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

Abstract

ABSTRACTBackgroundThe 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.