FIND ARTICLE

Volume: 
Issue: 
3
Date of issue: 

Doxorubicin (DOX ) and other anthracyclines are commonly used in the treatment of cancer, both leukemias and solid tumors. The clinical use of these drugs is limited by side effects , especially the cardiotoxicity , myelosuppression , or damage to the kidneys . Efforts are therefore numerous studies aimed at reducing the side effects and increase the efficacy of doxorubicin and other anthracyclines . One alternative strategy is the use of drugs conveyors , such as liposomes, dendrimers , or the antibody nanoparticles . Conveyors allow for an increase in the intracellular concentration of drugs in tumor cells, and the reduction of the effects of multidrug resistance . This article presents the current knowledge of a very promising line of research using conveyors protein and peptide . The peptides used as drug carriers include recurring lysine or arginine residues . They are connected through DOX samoodłączający a linker that spontaneously under certain conditions to release the drug . An example of this type of linker is p- aminobenzylokarbonyl ( PABC ), which disconnects the drug with a low pH. During the synthesis of peptides, which are components of the conjugate , is taken into account such amino acid sequences which are specifically recognized by overexpressing the enzymes in tumor cells or in their environment. These include cathepsins , metalloproteinases and serine protease PSA . The paper discusses the prodrugs which contain in their structure of the peptides that are substrates for the matrix metalloproteinases , especially MMP2 and MMP9 . These proteinases are involved in tumor progression , angiogenesis and metastasis . They are produced by tumor cells and tumor stroma cells and therefore release of the active agent from the prodrug takes place in tumors . Another important issue discussed in the article is the use, during the preparation of the conjugate , certain amino acid sequences that are recognized by receptors present in increased levels on tumor cells. For these receptors include, among others av - integrin receptors for transferrin and for peptide hormones . Integrins , participating in selective adhesion ligands recognize a specific group of amino acids, the tripeptide arginine - glycine - aspartic acid, also known as the RGD sequence . Attaching such a peptide to the anthracycline prodrug enhancing uptake by tumor cells . Used by other receptors are also prodrugs asjaloglikoproteinowe receptors present on the surface of hepatocytes . Conjugate recognized by receptors asjaloglikoprotein is doxo - EMCH , transported by laktozoaminowanej derived albumin ( L- HSA) . It also discusses the receptor for gonadotropin-releasing hormone , somatostatin , bombesin and calcitonin . Prodrugs of DOX containing ligands ( peptides) , which exhibit high affinity for hormone receptors , get into the tumor cell by means of endocytosis. Peptide Prodrugs are often connected also to facilitate transport of large macromolecules drug selectively to the tumor cells . One of these macromolecules is albumin ( exogenous or endogenous ), which in many types of conveyors is attached to the cysteine ​​conjugate ( the Cys ) at position 34 in the area of the tumor is often unknown functional lymphatic drainage , which results in retention of macromolecules in the tumor. Increased serum albumin in this area is also linked to the intensive metabolism of cancer cells for which the albumin is a source of energy for the processes of life . A major problem in cancer chemotherapy is commonly occurring phenomenon of resistance to cancer chemotherapeutic agents used . The main protein of multidrug resistance P -glycoprotein is a major achievement in research on drug delivery systems have proved conjugates that contain in addition to the typical elements ( carrier, linker , a drug ) is also an inhibitor of P -gp , which after removing tumor cells restored their sensitivity to the effect of DOX .

The Editorial Board
Andrzej Łukaszyk - przewodniczący, Zofia Bielańska-Osuchowska, Szczepan Biliński, Mieczysław Chorąży, Aleksander Koj, Włodzimierz Korochoda, Leszek Kuźnicki, Aleksandra Stojałowska, Lech Wojtczak

Editorial address:
Katedra i Zakład Histologii i Embriologii Uniwersytetu Medycznego w Poznaniu, ul. Święcickiego 6, 60-781 Poznań, tel. +48 61 8546453, fax. +48 61 8546440, email: mnowicki@ump.edu.pl

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