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Secreted protein acidic and rich in cysteine (SPARC) as chemotherapeutic sensitizers

a chemotherapeutic and sensitizing technology, applied in the field of cancer therapy sensitizing compositions and methods, can solve the problems of high cancer mortality rate, impede tumor regression and cure, and complex mechanisms involved in the mechanism of therapeutic resistan

Inactive Publication Date: 2013-08-01
THE UNIV OF BRITISH COLUMBIA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The invention provides isolated polynucleotides and polypeptides that have cancer therapeutic sensitizing activity. These polynucleotides and polypeptides can be used alone or in combination with other cancer therapeutic agents to enhance the effectiveness of cancer treatment. The isolated polynucleotides and polypeptides can also be delivered using a vector or host cell to further enhance their therapeutic activity. The invention also provides methods for sensitizing cancerous cells to a cancer therapeutic regimen by delivering a vector or polypeptide containing the isolated polynucleotides or polypeptides to a cell and then treating the cell with a cancer therapeutic agent.

Problems solved by technology

Resistance develops following exposure to chemotherapy and further impedes tumor regression and cure.
It is this chemotherapy resistance leading to treatment failure that accounts for the high mortality rates in cancer.
The mechanisms involved in therapeutic resistance are varied and may be very complex.
However, Cu2+ binding activity alone does not appear to be sufficient for a peptide to stimulate angiogenesis (Lane et al 1994.

Method used

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  • Secreted protein acidic and rich in cysteine (SPARC) as chemotherapeutic sensitizers
  • Secreted protein acidic and rich in cysteine (SPARC) as chemotherapeutic sensitizers
  • Secreted protein acidic and rich in cysteine (SPARC) as chemotherapeutic sensitizers

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0140]Sensitive (MIP101—FIG. 1) and multi-drug resistant (MIP / CPT—FIG. 2) cells were transiently transfected and assayed for survival upon exposure to irinotecan (CPT). Cell viability was quantified by an MTS assay. Transfection of both SEQ ID NO: 2 and SEQ ID NO: 4 had a similar effect by decreasing cell viability in the resistant MIP / CPT cells compared to that of the full length SPARC vector. Resistant MIP / CPT cells transfected with control (empty vector) remained viable despite exposure to 500 uM CPT-11.

example 2

Use of SPARC Peptide Chemosensitizers In Vitro

[0141]This example demonstrates the utility of the inventive SPARC peptide chemosensitizers in an in vitro model system.

[0142]Shorter peptides corresponding to various regions of either the N-terminal acidic region or the follistatin domain were synthesized to further narrow the peptide sequences demonstrating chemosensitizing activity. MIP101 sensitive or resistant to 5-FU (MIP / 5FU) cells were exposed to the B14 peptide (SEQ ID NO. 9) as described. In both resistant and sensitive cells, the peptide alone, at either of the concentrations tested did not significantly affect viability (FIG. 4). As expected the resistant cells exhibited greater viability in the presence of 5-FU alone—with the addition of the B 14 peptide at 96 or 200 μg / ml, cell viability decreased compared to 5-FU alone, indicating that the presence of the peptide increases the sensitivity of the resistant cells to the chemotherapeutic agent.

[0143]A similar trend is observ...

example 3

Use of SPARC Peptide Chemosensitizers in Vivo

[0145]This example demonstrates A utility of the inventive SPARC peptide chemosensitizers in a tumor xenograft model system.

[0146]Tumor xenograft animal models were used to assess the effect of overexpressing different SPARC fragments on tumor progression in vivo. MIP 101 cells with stable transfection and expression of SPARC (MIP / SP) or different biological fragments representing the N-terminus (MIP / NT), follistatin (MIP / FS) and extracellular (MIP / EC) domains of SPARC were used for the tumor xenograft model. NIH nude mice (6 weeks old, Taconic Laboratories, Germantown, N.Y.) were implanted with 1×106 cells at the left flank. Treatment regimens were initiated once the average tumor size reached 75-100 mm3 in volume. Tumors were measured using a hand-held caliper (Fisher Scientific International, Inc. Hampton, N.H.) with concurrent body weight measurements until the completion of the study. Chemotherapy was provided using a 3-week cycle re...

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Abstract

The present invention relates to compositions and methods of use thereof for cancer therapy sensitization. Such compositions comprise functional fragments of the nucleotide and / or polypeptide sequences of a Secreted Protein Acidic and Rich in Cysteine (SPARC). The compositions can be used in combination with existing chemotherapeutic agents for treatment of cancers.

Description

FIELD OF THE INVENTION[0001]The invention relates to cancer therapy sensitizing compositions and methods, specifically polypeptides and polynucleotides relating to the SPARC protein and the SPARC gene.BACKGROUND OF THE INVENTION[0002]Cancer is one of the leading causes of death in humans and while standard chemotherapy, radiotherapy and surgical intervention successfully reduce tumor load in many cases, resistance to chemotherapeutic intervention is not uncommon, especially in solid tumors. Resistance develops following exposure to chemotherapy and further impedes tumor regression and cure. It is this chemotherapy resistance leading to treatment failure that accounts for the high mortality rates in cancer.[0003]The molecular basis of chemotherapy resistance is largely genetic, and can take many forms. Many mutations responsible for the initial development of tumors may also contribute to drug resistance. For example, loss of DNA mismatch repair (MMR) gene function has been associate...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07K14/47A61K45/06A61K38/17
CPCA61K38/00A61K48/00C07K14/47A61K38/1709A61K45/06C07K14/705A61P35/00A61P43/00
Inventor TAI, ISABELLA T.
Owner THE UNIV OF BRITISH COLUMBIA
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