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Physico-Chemical Characteristics of Carcinogens

#3671


Investigation of the Correlation Between Physico-Chemical and Medico-Biological Characteristics of Organic Chemicals

Tech Area / Field

  • ENV-MRA/Modelling and Risk Assessment/Environment
  • CHE-THE/Physical and Theoretical Chemistry/Chemistry

Status
3 Approved without Funding

Registration date
13.12.2006

Leading Institute
MIFI, Russia, Moscow

Supporting institutes

  • Research Institute for Applied Mechanics (NIIPM), Russia, Moscow\nCancer Research Center, Russia, Moscow

Collaborators

  • University of Pennsylvania / School of Veterinary Medicine / Department of Animal Biology, USA, PA, Philadelphia\nFreie Universität Berlin / Institut für Chemie, Germany, Berlin

Project summary

The objective of this project is to reveal the physicochemical characteristics of molecules that are responsible for their mutagen and carcinogen activity and to develop the scientific basis of chemical carcinogens and mutagens screening in the environment. The main outcome of this project may consist in scientific background for establishment of efficacious service of carcinogen safety analogical to protection from radiation-induced diseases. Effective carcinogen detection will help to reduce environmental pollution and minimize the cancer risk.

Cancer is the second most common cause for mortality in developed countries. The main cause of human cancer (according to some estimates – 90%) are chemicals, namely carcinogens, affecting cell genome. Now in ordinary life and in industry a large amount of chemicals are used and some of them are carcinogen hazard. Many chemicals, some of them carcinogens, are appearing uncontrollably as wastes of life or industry.

The current methods of carcinogen detection demand much time, funding, resources and experienced personnel and can be used only in specially equipped laboratories. The carcinogen identification could be essentially improved by using physico-chemical methods. There is serious scientific ground to consider that the correlation between carcinogen activity and some combination of physicochemical parameters can be found.

The search for the correlation between molecule properties, mainly structure, and biological activity has been performed for many years in the frame of the special scientific focus named QSAR (Quantitative Structure Activity Relationship). Until recently the majority of QSAR works have used the geometrical, structural and energetic characteristics of molecules, which can be combined by the term "static". In the present Project the main attention will be paid to the "kinetic" characteristics, which indicate the probability of various chemical reactions. In our opinion the "kinetic" characteristics, such as charge transfer reactions rather than only "static" characteristics, could be more informative for explaining the role of various molecules in the biological processes, especially with respect to chemical carcinogenesis or at least could essentially enrich the basis of carcinogenicity prediction.

Until now scientific searches have been complicated by lack of knowledge of both the physical and the biological aspects of such problems. But now, the data of at least several reactions for many hundreds or even thousands of substances are available and the search for correlation could be done on a new much stronger basis.

The use of modern vast data bases of chemical carcinogenic and mutagenic characteristics as well as of their physicochemical parameters allows to apply the contemporary methods of statistical analysis to the problem of the phisico-biological correlations.

In the present project takes part:

  • the group of physicists from Moscow Engineering and Physical Institute that has long-term experience in experimental and theoretical investigations of electron attachment in gases and liquids and in comparison of the obtained results with the data of biological activity;
  • the group of biologists-oncologists from the Institute of Carcinogenesis that is a leading laboratory in Russia in the field of development and application of short-term tests identifying potential carcinogens;
  • the group of workers of the defense profile enterprise Institute of Applied Mechanics, that have a considerable experience in processing extensive array of information obtained in tests of space rockets and missiles.

On the basis of collected material the databases on biological properties of molecules and on their physicochemical characteristics will be built up. From the analysis of the databases the physicochemical characteristics of molecules that responsible for their carcinogenic activity will be revealed that allows to contribute to the solution of the fundamental problem of the mechanism of chemical carcinogenesis.

The revealed correlation of physicochemical and medico-biological parameters of molecules can be used for the development of devices – detectors of potential carcinogens.

In providing planned works the participation of the scientists and engineers of Federal Cosmic Agency can be of priceless help because they have rich experience in processing vast amount of information.

It is assumed that after fulfilling of this project the developed devices will be produced and former weapon industries can play a significant role taking part in the humane deal of fight for ecological clearness of environment and for the people’s health.

The proposed project would help Russian scientists and in particular the workers of defense enterprises to establish wider international scientific contacts. Successful collaboration in this project could sow the seeds for new contracts between Western institutions and firms and Russian industries.

The creation of protected databases that provides possibility of its prompt updating, data exchange between collaborators, production of reliable statistic conclusions, and also descriptive presentation of information in tables and graphs is corresponded to the experience and qualification of the scientists and engineers connected by their last activity with the production of rocket weapon. Computer power and technologies that are in the disposal of the Institute of Applied Mechanics will help to obtain reliable information and develop an analytical base to effectively solve the problem of short-term carcinogen detection.

In the present project the «static» and «kinetic» characteristics of molecules will be studied. The main attention is paid to the “kinetic” reactions with the charge transfer, in particular, the reactions of electron attachment in neutral buffer media. To collect the database we plan to use the published data, to calculate the reaction parameters and to measure them if there is no reliable published data and their calculation is difficult. Our practice shows that it is possible to test 3 - 4 chemicals per week.

The great interest to the work has been expressed by the foreign collaborators that represent the Institutions of both physical and biological profiles. Their participation can considerably help in our studies and will be fruitfull for their research institutions.

The achievements of the modern radical theory of toxicity will be used as the methodological base of the project. The parameters that determine the possibility of reactions that lead to free-radical production and the possibility of free-radical interactions with DNA bases will be chosen from the set of molecule physico-chemical characteristics.

Besides it is well known that most of the carcinogens persist in the environment in an inactive procarcinogenic form. For activation, these compounds should be transformed by cell enzymes, mainly isoforms of cytochrome P-450. Therefore, an essential parameter in recognition of potential carcinogens should be knowledge of properties which define their interaction with particular activating isoenzyme. For this purpose studies will be carried out using strains of bacteria and Drosophila expressing certain P-450 isoforms. It will allow selecting groups of compounds subjected to particular isoform. Searching for the common physical and chemical properties inside of such group can approach us to understanding of properties of the initial molecule necessary for interaction with these metabolizing systems.

Resolution of this problem will require the usage and improvement of molecular genetics methods, for creation lines of pro- and eukaryotic organisms with given properties of drug metabolizing systems.

The scientific institutions, business and private experts from the USA, the countries of European community, Japan and Norway are invited for collaboration in the framework of this project.


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