Therapy with a protein-peptide complex from embryonic stem cells as a method of reducing nephrotoxic effect of chemotherapy drug cisplatin

Background. One of the serious complications of chemotherapy with cisplatin is its nephrotoxic effect. Different variants of hydration therapy and thiol-containing drugs are used to prevent deterioration of renal function. However, if high doses of cisplatin are necessary, the effectiveness of therapy is limited, and the use of pharmacological agents is often accompanied by undesirable side effects, which forces the search for alternative ways of therapy.

Aim. To study the effectiveness of prevention of nephrotoxic effect of cisplatin using a protein-peptide complex isolated from the pig embryonic brain (EPPC).

Materials and methods. The study was conducted on 40 white mongrel male rats in 4 series. In the 1st series, rats were administered one intraperitoneal injection of cisplatin at a dose of 5 mg/kg. In the 2nd series, starting from the next day, an additional 10-day course of EPPC therapy was performed with daily intramuscular administration at a dose of 0.1 mL per rat. In the 3rd series, higher toxicity dose of cisplatin – 7 mg/kg – was used, and in the 4th series, EPPC therapy was used according to the same scheme as in the 2nd series. Severity of the toxic effect of cisplatin therapy was assessed by measuring biochemical parameters of blood and urine characterizing functional state of the kidneys on days 3, 7 and 14, and histological examination of the removed kidneys.

Results. When cisplatin was administered at 5 mg/kg dose, all animals survived. In rats of the control series, concentration of creatinine and urea in the blood increased significantly with peak values on day 3, exceeding normal values by 146 % and 214 %, respectively. Glomerular filtration rate decreased by 75 %, and sodium and calcium reabsorption decreased by 72 % and 74 %, respectively. With EPPC therapy, the maximum increase in creatinine and urea concentrations was 100 % and 122 %, respectively, glomerular filtration rate decreased by only 48 %, and sodium and calcium reabsorption decreased by 60 % and 59 %, respectively. In experiments with a highly toxic dose of cisplatin in the control series, 80 % of rats died, and with EPPC therapy, the mortality rate was 50 %. The maximum increase in creatinine and urea concentrations in the control series was 1177 % and 1500 %, respectively, whereas with EPPC therapy it was 707 % and 1150 %, respectively. The decrease in glomerular filtration rate in the control series was 85 %, while with EPPC therapy it was 65 %. Sodium and calcium reabsorption in the control experiments decreased by 81 % for both cations, and in the experimental series by 57 % and 58 %, respectively. Histological examination in control experiments revealed marked glomerulosclerosis with necrotic and dystrophic changes in the renal tubules, and in experiments with 7 mg/kg dose of cisplatin massive interstitial hemorrhages were observed. Histological changes were significantly less pronounced during EPPC therapy.

Conclusion. EPPC therapy significantly reduces the nephrotoxic effect of cisplatin, contributing to lower severity of impaired renal function and mortality when using the drug at high doses. 

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