Abstract
Introduction.This article presents a fragment of a preclinical toxicological study of a new Russian anticancer drug derived from n-glycoside indolokarbazole LCS-1208 – study of cardiotoxicity, which is one of the specific complications of anticancer chemotherapy.Objective.Preclinical toxicological study of the effect of the drug LCS-1208 on the cardiovascular system of animals to assess its cardiotoxic effects.Materials and methods.Studies were conducted on 40 healthy non-harmless mongrel male rats and 4 dogs Beagle, male and female. The drug was administered daily 15 times to rats-intraperitoneal in total doses of 50, 100 and 200 mg/kg; to dogs – intravenously in total doses of 20 and 30 mg/kg. The period of observation of rats was 30 days, for dogs was 60 days. Changes in electrocardiogram indices, macroscopic and histological picture of heart changes and changes in biochemical parameters of enzymes activity – lactate dehydrogenase and aspartate aminotransferase were evaluated.Results.In rats LCS-1208 throughout the period of observation caused functional changes in electrocardiogram: increase in PQ and QT intervals and cardiac rhythm disturbance (loss of R wave), which indicates a violation of electrical conductivity. Morphological changes in the heart muscle were detected on the 3rd day of observation in total doses of 100 and 200 mg/kg, which remained until 30 days of observation only in animals receiving the drug in the total dose of 200 mg/kg. In some dogs for different periods of observation the drug caused functional changes in the electrical activity of the heart: an increase in the QRS interval, the inversion of the T wave, the appearance of a deep Q wave and an increase in the activity of lactate dehydrogenase and aspartate aminotransferase compared to back ground indicators. Morphological changes in the heart muscle were detected on the 3rd day of observation only in the total dose of 30 mg/kg, which persisted up to 60 days of observation.Conclusion.It was found that the new Russian anticancer drug LHC-1208, a derivative of indocarbazole N-glycoside, has a cardiotoxic effect, causing functional changes in the cardiovascular system of rats in all doses studied, and in dogs only in the maximum dose. Morphologically, cardiotoxicity is not confirmed in animals receiving a minimal dose of the drug, but only in animals receiving the maximum dose of the drug.
Highlights
This article presents a fragment of a preclinical toxicological study of a new Russian anticancer drug derived from n-glycoside indolokarbazole LCS-1208 – study of cardiotoxicity, which is one of the specific complications of anticancer chemotherapy
Studies were conducted on 40 healthy non-harmless mongrel male rats and 4 dogs Beagle, male and female
The drug was administered daily 15 times to rats-intraperitoneal in total doses of 50, 100 and 200 mg/kg; to dogs – intravenously in total doses of 20 and 30 mg/kg
Summary
У крыс ЛХС-1208 на протяжении всего срока наблюдения вызывал функциональные изменения показателей электрокардиограммы: увеличение интервалов PQ и QT и нарушение сердечного ритма (выпадение зубца R), что свидетельствует о нарушении электрической проводимости. Морфологические изменения в сердечной мышце были выявлены на 3-и сутки наблюдения в суммарных дозах 100 и 200 мг/кг, которые сохранялись до 30 сут наблюдения только у животных, получавших препарат в суммарной дозе 200 мг/кг. У собак на разных сроках наблюдения препарат вызывал функциональные изменения электрической активности сердца: увеличение интервала QRS, инверсию зубца Т, появление глубокого зубца Q. Морфологические изменения в сердечной мышце были выявлены на 3-и сутки наблюдения только в суммарной дозе 30 мг/кг, которые сохранялись до 60 сут наблюдения. Установлено, что новый российский противоопухолевый препарат ЛХС-1208 обладает кардиотоксическим действием, вызывая функциональные изменения сердечно-сосудистой системы крыс во всех изученных дозах, а собак – только после применения препарата в максимальной дозе. Blokhin National Medical Research Center of Oncology, Ministry of Health of Russia; 24 Kashirskoe Shosse, Moscow 115478, Russia
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