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Proceedings of the 31 st European Peptide SymposiumMichal Lebl, Morten Meldal, Knud J. Jensen, Thomas Hoeg-Jensen (Editors)European Peptide Society, 2010Delta-Sleep Inducing Peptide (DSIP) and Its Analogues:Studies On Their Therapeutic PotencyInessa I. Mikhaleva 1* , Igor A. Prudchenko 1 , Eugeniy S. Efremov 1 ,Ludmila V. Onoprienko 1 , Leonid D. Chikin 1 , Raisa I. Yakubovskaya 2 ,Elena P. Nemtsova 2 , and Olga A. Bezborodova 21 Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences,Moscow, 117997, Russia; 2 Gertsen Scientific-Research Cancer Institute,Moscow, 125284, RussiaIntroductionAt present, one of the topical lines of development of the modern oncology is a search forways to significant improvement of selectivity of therapeutic anti-tumor agents anddecrease in toxicity of the anti-tumor therapy. In this connection we have undertaken thestudies of delta-sleep inducing peptide (DSIP) [1] and its analogues as potent agentscapable to mitigate some adverse effects of widely used cytostatic drugs. We have studiedstructure-functional peculiarities, biological properties, and mechanism of action of DSIPover a long period of time. As a result, pronounced stress-protective activity of thisregulatory factor was revealed, and biochemical mechanisms of its realization areinvestigated [2-4]. Previously, we have detected the ability of DSIP to increase theanti-tumor resistance of animals under the conditions of inoculation of tumor cells underthe background of stress and to inhibit dissemination (metastasis) of Lewis carcinoma afterits surgical removal [5]. The DSIP was found capable to limit the spontaneouscarcinogenesis and mutagenesis [6]. Results of the previous studies demonstrate that someof DSIP-related compounds might be promising for oncological practice, in particular, forpossible inhibition of metastasis, decrease in the toxic effects of a cytostatic, and limitationof disorders of neuroendocrine status.Results and DiscussionDetoxifying effects of DSIP and a number of its analogues were examined on models oftoxicosis induced by cytostatic agents cisplatin and cyclophosphan. The animals (the BDF1female mice) were intravenously injected one time with cisplatin or cyclophosphan at dosesof 15 mg/kg or 450 mg/kg, respectively. The animal death from the acute cisplatin-inducedtoxicity was observed. The tested peptides (Р1-P10 and DSIP) were intravenouslyadministered at single doses of 50 and 250 µg/kg respectively during four days (the coursedoses of 200 and 1000 µg/kg, respectively) after the cisplatin injection. The animal deathfrom the acute cisplatin-induced toxicity was observed, and hematolytic and biochemicalparameters of blood of the survived animals were evaluated. DSIP and its P1, P2, P5 andP7 analogues facilitated a decrease in the cisplatin toxicity, in particular, they decreased theanimal mortality in 1,5 times (Figure 1). The P1 peptide exhibited the most positive effect;its four-times administration at a course dose of 200 µg/kg 24 h after the cisplatinintroduction resulted in the significant (up to 17%) decrease in the mortality, whereas theanimal death in the control group was as high as 50-67%. DSIP was active as P1 only atcourse dose 1000 µg/kg.Administration of the peptide facilitated the remarkable decrease in hepatotoxicity andnephrotoxicity of the cytostatic. Combinational administration of cisplatin with DSIP or itsP1 analogue to the animals with transplanted Lewis lung carcinoma (LLC) did not abandonthe therapeutic effect of cisplatin, but did not cause its increase as well. Only biologicallyinsignificant decrease in the animal death from the acute toxicity of the cytostatic wasobserved on the model of toxicosis that was induced by the toxic dose of cyclophosphan.Investigation of the influence of the peptides on the growth of the primary tumor andprocesses of metastasis of the Lewis lung carcinoma demonstrated that the peptides at thestudied doses and chosen limited experimental protocol had no stimulating or inhibitingeffect on the growth of the primary tumor and processes of metastasis (without the removalof the primary focus). Peptides were nontoxic towards organisms of the tumor-bearinganimals. We have detected the dependence of these peptides protective effects on a type of314