The major mechanisms of disruption of the arginine/citrulline cycle in the pathogenesis of cytostatic-induced intestinal injury in patients with chronic lymphoproliferative diseases and methods of their correction

Abstract

Objective — on the basis of investigation of the role of oxidative stress in disruption of arginine/citrulline cycle with the use of citrulline as a marker of intestinal functional capacity, to provide ground for administration of S‑ademetionine (S‑AMe) in combination with Bifidobacterium infantis 35624 (B. infantis 35624) in patients with chronic lymphoproliferative disorders (CLPD) for prophylaxis of cytostatic‑induced mucositis during chemotherapy (CT). Materials and methods. Examinations involved 38 patients with CLPD, including 8 (21%) females and 30 (79%) males aged 30—76 years. Patients with CLPD and registered diarrheal syndrome against the background of CLPD progression have been enrolled in the study. All patients received CT according to the current guidelines. Depending on the type of concomitant therapy, patients were divided into three groups: group І (n=13) included patients with CLPD, who underwent CT only; patients of group ІI (n=12) received CT and S‑Ame in a dose of 1000 mg/day intravenously for 10 days and then in a dose of 500 mg twice a day for 20 days; patients of group ІII (n=13) during CT received S‑AMe, in a dose of 1000 mg/day intravenously for 10 days, then in a dose of 500 mg twice a day for 20 days with concomitant B. infantis 35624 1 capsule/day for 30 days. Control group consisted of 20 practically healthy subjects (9 (45%) females and 11 (55%) males, aged 22 to 26 years. The examinations were conducted twice: before CT and after the three courses of CT. Blood serum examinations included levels of substances that form a trimethine complex (TBARS) with 2‑thiobarbituric acid, assessment of catalase activity, arginine and citrulline levels and arginase activity. Results. At baseline examinations of patients of groups I, II and III, levels of TBARS in blood serum exceeded the norm in 1.4 (p=0.0479), 1.3 (p=0.0122) and 1.4 times (р=0.026), respectively. Blood serum citrulline level in the group I was in 1.2 times (p=0.0171) lower than in controls. The negative correlation was determined between serum citrulline levels and TBARS levels in the group I (r=–0.52; p=0.02). After the 3rd course of CT in patients of I group, the concentration of TBARS was in 1.3 times (p=0.0002) higher vs baseline values, and in 1.8 times (p=0.0012) higher than in controls. In patients of the II and III groups, serum TBARS levels were in 1.39 (p=0.0005) and 1.46 times (p=0.0002) lower compared to the group I of patients. The application of S‑Ame and B. infantis 35624 combination in group III patients allowed an increase serum citrulline levels in 1.4 times (p=0.0002) compared to group І and in 1.1 times (p=0.001) compared to group ІІ. Conclusions. The conduction of chemotherapy in patients with chronic lymphoproliferative disorders is associated with an increased risk of cytostatic‑induced mucositis, oxidative stress plays a crucial role in its pathogenesis. The application of S‑ademetionine in combination with Bifidobacterium infantis 35624 allows to prevent intestinal injury during chemotherapy.