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Treatment of Solid Tumours

a solid tumour and treatment technology, applied in the field of solid tumour treatment, can solve the problems of poor penetration into the 3-d tumour, unable to meet the needs of chemotherapy,

Inactive Publication Date: 2014-03-13
VIVOLUX
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0013]The compound of the invention is a cell permeable iron chelator. While not wishing to bound by theory, the inv

Problems solved by technology

Developing drugs for solid tumours is associated with specific problems due to complex biophysical and metabolic conditions in 3-D tumour tissue which may be difficult to mimic in experimental in vitro systems.
Hypoxia and limited diffusion of nutrients is known to lead to quiescence and resistance to conventional anticancer agents and radiation therapy.
Furthermore, anticancer drugs must be able to penetrate into tumour parenchyme to reach cancer cells at toxic concentrations.
Some drugs that are in clinical use for the treatment of solid tumours show poor penetration into 3-D tumour masses, which may be one of the reasons for their limited efficacy (1).

Method used

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Examples

Experimental program
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Effect test

example 1

The Compound of the Invention Induces Apoptosis and Reduces Viability of MCS

[0045]Treatment of MCS with CB21 for 6 h followed by incubation for 96 h in drug-free medium resulted in MCS of smaller size with central areas of necrosis (FIG. 2a). Caspase-3 induction was modest compared to NSC647889. Importantly, treatment of MCS for 6 hours with CB21 reduced the clonogenicity to b). The decrease in clonogenicity was stronger than that observed for cisplatin, irinotecan and doxorubicin (despite the use of concentrations of 5-10 μM; >10-fold the IC50 of these compounds in monolayer cultures). Treatment of monolayer HCT116 cells with CB21 resulted in a slight increase in cell numbers between 0 to 24 h, followed by loss of cells (FIG. 2c). Examination of 5-ethynyl-2′-deoxyuridine incorporation (EdU) in CB21-treated cells showed that DNA synthesis was almost completely abrogated at 24 hours (FIG. 2d, 2e). CB21 was equally effective on cells where the p53 tumour suppressor gene had been disr...

example 2

The Compound of the Invention is a Cell Permeable Iron Chelator

[0046]To generate hypotheses regarding the mechanism of action of CB21, the Connectivity Map (CMap) (15), a compendium of gene expression signatures from drug-treated cell lines, was used. The changes in gene expression elicited by CB21 were most similar to those of ciclopiroxolamine (CPX), an antimycotic agent with iron chelating capacity (17) (FIG. 3a). To test whether the cytotoxic activity of CB21 was dependent on iron depletion, iron chloride was added to HCT116 cells prior to the addition of CB21. Iron chloride was found to totally abrogate the effect of CB21 (FIG. 3b), both on HCT116 cells expressing wtp53 as on HCT116 cells where the p53 gene has been disrupted.

[0047]The anti-proliferative activity of CB21 was compared with that of other known iron chelators. CB21 was found to be more potent than VLX50, deferasirox, ciclopiroxolamine, deferoxamine (FIG. 3c). Structure-activity relationships were examined by use ...

example 3

The Compound of the Invention Induces a Widespread Autophagic Response

[0048]The anti-tumourigenic activity of iron chelators is generally attributed to inhibition of ribonucleotide reductase, leading to inhibition of cell proliferation (18). MCSs contain mostly non-proliferating cells. The finding of induction of cytotoxic effects on MCSs by the iron chelator CB21 thus was unexpected. The mechanism(s) of action was studied in more detail. Visual inspection of CB21-treated cells revealed that cells contained multiple large cytoplasmic vesicles (FIG. 4a). These vesicles stained positively with an antibody to microtubule associated protein 1 light chain 3 (LC3), suggesting that they were associated with autophagy. LC3 staining was observed at 24 h and was stronger at 42 h (FIG. 4b). Western blot analysis showed that treatment of HCT116 monolayer cells with CB21 induced a strong increase in the levels of both LC3-I and LC3-II (FIG. 4c). LC3-II (the PE-conjugated form of LC3) is a prote...

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Abstract

A cell permeable iron chelator, optionally in combination with an autophagy inhibiting agent, is used for treating a solid cancer tumour in a person. A preferred chelator is an alkyl substituted N-(1-pyridine-2-yl-methylidene)-N-(9H-1,3,4,9-tetraaza-fluoren-2-yl)-hydrazine. A preferred autophagy inhibiting agent is chloroquine. Also disclosed is a pharmaceutical composition comprising iron chelator, pharmaceutically acceptable carrier and, optionally, autophagy inhibiting agent; and a method of treating cancer by administering cancer combating-effective amount(s) of the iron chelator or the combination of iron chelator and autophagy inhibiting agent.

Description

FIELD OF THE INVENTION[0001]The present invention relates to a treatment of a solid tumour, in particular a disseminated solid tumour, in a person affected by cancer and to a means for such treatment.BACKGROUND OF THE INVENTION[0002]New and effective anticancer drugs need to be developed for patients that suffer from disseminated cancer. Developing drugs for solid tumours is associated with specific problems due to complex biophysical and metabolic conditions in 3-D tumour tissue which may be difficult to mimic in experimental in vitro systems. Hypoxia and limited diffusion of nutrients is known to lead to quiescence and resistance to conventional anticancer agents and radiation therapy. Furthermore, anticancer drugs must be able to penetrate into tumour parenchyme to reach cancer cells at toxic concentrations. Some drugs that are in clinical use for the treatment of solid tumours show poor penetration into 3-D tumour masses, which may be one of the reasons for their limited efficac...

Claims

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Application Information

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IPC IPC(8): A61K31/53A61K45/06C07D487/04
CPCA61K31/53A61K45/06C07D487/04A61K31/16A61K31/4196A61K31/4412A61K31/4706A61K31/365A61K31/4422A61K31/70A61P35/00A61P43/00A61K2300/00
Inventor LINDER, STIGFRYKNAS, MARTENLARSSON, ROLF
Owner VIVOLUX
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