Plasma pharmacokinetics and tissue distribution of L-lysine α-oxidase from Trichoderma cf. aureoviride RIFAI VKM F- 4268D in mice

L-lysine α-oxidase (LO) is an L-amino acid oxidase with antitumor, antimicrobial and antiviral properties. Pharmacokinetic (PK) studies were carried out by measuring LO concentration in plasma and tissue samples by enzyme immunoassay. L-lysine concentration in samples was measured spectrophotometrically using LO. After single i.v. injection of 1.0, 1.5, 3.0 mg/kg the circulating T_1/2 of enzyme in mice varied from 51 to 74 min and the AUC_0–inf values were 6.54 ± 0.46, 8.66 ± 0.59, 9.47 ± 1.45 μg/ml × h, respectively. LO was distributed in tissues and determined within 48 h after administration with maximal accumulation in liver and heart tissues. Mean time to reach the maximum concentration was highest for the liver—9 h, kidney—1 h and 15 min for the tissues of heart, spleen and brain. T_1/2 of LO in tissues ranged from 7.75 ± 0.73 to 26.10 ± 2.60 h. In mice, plasma L-lysine decreased by 79% 15 min after LO administration in dose 1.6 mg/kg. The serum L-lysine levels remained very low from 1 to 9 h (< 25 μM, 17%), indicating an acute lack of L-lysine in animals for at least 9 h. Concentration of L-lysine in serum restored only 24 h after LO administration. The results of LO PK study show that it might be considered as a promising enzyme for further investigation as a potential anticancer agent.

     

Mesenchymal stem cells as tool for antitumor therapy

The development of antitumor preparations with low toxicity and high selectivity of action is one of the top priorities of cancer gene therapy. Mesenchymal stem cells possess natural tropism towards tumors, a property that makes it possible to use them as vehicles for the targeted delivery of therapeutic genes to tumors of various etiologies. At present, genes that encode enzymes (cytosine deaminase, thymidine kinase, carboxyl esterase), cytokines (IL-2, IL-4, IL-12, and IFN-β), and apoptosis inducing factors (TRAIL) are used as therapeutic genes. Mesenchymal stem cells, as demonstrated using experimental models of tumors of various etiologies, as well as animals with metastases in brain and lungs, are able to successfully deliver therapeutic genes into tumors and produce a significant antitumor effect. However, to effectively use this therapeutic strategy in a clinical setting, a number of technical problems must be solved.