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Chromosome Aberrations Caused by Antitumor Preparations

#A-301


DNA and Chromosome Alteration Caused by Newly Synthesized Potential Antitumor and Carcinogenic Compounds. Comparison with Radiation Effects

Tech Area / Field

  • BIO-CGM/Cytology, Genetics and Molecular Biology/Biotechnology
  • BIO-RAD/Radiobiology/Biotechnology
  • MED-OTH/Other/Medicine

Status
8 Project completed

Registration date
03.11.1998

Completion date
02.03.2001

Senior Project Manager
Lapidus O V

Leading Institute
Yerevan State University, Armenia, Yerevan

Collaborators

  • Georgia Institute of Technology, USA, GA, Atlanta\nArizona State University, USA, AZ, Tempe\nUS Department of Health & Human Services / National Institute of Health / Institute of Child Health and Human Development, USA, MD, Bethesda\nUniversity of Illinois, USA, IL, Chicago\nUniversità degli Studi di Firenze, Italy, Florence

Project summary

The general characteristics of the problem. It is known that the ionizing radiation is one of the most strongly acting agents, provoking in the native cell the breaches of genetic material (chromosome aberrations). At the present time there was correctly shown that the ionizing radiation, with some carcinogenic substances, is one of the reasons of oncologycal diseases. But both, the ionizing radiation and some toxic substances (for example, the salts of heavy metals) are widely utilized in the medical practice as the elements of antitumor therapy. Thus, the study of the mechanisms of changes in the genetic apparatus under the influence of the radiation and toxic compounds is urgent both for the study of tumor arising mechanisms and for the medical effect forecasting.

It should be noted that at present the concrete mechanisms of the changes arising in the genetic material under the influence of those or other agents are studied weakly, and it becomes evident the necessity of their elucidation. At the present time the more and more clinical physicians and biologists are inclined to the opinion that in the basis of tumor formation under the influence of radiation and different agents it take place the changes in the DNA molecular structure - "the most important molecule" of the genetic material.

In our project will be investigated the interaction of DNA with the two types of agents:

1. Intercalators (plane molecules, inculcating into the structure of DNA double helix reversibly). Metalporphyrins will be used.

2. The salts of heavy metal (active substances, irreversibly binding with DNA molecule). Platinum and other heavy metal compounds will be used.

Objectives. In the framework of proposed project it is supposed:

1. To synthesize the metalporphyrins of different structures for studying their interaction with DNA.

2. To investigate the mechanism of interaction of chemical agents, reversibly (metalporphyrins) and irreversibly (platinum compounds) binding with DNA.

3. To determine the chromosome aberrations in the genetic apparatus of cells of testing animals under the influence of investigating agents.

4. On the basis of theoretical elaboration from the experimental melting curves of DNA to get the DNA stability's thermodynamic parameters, characterizing the influence of different agents.

5. To get spectroscopically additional information about the mechanisms of interaction of DNA with the chemical agents in the norm and pathology.

6. To elucidate the correlation between the parameters of interaction of agents with DNA, from one side, and its biological activity, from the other.

7. On the basis of analysis of interaction parameters of DNA with different types of agents and on the basis of elucidated correlation of these parameters with biological activity to forecast the structural peculiarities of new agents for going out to synthesis of new medicines with premeditated properties.

The solution of tasks, presented in the project, becomes possible owing that by authors of project were obtained methods of:


1. Determination of specificity of interaction between DNA and agents.
2. Synthesis of metalporphyrins with different chemical structures.
3. Determination of chromosome aberrations.

The significance of carrying out investigations consists in that owing to them in the framework of this project it is found possible the consecutive study of different agents influence on the genetic material on different structural levels.

Thus, the proposed project is devoted to delicate and weakly studied mechanisms of agents influence on the genetic apparatus and is directed to the getting of the effective antitumor medicines.

In the results of this project can be interested:

1) Scientific centers, carrying on investigations in the field of:

- macromolecule's physics,
- molecular biology,
- molecular biophysics,
- molecular pharmacology,
- induced mutagenesis,
- radiation medicine.


2) The industrial firms producing medical preparations.

Theoretical (fundamental) significance of the project consists in the deepening and development of the notions about the influence of radiation and chemical agents on the genetic material and elucidation of the essential details of the mechanism of carcinogenesis.

Applied significance consists in that the results of project will allow elucidating the physical and chemical principles of the action of pharmacological preparations on the genetic material. Taking into account the nature of interaction between the DNA and agents will be more detailed elucidated the mechanism of action of already known medical preparations and correspondingly will appear the possibility of their objective classification. On the basis of estimation of interaction mechanism of DNA with agents will appear the possibility of forecasting the structure of chemical substances with improved antitumor properties.

Economic aspects. The forecasting of the principles of structural organization of medical preparations, interacting with DNA, will allow with less expenses and in more short periods to get new, more effective medical preparations with premeditated properties.

Types of Collaboration


· Participation in the development of project proposal and work plan.
· Exchange of information during project implementation.
· Mutual review of technical reports.
· Joint seminars, workshops, meetings, consultations.
· Verification of results using independent methods and/or equipment.
· Sharing of scarce materials, samples, resources.
· Joint or parallel investigations.
· Consultation on Intellectual Property Rights, in case of joint invention.
· Other types of collaboration are possible.

We greet the participation of foreign collaborators in our project.


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