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Germanium-Organic Complexes with Anti-Tumor Activity

#2433


Creating Complexes of Germanium-Organic Compounds with Anti-Cancerogenic Activity, Assessment of Their Anti-Tumor Activity and Harmlessness

Tech Area / Field

  • MED-DRG/Drug Discovery/Medicine
  • BIO-CHM/Biochemistry/Biotechnology
  • BIO-CGM/Cytology, Genetics and Molecular Biology/Biotechnology

Status
3 Approved without Funding

Registration date
27.02.2002

Leading Institute
Scientific Research Institute of Chemistry and Technology of Organo-Element Compounds, Russia, Moscow

Supporting institutes

  • Research Center of Toxicology and Hygienic Regulation of Biopreparations, Russia, Moscow reg., Serpukhov

Collaborators

  • CNRS, France, Paris\nVAREBIOTEC / Valorisation de Recherches en Biotechnologie, France, Meudon

Project summary

The goal of the Project is development of novel anti-cancer preparations of new generation, which excel by high efficiency, low toxicity, and high prophylaxis effect.

Treatment and prophylaxis of neoformations, mechanisms of anti-cancer control, primary and acquired resistance towards tumors are among the most complicated problems of up-to-date medical theory and practice.

In the given Project it is proposed to investigate anti-carcinogenic effect organogermanium compounds (OGC) and complexes of organogermanium compounds with phosphatized polypeptides having compound structure (PhPP), as well as with known anti-cancer preparations.

Investigation of anti-tumor activity of six germatranes (tricyclic organogermanium derivatives of triethanolamine) having general form R-Ge(OCH2CH2)3N in five test-systems showed their high efficiency. Thus, 1-hydroxygermatrane prolonged life of mice with Ehrlich ascites carcinoma by 78% comparing with the control. 1- trimethylxyloxygermatrane expressed approximately the same activity (75%) towards sarcoma 37, 1-trimethylgermoxy- and 1-hydroxygermatrane expressed rather less activity. A number of investigations concerning study of anti-tumor activity of 2-carboxyethylgermanium sesquioxide and its derivatives showed that those compounds are promising as anti-tumor preparations.

A lot of investigations on study of anti-tumor activity of organogermanium compounds allowed to draw up a conclusion that one of mechanisms of OGC effect is their capability of inducing endogenous interferon, which is a natural effective, and practically non-toxic means for prophylaxis and therapy, in organism. Another mechanism of OGC anti-tumor activity can be their direct or indirect stimulating effect on production of tumor necrosis factor (TNF). It is known that macrophages (MPh) and NK-cells, activated ones especially, can impede growth of tumor or destroy it. Experiments in animals have demonstrated that at stimulation macrophages extract TNF-a, which destroys some tumors in vivo. It was shown that in 48 hours after OGC peroral introduction, mice peritoneal exudation displayed anti-tumor activity, which disappeared after suppression of macrophage activity with the help of iron carbonyl.

Specialists from Russian State Research Center GNIICHTEOS found out that germatranes form complexes with various chemical compounds and medical preparations in particular. To assess nature of germatrane molecule interaction with other molecules, computer calculations of these molecules and their complexes using semiempiric method АМ1 were conducted. Soundness of the complex was assessed by amount of energy necessary for its decomposition. For the first time in the world specialists from SRC RF GNIICHTEOS developed a theory of formation of complexes of germatranes and their analogues with various biologically active compounds. Binding energy in these complexes is 15-40 kilocalories/mole, what is likely to facilitate biotransformation of biologically active molecules in conditions of a living organism, leads to normalization of fermentative processes, and increases bioavailability of these molecules.

Obtained by us preliminary data concerning study of specific activity of OGC complexes with known anti-cancer preparations showed considerable increase of anti-tumor effect of these preparations.

It is proposed to investigate complexes of anti-tumor preparations with the following OGC:

1-hydroxygermatrane, 1-hydroxygermatrane phosphate, and 1-adamantilegermatrane. Preparations with determined specific activity were chosen as the second component of germanium-containing complexes: SARCOLYSINE, EMBIKHIM, CYCLOPHOSPHAMIDE – alkylating; METHOTREXATE, FTORAFUR – antimetabolites; VINCRISTINE – alkaloid; HEXAMETHYLMYCIN – antibiotic, and preparations from other groups (NATULAN, etc.).

Assessment of anti-cancerogenic activity of OGC complexes with anti-tumor preparations will probably be the beginning of introduction of novel class of anti-tumor preparations, which will be considerably more efficient and less toxic that initial components, in medical practice.

It is planned to use phosphatized polypeptides of compound structure and complexes of PPP with OGC as promising substances to create anti-tumor preparations. PPP series was developed and synthesized in Paris by Professors C. Garbay and N. Gresh from Universite Rene-Descarte [4, 11]. There are investigations corroborating high anti-tumor activity of PPP in vitro, but this compound is not stable. OGC reveals complex anti-tumor activity and is characterized by high bioavailability. It is supposed that obtained OGC and PPP complexes will possess increased stability and bioavailability, as well as complex anti-tumor activity conditioned by anti-tumor effect of each composing component.

At implementation of work on the Project it is supposed to conduct the following basic investigations:

– to obtain OGC - PPP complexes and OGC complexes with known anti-tumor preparations and study physical-and-chemical properties of all obtained complexes;


– to conduct computer calculation of obtained complex structure;
– to conduct screening of OGC anti-tumor activity and their complexes in test-systems in vitro;
– to assess anti-tumor activity of preparations selected as a result of screening in vitro, in vivo in lines of mice re-inoculated tumors;
– to study prophylactic effect of OGC selected as a result of screening in vitro in lines of mice re-inoculated tumors;
– to conduct preliminary pre-clinical assessment of 1-hydroxygermatrane and one or two complexes of the most promising ones, having pronounced anti-tumor activity, in laboratory animals.

Research staff involved in the proposed Project includes scientists and specialists from SRC RF GNIICHTEOS (Moscow) and RCT&HRB (Serpukhov).

SRC RF GNIICHTEOS is the leading institute of the Russian Federation in the area of synthesis and study of elementorganic compounds. The Institute specializes in development of ecologically clean, high efficient technologies and creation of elementorganic and non-organic materials of present day and future; works a lot in the area of creating novel medical preparations on the basis of organogermanium compounds.

RCT&HRB scientists have gained many-year experience in work on assessment of preparation carcinogenic activity as in vitro system in stationary cellular and primary tumor suspension cultures, so in vivo system in re-inoculated tumors of lab animals. RCT&HRB conducts preclinical examination of novel pharmacological preparations in accordance with methodical directives approved by Pharmacological Committee of the Ministry of Health of the Russian Federation. There is a state accreditation for the mentioned activities (#1296 of May 26, 1999).

Implementation of the given Project will considerably contribute to solving the ISTC goals directed to re-orientation of scientists and engineers engaged earlier in defense activities on health protection activities. Re-orientation of scientific interests and use of scientific and creative potential of Russian scientists in the interests of international scientific society will contribute to solution of national and international problems related to treatment of cancer diseases.

Foreign collaborators can participate in the Project. They can take part in discussion of Project plan and ways for its realization, information exchange during Project implementation, and joint symposia and workshops.


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