Biodistribution analysis of cisplatin in liposomal form in animals with cisplatinresistant and cisplatin-sensitive carcinoma

Aim: To analyze the relation between pharmacokinetics of cisplatin in liposomal form and antitumor efficacy toward cisplatinresistant and cisplatin-sensitive variants of Guerin carcinoma. Concentration of platinum was measured by atomic absorption spectrophotometry (С115М1 “Selmi”, Ukraine). Elimination constant was calculated based on the dynamics of cisplatin concentration in time period between 1 h to 24 h using nonlinear regression analysis. Area under curve (AUC24) was calculated by the trapezium method. Results: It was shown that for liposomal form of cisplatin (LCp) AUC24 in tumor practically didn’t depend on the level of the tumor sensitivity, while in animals with the resistant variant (CpRGC), AUC24 for free cisplatin (FCp) decreased by 70% less (p < 0.001) as compared to the sensitive tumor strain (CpSGC). Significant decrease of elimination constant of LCp compared to FCp in blood serum of rats bearing either CpRGC or CpSGC tumors favors cisplatin accumulation in tumor tissues with low vascularization level. The dynamics of cisplatin concentration in CpRGC variant was characterized by 90% higher level in 24 h after administration of LCp as compared to FCp (p < 0.05). This fact may explain increased antitumor efficacy of LCp compared to FCp toward CpRGC variant. In the study of kidney function, AUC24 index for LCp was by 68.6% (p < 0.01) and 50.7% (p < 0.05) lower than AUC24 index for FCp in rats with CpRGC and CpSGC variants, respectively. No significant differences have been found in biodistribution of cisplatin in both pharmaceutical forms in liver and lung in CpRGC-r CpSGC-bearing rats. Conclusion: The results suggest that cisplatin in liposomal form possesses higher specificity of antitumor action than free cisplatin

Alteration in lipid composition of plasma membranes of sensitive and resistant Guerin carcinoma cells due to the action of free and liposomal form of cisplatin

Aim - to study in vivo changes of lipid composition of plasma membranes of sensitive and resistant to cisplatin Guerin carcinoma cells under influence of free and liposomal cisplatin forms. The isolation of plasma membranes from parental (sensitive) and resistant to cisplatin Guerin carcinoma cells was by differential ultracentrifugation in sucrose density gradient. Lipids were detected by method of thin-layer chromatography. It was determined, that more effective action of cisplatin liposomal form on resistant cells is associated with essential abnormalities of conformation of plasma membrane due to change of lipid components and architectonics of rafts. It results in the increase of membrane fluidity. Conclusion: reconstructions in lipid composition of plasma membranes of cisplatin-resistant Guerin carcinoma cells provide more intensive delivery of drug into the cells, increase of its concentration and more effective interaction with cellular structural elements. Key Words: tumor, plasma membranes, lipids, drug resistance, cisplatin liposomal form

Alteration in lipid composition of plasma membranes of sensitive and resistant Guerin carcinoma cells due to the action of free and liposomal form of cisplatin

Aim: To study in vivo changes of lipid composition of plasma membranes of sensitive and resistant to cisplatin Guerin carcinoma cells under influence of free and liposomal cisplatin forms. Materials and Methods: The isolation of plasma membranes from parental (sensitive) and resistant to cisplatin Guerin carcinoma cells was by differential ultracentrifugation in sucrose density gradient. Lipids were detected by method of thin-layer chromatography. Results: It was determined that more effective action of cisplatin liposomal form on resistant cells is associated with essential abnormalities of conformation of plasma membrane due to change of lipid components and architectonics of rafts. It results in the increase of membrane fluidity. Conclusion: Reconstructions in lipid composition of plasma membranes of cisplatin-resistant Guerin carcinoma cells provide more intensive delivery of drug into the cells, increase of its concentration and more effective interaction with cellular structural elements

Global urban environmental change drives adaptation in white clover

Urbanization transforms environments in ways that alter biological evolution. We examined whether urban environmental change drives parallel evolution by sampling 110,019 white clover plants from 6169 populations in 160 cities globally. Plants were assayed for a Mendelian antiherbivore defense that also affects tolerance to abiotic stressors. Urban-rural gradients were associated with the evolution of clines in defense in 47% of cities throughout the world. Variation in the strength of clines was explained by environmental changes in drought stress and vegetation cover that varied among cities. Sequencing 2074 genomes from 26 cities revealed that the evolution of urban-rural clines was best explained by adaptive evolution, but the degree of parallel adaptation varied among cities. Our results demonstrate that urbanization leads to adaptation at a global scale