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.

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

AIM: To analyze the relation between pharmacokinetics of cisplatin in liposomal form and antitumor efficacy toward cisplatin-resistant and cisplatin-sensitive variants of Guerin carcinoma. METHODS: Concentration of platinum was measured by atomic absorption spectrophotometry (C115M1 "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- or CpSGC-bearing rats. CONCLUSION: The results suggest that cisplatin in liposomal form possesses higher specificity of antitumor action than free cisplatin.

Relation between pathomorphological response in tumors after neoadjuvant chemotherapy and clinico-morphological and molecular prognostic factors in patients with breast cancer.

AIM: To determine the correlation between tumor pathomorphological response (PMR) after neoadjuvant chemotherapy (NACT) and clinico-morphological and molecular prognostic factors in patients with breast cancer (BC), and to determine the possible impact of the PMR and estrogen receptors (ER), progesterone receptors (PR) and Her-2/neu BC status on the disease course. METHODS: The data from the medical history of patients on IIB stage (T2N1M0, T3N0M0) (n = 247), who received treatment with NACT, were used. The correlation between the parameters was determined using the Spearman's coefficient. Patient's survival was analyzed by Kaplan - Meier method. The association between PMR grades with the risk of disease relapse was estimated by Cox's regression analysis. RESULTS: PMR grade correlated with tumor differentiation grade (rho = 0.38; p 0.05) and BC subtypes (rho = 0.05; p > 0.05). The patients with the same PMR grades didn't differ by the number of lymph node metastases (p > 0.05) and differed by the presence of embolus in tumor vessels (p 0.05). The risk of disease relapse depended on PMR grade: for grade 2-3 it was significantly decreased (HR = 0.71, 95% CI - 0.25-2.9, p = 0.0037), and for grade 4-5 it was the highest (HR = -1.23, 95% CI - 0.24-5.05, P = 0.0001), while 0-1 grade had no impact on the risk of disease relapse (HR = 0.22, 95% CI 0.08-0.38; p = 0.7). CONCLUSION: The data of combined clinical, histological and immunohistochemical analysis have shown that PMR grades may serve as the criteria for individualization of adjuvant treatment of the patients with locally advanced BC.