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Combination comprising an atp analog and an adenosine receptor antagonist or a nucleobase/nucleoside analog for the treatment of cancer

a cancer and atp technology, applied in the field of cancer treatment, can solve the problems of unsatisfactory explanation of tki-induced diarrhea, difficult to achieve side effects, and failure of most of these studies

Inactive Publication Date: 2013-10-10
ALBERTA HEALTH SERVICES
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The patent text describes a method or composition that can reduce the side effect of diarrhea caused by the use of ATP analogues. The method or composition can also reduce the severity of the diarrhea. This is useful in reducing the risk of diarrhea and hand-foot syndrome in patients who need to use ATP analogues for medical purposes.

Problems solved by technology

To date, a satisfactory explanation for TKI-induced diarrhea has not been provided.
Many clinical studies have tried combining nucleoside analogs with TKIs for improved cancer treatment and most of these studies have failed.
The above limitations in conventional chemotherapy can result in problematic side effects and, consequently, dose reductions.
Additionally, there may be off-target effects of TKIs and other protein inhibitors that confound the findings of clinical trials that attempt to combine TKIs, or other protein inhibitors, with conventional chemotherapeutic agents.

Method used

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  • Combination comprising an atp analog and an adenosine receptor antagonist or a nucleobase/nucleoside analog for the treatment of cancer
  • Combination comprising an atp analog and an adenosine receptor antagonist or a nucleobase/nucleoside analog for the treatment of cancer
  • Combination comprising an atp analog and an adenosine receptor antagonist or a nucleobase/nucleoside analog for the treatment of cancer

Examples

Experimental program
Comparison scheme
Effect test

example 1

Effect of Zactima (Vandetanib), Iressa (Gefitinib) and Sutent (Sunitinib) on Nucleobase Transport

[0152]Human renal proximal tubule cells (hRPTCs) were seeded in 12-well plates at densities of 105 cells / well and grown for 7 days with medium changes every 3-4 days. On the day of experiments, growth medium was aspirated and cells were washed twice with 1.5 ml of 20 mM Tris-HCl buffer (pH 7.4) containing 150 mM NaCl, 1.2 mM MgCl2 and 1 mM CaCl2 (hereafter referred to as sodium buffer).

[0153]Inhibition of [3H] adenine transport in hRPTCs by the TKIs vandetanib, gefitinib and sunitinib was investigated by incubating hRPTC cultures with 1 μM [3H]adenine in sodium buffer at pH 7.4 in the absence or presence of graded concentrations of vandetanib, gefitinib and sunitinib. At the end of 2 minute incubations, cells were washed twice with sodium buffer and intracellular accumulation of [3H]adenine was determined by solubilizing cells with 5% Triton-X-100 and subsequent determination of radioact...

example 2

FOLFOX Regimen Including a TKI

[0155]An exemplary FOLFOX regimen including a TKI such as cediranib is described below:

Day 1:

[0156]Leucovorin 200 mg / m2 (0-2 hrs)

[0157]Oxaliplatin 85 mg / m2 (0-2 hrs)

[0158]5-Fluorouracil (5-FU) 400 mg / m2 (bolus at 2 hrs)

[0159]5-FU 600 mg / m2 (2-22 hrs)

Day 2:

[0160]Leucovorin 200 mg / m2 (0-2 hrs)

[0161]5-FU 400 mg / m2 (bolus at 2 hrs)

[0162]5-FU 600 mg / m2 (2-22 hrs)

Day 3-Day 10:

[0163]TKI such as Cediranib (30 mg / day)

Day 11-14:

[0164]No treatment

Day 15:

[0165]Cycle 2 starts

example 3

Effects of Adenosine, Adenosine Receptor Antagonists, and TKIs on Human Nucleoside Equilibrative Transporters (hENTS)

[0166]Introduction:

[0167]T84 cells are used as a model for epithelial chloride (Cl−) secretion (Strohmeier et al., J Biol Chem 1995, 270, 2387). Matthews et al. (Surgery 1994, 116, 150; J Clin Invest 1995, 96, 117) showed that adenosine released from cultured intestinal epithelial cells during hypoxia activates the Cl− secretion via activation of the adenosine receptors (A2b) (Stehle et al., Mol Endocrinol 1992, 6, 384). Tally et. al, (Surgery 1996, 120, 248) showed that human equilibrative nucleoside transporters (hENTs) localized on intestinal epithelial cells scavenge free adenosine thus regulating the concentrations of adenosine available to interact with adenosine receptors (A2b) localized on intestinal cells leading to activation of Cl− secretion and adenosine induced diarrheal response.

[0168]Methods:

[0169]T84 cells were routinely grown in DMEM / F12 (1:1) cell cu...

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Abstract

A method for treating an ATP analog-induced side effect in a subject comprises administering an effective amount of an adenosine receptor antagonist to the subject. A method for treating cancer in a subject comprises administering a nucleobase and / or nucleoside prior to administering an ATP analog.

Description

STATEMENT OF PRIORITY[0001]This application is a 35 U.S.C. §371 national phase application of International Application Serial No. PCT / CA2011 / 001177, filed Oct. 26, 2011, which claims the benefit, under 35 U.S.C. §119 (e), of U.S. Provisional Application No. 61 / 406,856; filed Oct. 26, 2010, the entire contents of which are incorporated by reference herein.FIELD OF THE INVENTION[0002]This invention relates to cancer treatment. More specifically, this invention relates to combination treatments for cancer.BACKGROUND OF THE INVENTION[0003]Throughout this application, various references are cited to describe more fully the state of the art to which this invention pertains. The disclosures of these references are hereby incorporated by reference into the present disclosure in their entirety.[0004]A major advance of decades of investigating carcinogenesis and metastasis has been targeted treatment development. Tyrosine kinases are popular targets for cancer treatment and include CD20, Her...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/522A61K31/5377A61K31/404A61K31/517
CPCA61K45/06A61K31/513A61K31/522A61K31/517A61K31/635A61K31/404A61K31/5377A61P1/12A61K2300/00
Inventor SAWYER, MICHAEL BRUCEDAMARAJU, VIJAYALAKSHMI
Owner ALBERTA HEALTH SERVICES
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