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Methods for Treating Hematopoietic Neoplasms

a hematopoietic neoplasm and neoplasm technology, applied in the direction of biocide, drug composition, active ingredients of phosphorous compounds, etc., can solve the problems of reducing affecting the survival rate of hematopoietic neoplasms, and vla4 expression by leukemic cells, etc., to achieve the effect of reducing

Inactive Publication Date: 2009-10-22
CHAPLIN DAVID +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

"The patent text describes the use of a drug called combretastatin A-4 phosphate (CA4P) to treat hematopoietic neoplasms (blood cancers) and non-solid tumors. The technical effect of this invention is the discovery of a new treatment for these types of cancer that targets a specific molecule involved in the growth of cancer cells. The use of CA4P has shown promising results in treating various types of cancer in pre-clinical and clinical studies."

Problems solved by technology

Indeed, expression of VLA4 by leukemic cells portends a poor prognosis and a decreased five-year survival rate.
Indeed, disruption of cytoskeletal stability of hematopoietic neoplasms may not only promote cell death directly, but also diminish the cellular interaction of the hematopoietic neoplasms with vascular cells, thereby increasing sensitivity to chemotherapy.

Method used

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  • Methods for Treating Hematopoietic Neoplasms
  • Methods for Treating Hematopoietic Neoplasms
  • Methods for Treating Hematopoietic Neoplasms

Examples

Experimental program
Comparison scheme
Effect test

example 1

A. Example 1

Combretastatin A4 Phosphate (CA4P) Inhibits Leukemic Cell Proliferation

[0065]Leukemic cells were seeded at 1×105 cells / ml in X-vivo medium (Bio-Whittaker, MA) with 5% FBS and CA4P or pre-incubated with the PARP-inhibitor DPQ or caspase-inhibitors Z-VAD-fmk and Q-VD-OPh (R&D, Minneapolis, Minn.). A panel of leukemic cells was incubated with CA4P at the different concentrations indicated in FIG. 1, and viable cells were counted after 48 hours using trypan blue exclusion. Results of four experiments in duplicate are expressed as the ratio of the percentage of viable cells / control±SEM (*p50 ranging from 2.5 to 5 nM (FIG. 1). The majority of the AML cell lines tested was sensitive to CA4P at a concentration of 2.5 nM or less. All leukemic cell lines, as well as a recently established primary leukemic cell line (R81) 16 were sensitive at low doses of CA4P (<10 nM).

example 2

B. Example 2

CA4P Causes Cell Cycle Arrest in G2 / M Phase

[0066]CA4P induces G2 / M arrest and cell death, as evidenced by increase in the sub-G0 / G1 peak (FIG. 2). Leukemic cells were seeded at 105 per ml in X-vivo supplemented with 5% FBS and then incubated with CA4P. KG1a leukemic cells were treated with CA4P at 0, 5 and 10 nM concentrations. After incubation for 48 hours, apoptotic cells were quantified by ApoAlert Annexin-V-fluorescine isothiocyanate (FITC) propidium iodide (PI) Apoptosis Kit (BD) using a Coulter Elite flow cytometer. In CA4P-treated cells, cell cycle analysis with propidium iodine (PI) showed G2 / M arrest and evidence of DNA fragmentation (sub G0-phase) at 48 hours.

example 3

C. Example 3

Combretastatin A-4 Phosphate Causes DNA Fragmentation and Morphological Evidence of Mitotic Catastrophe

[0067]DNA damage in CA4P-incubated leukemic cells was assessed by comet assay. The concept behind this assay is based upon the ability of denatured, cleaved DNA fragments to migrate out of the cell under the influence of an electric field, whereas undamaged DNA migrates more slowly and remains within the confines of the nucleus. Evaluation of the DNA “comet” tail shape and migration pattern allows for assessment of DNA damage. Results were expressed as the percentage of cells with a comet tail in 100 randomly selected, non-overlapping cells visualized by standard light microscopy. Quantification of the number of leukemic cells displaying a comet tail strongly increased after CA4P treatment (FIG. 3), consistent with CA4P-induced DNA damage. Results of three experiments in duplicate are expressed as the mean of the number of cells with a comet tail (%)±SEM (*p<0.05 as com...

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Abstract

This invention relates to methods for treating, preventing and / or managing hematopoietic neoplasm in a subject by administering to the subject combretastatin A-4 phosphate, or a pharmaceutically acceptable salt thereof. The method may further comprise co-administering a chemotherapeutic agent.

Description

I. CROSS REFERENCE TO RELATED APPLICATIONS[0001]This application claims the benefit of U.S. provisional patent application No. 60 / 989,786, filed 21 Nov. 2007.II. INTRODUCTION[0002]Although chemotherapy induces remission in the majority of adult patients with acute myeloid leukemia (AML), only small percent are cured with conventional chemotherapy. Relapse of leukemias is in part due to the persistence of minimal residual leukemias that remain viable within specialized niches, such as vascular niches. Hence, novel treatment strategies are urgently needed to block the interaction of hematopoietic neoplasms with activated vasculature, interfering with the establishment of pro-leukemic niches in various organs and to eradicate resistant disease.[0003]Adhesion of leukemic cells to stromal cells has been shown to confer increased resistance to chemotherapeutic agents and diminish the rate of apoptosis of the leukemic cells. This process, named cell adhesion-mediated drug resistance (CAM-D...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/7076A61K31/661A61K31/7064A61P35/00
CPCA61K31/52A61K31/661A61K31/675A61K31/7048A61K31/7068A61K2300/00A61K31/6615A61P35/00A61P35/02A61P43/00A61K45/06
Inventor CHAPLIN, DAVIDRAFII, SHAHIN
Owner CHAPLIN DAVID
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