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Combinations of receptor tyrosine kinase inhibitor with a1-acidic glycoprotein binding organic compound

A technology of tyrosine kinase and acid glycoprotein, which is applied in the field of pharmaceutical preparations and can solve problems such as increasing AGP levels and drug resistance

Inactive Publication Date: 2007-03-14
NOVARTIS AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

These results suggest that elevated AGP levels, whether from tumor induction or from treatment itself, can lead to the development of resistance to STI571

Method used

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  • Combinations of receptor tyrosine kinase inhibitor with a1-acidic glycoprotein binding organic compound
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  • Combinations of receptor tyrosine kinase inhibitor with a1-acidic glycoprotein binding organic compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0283] Example 1: STI571 potency correlates with initial tumor burden

[0284] Fifty million KU812 cells were injected subcutaneously into nude mice. Treatment was started after 1, 8 and 15 days, respectively, in the presence of approximately 50 million, 300 million and 1 billion leukemic cells (groups I to III). Although tumor regression was observed in all groups, cure was achieved only in the first two groups. Figure 1A shows the results of a representative experiment. While all animals in group I were reproducibly cured, mice in group II relapsed at rates between 33% and 40%; no cure was observed in group III. Relapses usually occurred 1 to 3 weeks after discontinuation of treatment. Figure 1B represents the combined results of 3 different experiments. There is a clear correlation between the amount of tumor present at the start of treatment and the outcome of treatment. One possible explanation for these results is that STI571 was not administered for long enough in ...

Embodiment 2

[0285] Example 2: Recurrent tumors exhibit resistance in vivo but retain sensitivity to STI571 in vitro

[0286]Animals showing recurrent tumors were re-treated with the same STI571 treatment program (11 day dosing schedule). Treatment begins when the tumor becomes visible again. Figure 2 shows a representative assay. Clearly, recurrent tumors responded weakly to the new treatment and eventually began growing similarly to tumors from untreated animals (dash line). Although leukemia cells are resistant to STI571 in vivo, their intrinsic sensitivity to STI571 is unknown. To investigate this question, tumors were excised from drug-resistant animals, cell suspensions were prepared and cells were plated in culture and the in vitro sensitivity to STI571 was determined within 24-48 hours as previously described (le Coutre P et al., Journal of the National Cancer Institute, Vol. 91, pp. 163-168, 1999). Figure 3 represents the results obtained from two such tumors. Apparently, leu...

Embodiment 3

[0287] Example 3: Plasma levels of STI571 in relapsed mice

[0288] One possible explanation for the results reported above resides in the increased metabolism of STI571 in pretreated animals, and the resulting low STI571 plasma levels. To investigate this question, tumor-bearing mice pretreated with STI571 or not (control) were sacrificed 0.5, 2.0 and 5.0 hours after acute treatment with STI571 and total plasma STI571 concentrations were determined by HPLC. The results are presented in Figure 5. Control and pretreated animals reached similar plasma levels at 30 minutes, and STI571 levels declined more rapidly in control animals compared to pretreated mice (p<0.01). Concentrations within tumors showed the opposite, with tumors from pretreated animals containing lower STI571 concentrations at all time points, which reached statistical significance at the 5 h time point. These results did not confirm our hypothesis and even showed that resistant animals maintained high STI571 ...

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Abstract

This invention relates to combinations of an abl-, PDGF-Receptor-and / or Kit receptor-tyrosine kinase inhibitor with an organic compound capable of binding to alpha 1-acidic glycoprotein (AGP), as well as to pharmaceutical preparations and / or therapies, in relation to disease states which respond to inhibition of abl-, PDGF-Receptor- and / or Kit-receptor tyrosine kinase. In particular, the invention relates to products or combinations comprising and abl-, PDGF-Receptor- and / or Kit receptor-tyrosine kinase inhibitor with an organic compound capable of binding to AGP, either in fixed combination or for chronologically staggered or simultaneous administration, and the combined used of both classes of compounds, either in fixed combination or for chronologically staggered or simultaneous administration, for the treatment of proliferative diseases, especially tumor diseases, especially those that can be treated by inhibition of abl-, PDGF-Receptor- and / or Kit receptor-tyrosine kinase activity.

Description

[0001] The present invention relates to abl-, PDGF-receptor- and / or Kit receptor tyrosine kinase inhibitors and a 1 - Combination of organic compounds on acid glycoprotein (AGP) and related to pharmaceutical preparations and / or therapies, which are responsive to inhibition of abl-, PDGF-receptor- and / or Kit-receptor tyrosine kinases related to disease status. In particular, the invention relates to inhibitors of abl-, PDGF-receptor- and / or Kit receptor-tyrosine kinases and a protein capable of binding to alpha 1 - Products or combinations of organic compounds on acid glycoprotein, which may be in a fixed combination, or for chronologically staggered or simultaneous administration, and also involve two types of compounds in a fixed combination or chronologically Staggered sequential or simultaneous administration for the treatment of proliferative diseases, especially tumor diseases, especially those diseases that can be treated by inhibiting abl-, PDGF-receptor- and / or Kit rece...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K31/506A61K31/7048A61P35/02C07D487/04A61K31/00A61K31/498A61K31/519A61K31/553A61K45/06A61P7/02A61P9/10A61P17/00A61P17/06A61P35/00A61P43/00C07D401/04C07D401/06C07D498/22C07H17/08
CPCA61K45/06A61K31/00A61P17/00A61P17/06A61P35/00A61P35/02A61P43/00A61P7/02A61P9/10A61K2300/00
Inventor C·甘巴科尔蒂-帕塞里尼P·勒库特
Owner NOVARTIS AG
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