Gastrin Modified Fragments
Synthesis and Biological Efficiency Investigation of Gastrin Modified Fragments as Drug Delivery Systems for Gastrointestinal Tract Tumors Treatment
Tech Area / Field
- MED-DRG/Drug Discovery/Medicine
- CHE-SYN/Basic and Synthetic Chemistry/Chemistry
3 Approved without Funding
State Research Institute of Organic Chemistry and Technology, Russia, Moscow
- Cancer Research Center, Russia, Moscow
- School of Medicine Creighton University, USA, NE, Omaha\nQueen's University of Belfast / The School of Pharmacy, UK, Belfast
Project summaryIt is difficult to use chemotherapeutic agents in gastrointestinal tract (GIT) tumours treatment.
Proposed project will permit to obtain new effective substances with high level of selective action on GIT tumours.
According to academician L.F.Larionov idea, nature metabolites, including hormones, may be carriers of cytotoxic groups to tumor cells, origin from target tissues for some hormones, which will lead to high selectivity of antitumor action.
In our opinion, gastrin and its different fragments use as cytotoxic groups carrier with antihormonal activity may be these active substances in gastrointestinal tumours. Possibility of gastrin fragments use has been confirmed by a number of experimental investigations. It is determined, that both gastrin and some fragments of its molecule (for example, C-terminal pentagastrin) had biological properties of indicated peptide hormone, including stimulation of men stomach cancer cells YG803 and HG823 prolifiration.
This point of view to antitumour preparations of high activity search has been already realised in oncology practice and cytotoxic groups have been connected to some irreplaceable aminoacids (Sarcolysin, Melphalan, Cyphelin) and steroid hormones (Stericyte, Estracyte, Busramustine).
The second trend of antitumor preparation for GIT treatment creation, will be realysed in proposal project, is synthesis af high-efficiency gastrin antagonists. It is proposed that these substances will block its receptors on the tumor cells membrane surface, what will lead to proliferation decrease. For this purpose peptide hormone gastrin fragments of different length (tetra-, penta-) will be synthesized and investigated. Some of them (C-terminal peptide), by the references, inhibit free gastrin connection with its receptors.
So, the main importance by the project carrying out will be attached to:
1. Synthesis and biological properties researching of gastrin agonists and antagonists among its fragments of different length (tetra-, penta-);
2. Synthesis and biological properties researching of gastrin cytotoxic analogous fragments of different length (tetra-, penta-).
Both investigation trends are perspective in equal degree and have essential novelty.
Project consists of 4 main aims, and each of these aims has scientific and practical importance.
The first task - to carry out methods of gastrin non-cytotoxic fragments synthesis, techniques of their eduction, purification and analysis, installation of these techniques in laboratory practice, working out of substances necessary quantities for biological investigations.
The second task - to carry out methods of gastrin fragments cytotoxic analogous synthesis by interaction of this hormone fragments with cytotoxic groups, techniques of their eduction, purification and analysis, installation of these techniques in laboratory practice, working out of substances necessary quantities for planned biological investigations on experimental animals.
The third task - to investigate specific hormonal properties of gastrin non-cytotoxic fragments to reveal agonists and antagonists and to determine the most active of them.
The forth task - to estimate antitumor properties of gastrin non-cytotoxic and cytotoxic analogous on experimental animals tumor growth models.
The main proposal result of the project will be new data of hormone gastrin and its cytotoxic analogous biological properties; choice of the most effective substance for GIT tumors treatment, perspective for further preclinical investigations.