [0002] current technology [0003] The following is a list of the prior art, which is considered to be relevant for describing the state of the art in the field of the invention. These documents will be cited here by indicating their numbers in the list below in parentheses. [0004] 1. Bedwell, D.M. et al. (1997). Suppression of a CFTR premature stopmutation in a bronchial epithelial cellline. Nat. Med. 3: 1280-1284. [0005] 2. Wilschanski, M., Yahav, Y., Yaacov, Y., Blau, H., Bentur, L., Rivlin, J., Aviram, M., Bdolah-Abram, T., Bebok, Z., Shushi , L., Kerem, B. and Kerem, E. (2003). Gentamicin-induced correction of CFTR function in patients with cystic fibrosis and CFTR stop mutations. Function modification of CFTR induced by mycin). N. Engl. J. Med. 15: 1433-1...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/7048A61P35/00
CPCA61K31/7048A61P35/00
Inventor 莉娜·罗西娜巴斯菲尔德
Owner RAMOT AT TEL AVIV UNIV LTD
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