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Nordihydroguaiartic derivatives for use in treatment of tumors

a technology of nordihydroguaiaretic acid and derivatives, which is applied in the field of nordihydroguaiaretic acid derivatives, can solve the problems of laborious and costly separation and purification of plant lignans, and sub>4/sub>n certainly limits its use to the lowest effective concentration

Inactive Publication Date: 2005-12-01
THE JOHN HOPKINS UNIV SCHOOL OF MEDICINE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0118] 19. Some of the Sp1-regulated cellular genes: Sartorelli, V.; Webster, K. A.; Kedes, L. Muscle-specif˜c expresison of the cardiac alpha-actin gene requires myodD1, CarG-hox binding factor and Sp1. Gene Dev. 1990, 4, 1811. Dailey, L.; Roberts, S. B.; Heintz, N. Purification of the histone H4 gene-specific transcription factors, H4TF-1 and H4TF-2. Gene Dev. 1988, 2, 1700. Means, A. L.; Farnham, P. J. Transcription initiation form the dihydrogolate reductase promoter is positioned by HIP-I binding at the initiation site. Mol. Cell Biol. 1990, 10, 653. Abravaya, K.; Phillips, B.; Morimoto, R. I. Heat shock-induced interaction so heat shock transcription factor and human hsp70 promoter examined by in vivo footprinting. Mol. Cell Biol. 1991, 11, 586. Leask, A.; Rosenberg, M.; Vassar, R.; Fuchs, E. Regulation fo a human epidermal keratin gene: Sequences and nuclear factors involve din keratinocyte-specific transcription. Gene Dev. 1990, 4, 1985. Desjardins, E.; Hay, N. Repeated CT elements bound by zinc finger proteins control the absolute and relative activities of the two principal huyman cmyc promoter. Mol. Cell Biol. 1993, 13, 5710. Sanchez, H. B.; Yieh, L.; Osborne, T. F. Cooperation by sterol regulatory element-binding proteins and Sp1 in sterol regulation of low-density lipoprotein receptor gene. J. Biol. Chem. 1995, 270, 1161. Lemaigre, F. P.; Lafontaine, D. A.; Courtois, S. J.; Durviaux, S. M.; Rousseau, G. G. Sp1 can displace GHF-1 from its distal binding site and stimulate transcription form growth hormone gene promoter. Mol.l Cell. Biol. 1990, 10, 1811.

Problems solved by technology

Isolation and purification of plant lignans, however, is labor intensive and costly.
Even so, the relatively low selective index of M4N certainly limits its use to the lowest effective concentration if the drug must be used systemically.

Method used

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  • Nordihydroguaiartic derivatives for use in treatment of tumors
  • Nordihydroguaiartic derivatives for use in treatment of tumors
  • Nordihydroguaiartic derivatives for use in treatment of tumors

Examples

Experimental program
Comparison scheme
Effect test

example 1

Effect of M4N and several other NDGA derivatives of SP1-regulated HPV E6 / E7 promoter activity.

[0058] The effect of M4N and several other NDGA derivatives of SP1-regulated HPV E6 / E7 promoter activity was examined using luciferase as a reporter. The assay depends upon DNA transfection of the HPV16 LCR (P97 promoter) fused to the luciferase reporter gene into C33A cells by calcium phosphate methods. C33A is a cervical tumor cell line (ATCC accession no. HTB-31) that does not contain any integrated HPV DNA, but has transcription factors necessary for a robust expression of the HPV early gene promoter. One day following DNA transfection various drug concentrations dissolved with the help of dimethyl sulfoxide (DMSO) were added to the cells. Thirty hours after drug treatment (so that the assay is complete within the standard forty-eight hours for transient transfection experiments), the cells were lysed and specific luciferase activity was determined (Luciferase Assay Systems, Promega, ...

example 2

Inhibition of E6 / E7 mRNA Synthesis Following M4N Treatment

[0060] Inhibition of E6 / E7 mRNA synthesis following M4N treatment was measured by RT-PCR in cervical cell line C3. Relative RT-PCR was performed with quantities of total cellular RNA standardized to the cell numbers counted. The RT-PCR product was analyzed on a 2% agarose gel. The results are shown in FIG. 3. The RT-PCR results indicated that the amplified cDNAs of the expected size for E7 (321 bp) and E6 (204 bp) were detected in the DMSO treated cells as early as cycle 22 of amplification. These same products were barely detectable in the drug treated RNA extracts following 30 cycles of amplification. No amplified products were detected for the no template PCR control or from total RNA extracts of the HPV16-negative C33a cell line.

example 3

Inhibition of Cervical C3 Cell Growth by M4N Treatment

[0061] HPV-16 transformed immortal mouse epithelial cells (C3 cells) were plated at a density of 105 cells per vial. After 24 hours, ½ of the vials were given growth media containing 40 μMM4N dissolved in 1% DMSO while the other half were given growth media containing only 1% DMSO. The results are shown in FIG. 4A. Within 24 hrs a difference in cell morphology between drug treated and control C3 cells was observed. The growth and division of the drug treated cells was markedly reduced in comparison to the untreated control, while the fraction of viable cells compared to the total cell count remained constant for both drug treated and DMSO only control cells. This indicates that M4N dramatically reduces cell division.

[0062] The effect on C3 growth following removal of M4N from the medium was also examined. C3 cells were plated at a density of 104 cells per vial. At time=0, ⅔ of the vials were given growth media supplemented wit...

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Abstract

Nordihydroguaiaretic acid derivatives and methods of use thereof for the treatment of tumors.

Description

[0001] This application claims priority to U.S. application Ser. No. 09 / 418,594, filed Oct. 15, 1999, which is hereby incorporated by reference.[0002] The invention described and claimed herein was made in part under a grant from the National Institutes of Health. The U.S. Government has certain rights in the invention.BACKGROUND OF THE INVENTION [0003] 1. Field of the Invention [0004] The invention relates to the use of nordihydroguaiaretic acid derivatives, in particular derivatives containing substituents of naturally occurring amino acids, for the treatment of tumors and viral infections. [0005] 2. Background Information [0006] Carcinogenesis is a multistage event affected by a variety of genetic and epigenetic factors and is typified by the outbreak of uncontrolled cell growth originated from different tissues. A universal goal for anticancer research lies in the development of a clinical treatment that is highly effective in curtailment of tumor growth, non-toxic to the host, ...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K47/20A61K31/05A61K31/09A61K31/198A61K31/22A61K31/223A61K31/225A61K31/401A61K31/405A61K31/417A61P35/00A61P35/04A61P43/00C07C229/12
CPCA61K9/0014A61K9/0019A61K31/05A61K31/198A61K31/417A61K31/225A61K31/401A61K31/405A61K31/22A61P31/18A61P35/00A61P35/04A61P43/00
Inventor HUANG, RU CHIH C.HELLER, JONATHAN D.HWU, JIH RUKING, KO YUNG
Owner THE JOHN HOPKINS UNIV SCHOOL OF MEDICINE
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