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Pyrazoloanthrone and derivatives thereof for the treatment of cancer expressing 'mullerian inhibiting substance' type ii receptor (misrii) and of excess androgen states

Inactive Publication Date: 2010-09-16
THE GENERAL HOSPITAL CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0027]Accordingly, the methods of the present invention are directed to use of pyrazoloathrone and functional derivatives thereof with other therapeutic agents, for example chemotherapy agents, wherein the chemotherapy agents, for example paclitaxel and / or MIS can be used at a lower dose as compared to when they are used in the absence of the pyrazoloathrone or functional derivative thereof. Accordingly, where the chemotherapeutic, such as paclitaxel or MIS are used at a lower dose, this often results in decreased side effects associated with use of such chemotherapeutics such as paclitaxel or MIS.
[0041]Another embodiment of the present invention relates to methods to treat a disease or disorder characterized by androgenic dependency, comprising administering to a subject an effective amount of the pharmaceutical composition comprising a pyrazoloanthrone or derivative or analogue as disclosed herein, for example SP600125, wherein the pharmaceutical composition reduces the level of at least one androgen in the plasma serum of the subject and results in a decrease in at least one symptom of a disease or disorder characterized by androgenic dependency.

Problems solved by technology

However, the production of large quantities of purified, biologically active MIS sufficient to be used therapeutically is challenging.

Method used

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  • Pyrazoloanthrone and derivatives thereof for the treatment of cancer expressing 'mullerian inhibiting substance' type ii receptor (misrii) and of excess androgen states
  • Pyrazoloanthrone and derivatives thereof for the treatment of cancer expressing 'mullerian inhibiting substance' type ii receptor (misrii) and of excess androgen states
  • Pyrazoloanthrone and derivatives thereof for the treatment of cancer expressing 'mullerian inhibiting substance' type ii receptor (misrii) and of excess androgen states

Examples

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Effect test

example 1

[0259]SP600125 activates a BMP-responsive promoter in conjunction with MISRII. MIS-specific signaling absolutely requires the MIS type II receptor and knockout studies in mice show phenocopy results when either MISRII or the MIS ligand is deleted (Behringer, 1994, Mishina, 1996). This allowed the inventors to develop an exquisitely precise screen for MIS signaling so that only cells that express MISRII initiate MIS downstream signaling. The inventors used the BRE-luciferase reporter in COS cells cotransfected with an expression vector containing the rat MISRII receptor cDNA (Teixeira, 1996). Screening of 15,000 compounds resulted in several hits that activated the MISRII at levels near those caused by its native ligand, MIS, in a reporter gene assay that identifies compounds that activate the BMP-responsive element through MISRII interaction. The first suitable candidate to undergo further analysis after the primary screen was the pyrazoloathrone derivative; antra[1,9-cd]pyrazol-6(2...

example 2

[0263]Synergy with SP600125 and MIS. In the next set of experiments, the inventors assessed whether addition of MIS and SP600125 resulted in an additive or cooperated to provide a synergistic effect on BRE-luciferase activity. COS7 cells were cotransfected with the luciferase reporters and the MISRII expression construct, treated with a combination of MIS and SP600125 and compared to cells treated with MIS alone. In FIG. 2A, the inventor discovered that MIS added at a final concentration of 0.5 ug / ml induced luciferase expression greater than ten-fold. Addition of as little as 5 uM SP600125 increased the MIS-mediated induction by approximately 16-fold, equivalent to an additional six-fold over MIS alone. Increasing the concentration of SP600125 to 10 uM and 25 uM resulted in inductions of 22- and 25-fold, respectively. Statistical analyses by two-way ANOVA showed a synergistic effect on the activation of BRE-luciferase when MIS and SP600125 were combined compared with either alone. ...

example 3

[0265]MIS does not activate the JNK pathway. In order to test the possibility that the effects observed with SP600125 are the result of an indirect effect of MISRII-mediated activation of the JNK-pathway the inventors treated MOVCAR7 cells with 5 μg / ml MIS and measured phosphorylation of JNK by immunoblotting (FIG. 3A). The known Jun kinase activator anisomycin was used as a positive control (Hazzalin, 1998). However, no phosphorylation beyond background was observed after 30 min MIS treatment, although a strong activation was achieved with 500 nM anisomycin. Further, MIS had no effect on phosphorylation of JNK by anisomycin. To examine the effects of SP600125 on phosphorylation of c-jun, a downstream target for phosphorylation by JNK, the inventors pre-treated MOVCAR cells with SP600125 before treatment with anisomycin and assessed phospho-c-jun by western blot analysis (FIG. 3B). While the inventors observed inhibition of c-jun phosphorylation with 25 uM SP600125, at 10 uM SP60012...

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Abstract

The present invention relates to pyrazoloanthrones or functional derivatives or functional analogues thereof to activate MIS receptor-mediated downstream effects in a cell. In particular, the present invention relates to method to prevent and treat cancer that expresses MIS receptor type II (MISRII) by administering to a subject at least one pyrazoloanthrone or a functional derivative or a functional analogue thereof. Another aspect of the present invention relates to methods to lower plasma androgen levels in a subject, and / or for the treatment of a subject with a disease characterized by excess androgen, whereby the subject is administered at least one pyrazoloanthrone or a functional derivative or a functional analogue thereof. Another aspect provides pharmaceutical compositions comprising at least one pyrazoloanthrone or functional a derivative or a functional analogue thereof, and optionally with one or more additional agents such as chemotherapeutic agents. Another aspect of the present invention relates to methods to decrease the dose of a chemotherapeutic agent by administering the chemotherapeutic agent with a pyrazoloanthrone or a functional derivative or a functional analogue thereof that lowers the effective dose of the chemotherapeutic agent, such as for example, paclitaxel.

Description

CROSS REFERENCED APPLICATIONS[0001]This application claims benefit under 35 U.S.C. 119(e) of U.S. Provisional Application Ser. No. 60 / 919,429, filed on Mar., 22, 2007 the contents of which are incorporated herein in their entirety by reference.GOVERNMENT SUPPORT[0002]This application was made with government support under Grant No CA017393-30S1 awarded by the National Institutes for Health (NIH). The Government of the United States has certain rights in the invention.BACKGROUND OF THE INVENTION[0003]Cancer is characterized by uncontrolled growth, proliferation, and migration of cells. Cancer is the second leading cause of death with 500,000 deaths and an estimated 1.3 million new cases in the United States in 1996. The role of signal transduction pathways contributing to cell transformation and cancer is a generally accepted concept.[0004]Müllerian Inhibiting Substance (MIS) is a glycoprotein hormone secreted by the newly differentiating testis during the fetal period where it is re...

Claims

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Application Information

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IPC IPC(8): C12Q1/68
CPCC12Q1/6886A61K38/22A61P35/00A61K31/416
Inventor TEIXEIRA, JOSEDONAHOE, PATRICIA K
Owner THE GENERAL HOSPITAL CORP
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