Meurling 26/1

Guanidine compounds have important biochemical properties. Aminoguanidine, as an example, is an anti-oxidant, a nitric oxide synthase inhibitor (NOS) which prevents nitric oxide formation, and an inhibitor of advanced glycosylation end products (AGEs). As an anti-oxidant, aminoguanidine may affect the formation of atherosclerotic lesions through protection from LDL oxidation. Inhibition of AGEs could have a preventive effect on the tissue damage caused by diabetes where AGEs are considered to be an important factor. The role of NO in cancer is complex and not fully understood, but it may have influence on growth and progression. In this study, the tumor growth inhibitory effect of conjugated guanidine (i.e. a polyguanidine) was investigated. The effect on tumor cell growth was studied in cultures of prostate, breast, bladder and renal cell cancer, and a fluorometric cytotoxicity assay was performed. Guanidine conjugates were prepared by reacting aminoguanidine or agmatine with periodate oxidized dextran followed by reductive amination. The cytotoxic effect was compared with an anthracycline (adriamycin). The dextran-guanidine conjugates were cytotoxic at low micromolar concentrations, and the dextranaminoguanidine conjugate (GDC) had the highest efficacy, being more efficient than adriamycin, in all of the tested tumor cell lines. Breast and prostate cancer cells were the most sensitive. At 0.5 μM, GDC killed >95% of the breast cancer cells compared to 25% for Adriamycine. In prostate cancer cells, GDC killed ~55% of the cells at 0.1 μM and 100% of the cells at 0.5 μM compared to ~22 and ~62%, respectively, for adriamycin. Unconjugated aminoguanidine and agmatine did not seem to affect tumor cell growth even at high concentrations (mM). Polymerconjugated guanidine is a potentially useful template for the construction of therapeutic tumor targeting cytotoxic agents. Introduction The guanidine group is present in a large number of biologically active compounds including drugs and drug candidates. Applications for such compounds include prevention of cardiovascular damage, antihistamine, antiinflammatory, antidiabetic, antibacterial/antiviral, and as anticancer drugs. The guanidine sidegroup contributes to the variety of applications of these compounds deriving from its ability to recognize receptors by noncovalent interactions, e.g. hydrogen-bonding and electrostatic binding. (1). Examples of guanidine compounds are aminoguanidine, metformin, arginine and agmatine. Aminoguanidine is an anti-oxidant and an inhibitor of advanced glycosylation end products (AGEs), and its properties may slow the formation of atherosclerotic lesions and cardiovascular damage through protection from LDL oxidation and the tissue damaging effects of AGEs. In fact, glycosylation of proteins (the ‘Maillard reaction’) is one of the most important causes of aging/degeneration, perhaps equally important as the process of oxidation. The product of the Maillard reaction (an ‘Amadori product’) may then crosslink with other proteins resulting in irreversible bonding. AGE formation happens as a result of normal aging and is accelerated during hyperglycemic states such as diabetes. Aminoguanidine is currently supplied as a non-prescription drug in the US, and its role in the treatment of disease is being investigated in clinical research. Metformin is a bi-guanidine and the most commonly prescribed drug for type 2 diabetes. It improves hyperglycemia primarily through suppression of hepatic glucose production and can lower the occurrence of cardiovascular damage (2-6). Arginine has a guanidine sidegroup and is a semi-essential amino acid with multiple key roles in cellular metabolism. It is an important precursor in the biosynthesis of a number of substances. Arginine is essential in cellular growth and recovery after injury and stimulates the release of several hormones (7). It is the sole precursor for nitric oxide (NO), a messenger molecule with multiple functions. The exact role of NO in cancer is not fully understood but may influence tumor initiation, promotion and progression (8). In contrast, aminoguanidine is a nitric oxide synthase inhibitor (NOS) which prevents NO formation (9). Additionally, aminoguanidine is a chaotrope, i.e. it can disrupt the three-dimensional structure of macromolecules and DNA/RNA (denaturation). A high concentration is required to have this effect. INTERNATIONAL JOURNAL OF ONCOLOGY 35: 281-285, 2009 281 Polymer-conjugated guanidine is a potentially useful anti-tumor agent LENNART MEURLING, MARCELA MÁRQUEZ, STEN NILSSON and ANDERS R. HOLMBERG Department of Oncology and Pathology, Karolinska Institute, SE-171 76 Stockholm, Sweden Received January 26, 2009; Accepted March 13, 2009 DOI: 10.3892/ijo_00000338 _________________________________________ Correspondence to: Dr Anders R. Holmberg, Urologic Oncology Group, CCK R8/3, Karolinska University Hospital, Karolinska Institute, SE-171 76 Stockholm, Sweden E-mail: [email protected]