Compositions, packaged pharmaceuticals, and methods of using posaconazole for the sensitization of resistant tumors

A technology for posaconazole and a composition, which is applied in the fields of botanical equipment and methods, antitumor drugs, drug combinations, etc., can solve the problems of not showing direct inhibition and the like

Inactive Publication Date: 2020-05-01
V J 班格万丁
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, unlike itraconazole, posaconazole has never been shown to directly inhibit P-gp / MDR-1 / ABCB1

Method used

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  • Compositions, packaged pharmaceuticals, and methods of using posaconazole for the sensitization of resistant tumors
  • Compositions, packaged pharmaceuticals, and methods of using posaconazole for the sensitization of resistant tumors
  • Compositions, packaged pharmaceuticals, and methods of using posaconazole for the sensitization of resistant tumors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0084] Cancer cells grown in vitro can be treated with chemotherapeutic drugs alone or concurrently with hedgehog pathway modulators, including itraconazole. Differences in cell death between cells treated with chemotherapy alone or concurrently with a hedgehog pathway modulator determined the degree of synergistic killing by the combination therapy. Two-dimensional dose-response in which successive ten-fold doses of cyclopamine and itraconazole de-escalation were performed to demonstrate the efficacy of vincristine and docetaxel in naive cell lines isolated and established before chemotherapy Sensitization was modeled as first-line therapy: H295, Kelly and drug-resistant cell lines that had received chemotherapy prior to isolation and establishment: as models for second-line therapy: HeLa and Caco-2 cells. As cyclopamine and itraconazole were reduced from 10 micromolar to 1 micromolar to 0.1 micromolar, the chemotherapeutic concentrations required to stop proliferation and ki...

Embodiment 2

[0091] Hedgehog pathway regulators, including posaconazole and itraconazole, were used as pre-treatment agents to shut down the Hedgehog pathway and thus downregulate ABC transporter expression. This in turn reduces the efflux of chemotherapeutic drugs. Differences in cell death between cells treated with chemotherapy and cells pretreated with a hedgehog pathway modulator determined the degree of synergistic killing of the combination treatment.

Embodiment 3

[0093] Drug de-escalation determined the synergistic killing effect of combination therapy in which conventional-dose, defined-dose hedgehog pathway modulators (including posaconazole and itraconazole) were given, but in each study, Chemotherapy doses were gradually reduced. The de-escalation study showed whether these combinations could reduce the side effects of hedgehog pathway modulators and the known toxicity of chemotherapy drugs to patients, while being effective at killing tumors.

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Abstract

Compositions, packaged pharmaceuticals, and methods of treatment by the sensitization of resistant tumors are provided. The compositions comprise posaconazole and a chemotherapeutic agent. Tumor cellsin mammalian subjects treated with posaconazole are sensitized to the effects of the chemotherapeutic agent, thus increasing the therapeutic index of the agent and reducing toxicity to the subject.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS [0002] This application claims the benefit of US Provisional Application No. 62 / 484,852, filed April 12, 2017, the disclosure of which is incorporated herein by reference in its entirety. Background technique [0003] Most first-line chemotherapy drugs can destroy large numbers of tumor cells, but not cancer stem cells, which are the cells that contribute to tumor recurrence or recurrence, further development, metastasis and subsequent chemoresistance. This suggests that cancer stem cells may be 'intrinsically' resistant to chemotherapy, or have induced resistance during the first line of treatment by acquiring mutations that occur in the second line of the treatment regimen and are present in the treatment setting. Therefore, targeting cancer stem cells as a first-line therapeutic target can eliminate inherently drug-resistant cancer cells, prevent the acquisition of drug-resistant mutations, limit further cancer progression an...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A01N43/48A61K31/496A61P35/00
CPCA61K31/496A61P35/00A61K45/06A61K31/337A61K31/475A61K2300/00
Inventor V·J·班格万丁
Owner V J 班格万丁
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