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Novel Pharmaceuticals for Cancer Diagnostic and Treatment

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Novel Pharmaceutical Preparations for Cancer Diagnostic and Treatment on the Base of HLDF

Tech Area / Field

  • BIO-CHM/Biochemistry/Biotechnology
  • MED-DID/Diagnostics & Devices/Medicine
  • MED-DRG/Drug Discovery/Medicine

Status
8 Project completed

Registration date
12.11.2002

Completion date
29.07.2009

Senior Project Manager
Visser H

Leading Institute
Institute of Bioorganic Chemistry, Russia, Moscow

Supporting institutes

  • State Research Center of Virology and Biotechnology VECTOR, Russia, Novosibirsk reg., Koltsovo

Collaborators

  • University of Missouri - Kansas City / School of Pharmacy, USA, MO, Kansas City\nVas Gene Therapeutics, Inc., USA, CA, Los-Angeles\nUniversity of Maryland at Baltimore / Departmemnt of Medicine, USA, MD, Baltimore

Project summary

A dramatic increase in the incidence of cancer diseases and a shortage of effective therapeutic strategies for their treatment make the search for endogenous bioregulators capable of arresting malignant cell growth and metastasis of tumors extremely important objectives. The attention of many researchers is now focused on preparations that induce cell differentiation because the pathogenesis of many malignant tumors is related to aberrations in normal cell differentiation. Protein differentiation factors and their biologically active peptide fragments appear to be extremely promising in tumor therapy as independent remedies or as therapeutics supplementing the action of cytostatic drugs that kill malignant cells.

One of these promising proteins is HLDF, a small protein with molecular mass of 8.2 kDa. Our laboratory first isolated HLDF several years ago from a culture of human promyelocyte leukemia HL-60 cells treated with all-E-retinoic acid. The protein induced differentiation of original cells via the granulocytic pathway (Kostanyan I.A. et al. 1994, 1995). The investigation of HLDF was performed as part of ISTC Project 463. It was shown that HLDF had no specific receptors on the surface of HL-60 cells but could affect the fluidity of cell membrane and thus affect the binding of cytokines involved in the process of proliferation and differentiation. A hexamer peptide (HLDF-6) was identified which retained the ability of the full-size factor to induce differentiation with concomitant arrest of cell proliferation using HL-60 cells. This peptide was shown to possess protective and antitumor properties (Kostanyan et al. 2000). These results support preclinical testing of this novel peptide with the aim of developing novel chemotherapeutic strategies that would target cancer.

In addition to its role in the induction of cell differentiation, HLDF exhibits a non-specific nuclease activity and plays an important role in the promotion of apoptosis (cell programmed death) in HL60 cells. The amino acid sequence of an 8-dim fragment of HLDF (HLDF-8) with nuclease activity was identified and its biological activity was studied. HLDF-8 was shown to cleave all the forms of DNA in vitro. Both the peptide and the whole factor were shown to induce apoptosis. The data suggest HLDF-8 to obtain antitumor activity causing the death of tumor cells through apoptosis.

Polyclonal antibodies to the differentiation factor obtained during execution of the ISTC Project 463 differently bind to malignant and benign cells. We have shown that the differentiation factor can be used as immunohistochemical marker of early neoplastic processes (Dranitsyna et al. 2000). The preliminary experiments have shown its significantly higher efficiency in revealing early stages of neoplastic cells transformation in comparison to markers in current use. Thus we plan to use antibodies to HLDF to design a diagnostic tool for detection of cancer in its earliest stages and propose to use this strategy for improving cancer surgery.

The structural analysis of HLDF cDNA showed its high homology with the sequence of cDNA coding human ribosomal protein S21 (rpS21) (Bhat and Morrison, 1993; Smirnova et al., 2000). However, the amino acid sequences of the proteins have no homology, because two point deletions in HLDF cDNA shift the reading frame. This suggests that HLDF mRNA is expressed in differentiated HL-60 cells as a result of post-transcriptional modifications of pre-mRNA for rpS21. The elucidation of mechanisms and conditions of HLDF expression in differentiated and apoptotic cells should provide important new insights into the causes of cell tumorogenesis and potentially find new approaches for prevention of this process or the elimination of malignant cells.

This project is based on the results obtained during the fulfillment of ISTC Project 463.

The aim of this project is investigation of mechanisms of HLDF expression in the cell and the role of HLDF and its biological fragments in cellular processes such as cell differentiation and apoptosis, that potentially would form the basis for the development of effective drugs for cancer therapy that would likely be less expensive and less toxic than drugs in current use. In addition, the antibodies to HLDF could serve as novel diagnostic tools for the early detection of malignant tumors.


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The International Science and Technology Center (ISTC) is an intergovernmental organization connecting scientists from Kazakhstan, Armenia, Tajikistan, Kyrgyzstan, and Georgia with their peers and research organizations in the EU, Japan, Republic of Korea, Norway and the United States.

 

ISTC facilitates international science projects and assists the global scientific and business community to source and engage with CIS and Georgian institutes that develop or possess an excellence of scientific know-how.

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