Synthesis and Antitumor Activity of 2-[3-(2-Chloroethyl)-3-Nitrosoureido]-1,3-Propanediol (Chlonisol)

Стуков, А. Н.; Esikov, K. A.; Usmanova, L. M.; Kharitonova, N. N.; Vershinina, S.F.; Zmitrichenko, Yu. G.; Филатова, Л. В.; Latipova, D.Kh. Latipova; Semenov, Aleksandr; Беспалов, В. Г.; Semiglazova, T. Yu.

doi:10.1007/s11094-020-02242-7

Cited by 5 publications

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“…Тестируемые вещества (препараты). В экспериментах использовался ломустин (МЕДАК ГМБХ, Германия) и хлонизол, синтезированный фирмой КемКонсалт (Санкт-Петербург) по нашей оригинальной методике [2].…”

Section: материалы и методы / Materials and Methodsunclassified

“…Н.Н. Петрова» Минздрава России в течение ряда лет изучается 2-[3-(2-хлорэтил)-3-нитрозоуреидо]-1,3-пропандиол (хлонизол) как новый потенциально активный противоопухолевый препарат [1][2][3]. Это соединение относится к группе алкилнитрозоуреидопропандиолов, которые по химическому строению близки к нитрозоалкилмочевинам и являются препаратами алкилирующего механизма действия.…”

Section: введение / Introductionunclassified

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Activity of 2-[3-(2-chloroethyl)-3-nitrosoureido]-1,3-propandyоl (chlonisol) versus lomustine in intracranial transplanted tumor model in mice

Zmitrichenko

Стуков

Aleksandrov

et al. 2022

Fk&Fd

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Background. Alkylating drugs have been used in tumor chemo therapy for many decades, and the search for effective compounds continues.The aim of the study was to study the activity of the developed new compound – 2-[3-(2-chloroethyl)-3-nitrosoureido]-1,3-propanediol (chlonisol) in comparison with lomustine (CCNU) from the nitrosoalkylurea group, which is similar in chemical structure, in the model of intracranially transplanted Ehrlich's tumor and sarcoma 180 in mice.Methods. According to the developed technique, 64 female mice of the BALB/c line were punctured in the skull under anesthesia and inoculated with tumor cells of Ehrlich's carcinoma or sarcoma 180 in 0.9 % sodium chloride solution. After 24 hours, the test substances were administered at the maximum tolerated doses – chlonisol (20 mg/kg, i.p.) and lomustine (50 mg/kg, orally), once. The effect was compared with the control (solvent injection).Results. Chlonisol significantly increased the median overall survival (MOS) of animals after intracranial transplantation of both Ehrlich's tumor (by 39 %) and sarcoma 180 (by 84 %) compared with control (p<0.0001). Chlonisol reduced the risk of death in mice by 73 % compared to control in Ehrlich tumor transplantation and by 83 % in sarcoma 180 (p<0.0001). In contrast, lomustine did not show a significant therapeutic effect in intracranial transplantation of both tumors.Conclusion. The high activity of chlonisol in comparison with lomustine gives reason to consider it as a potential cytostatic agent in the treatment of nervous system tumors.

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Section: материалы и методы / Materials and Methodsunclassified

Section: введение / Introductionunclassified

Activity of 2-[3-(2-chloroethyl)-3-nitrosoureido]-1,3-propandyоl (chlonisol) versus lomustine in intracranial transplanted tumor model in mice

Zmitrichenko

Стуков

Aleksandrov

et al. 2022

Fk&Fd

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“…As far as cytogenetic activity is concerned, chlonisol exceeds all other NAU-class drugs studied earlier. (Stukov et al . 2020).…”

Section: Introductionmentioning

confidence: 99%

Effect of Chlonisol (2-[3-(2-chloroethyl)-3-nitrosoureido]-1,3-propanediol) on Overall Survival in Laboratory Rodents with Intracranial Tumors: A Meta-analysis of Preclinical Studies

Murazov

Стуков

Zmitrichenko

2022

Preprint

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BackgroundThe need for new, effective, and affordable drugs for the treatment of primary and metastatic brain tumors remains unsatisfactory. Preclinical studies of chlonisol (2-[3-(2-chloroethyl)-3-nitrosoureido]-1,3-propanediol) showed promising results in the treatment of experimental intracranial tumors.ObjectivesTo apply a meta-analytical approach to estimate the combined effect size of chlonisol on overall survival (OS) in rodents with brain tumor transplants.Search strategyData for the meta-analysis were obtained from the laboratory’s internal database from reports of preclinical studies of chlonisol.Selection criteriaEligible studies were parallel preclinical trials in rodents (mice, rats) with intracranially transplanted tumors. Chlonisol was compared with active control treatment (lomustine or temozolomide). All cytostatics were administered at the maximum tolerated dose (MTD). The duration of the studies was at least 90 days. The main outcome was OS-HR (hazard ratio).Data analysisWe applied the inverse variance technique for the meta-analysis of HRs. In HR analysis we adopted a random-effect model.ResultsThe analysis included seven trials with 132 rodents. Studies were conducted between 2016 and 2022. As a murine intracranial grafts we used Ehrlich’s carcinoma, Sarcoma 180 and the HER2-positive mammary tumor derived from a female FVB/N HER-2/neu transgenic mouse. Glioma 35 was transplanted into rats. Compared with active control, oral or intraperitoneal administration of chlonisol at MTD of 20 mg/kg, significantly reduced the risk of death by 63% (HR=0.37; 95% CI: 0.24-0.56; P<0.00001) in animals with intracranial tumors. The direction in favor of chlonisol was stable across studies despite the use of different animals and transplants, the routes of administration of chlonisol, and control treatment. No significant heterogeneity was observed between the studies (Tau2 = 0.03; Chi2 = 6.52; df = 6; P = 0.33; I2 = 8%).ConclusionCompared with lomustine and temozolomide, chlonisol treatment in MTD provides an important advantage in OS in animals with intracranial tumors. Our results may serve as a basis for further study of chlonisol as a chemotherapy agent for primary and metastatic brain tumors.

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Comparative Activity of Chlonisol and Temozolomide in Mice After Intracranial Transplantation of Ehrlich Carcinoma and HER2-Positive Breast Cancer

et al. 2022

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Synthesis and Antitumor Activity of 2-[3-(2-Chloroethyl)-3-Nitrosoureido]-1,3-Propanediol (Chlonisol)

Cited by 5 publications

References 1 publication

Activity of 2-[3-(2-chloroethyl)-3-nitrosoureido]-1,3-propandyоl (chlonisol) versus lomustine in intracranial transplanted tumor model in mice

Activity of 2-[3-(2-chloroethyl)-3-nitrosoureido]-1,3-propandyоl (chlonisol) versus lomustine in intracranial transplanted tumor model in mice

Effect of Chlonisol (2-[3-(2-chloroethyl)-3-nitrosoureido]-1,3-propanediol) on Overall Survival in Laboratory Rodents with Intracranial Tumors: A Meta-analysis of Preclinical Studies

Comparative Activity of Chlonisol and Temozolomide in Mice After Intracranial Transplantation of Ehrlich Carcinoma and HER2-Positive Breast Cancer

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