Cytotoxic Effects of Chemotherapeutic Drugs and Heterocyclic Compounds at Application on the Cells of Primary Culture of Neuroepithelium Tumors

Vladimir      A. Kulchitsky; Vladimir      I. Potkin; Yuri      S. Zubenko; Alexander      N. Chernov; Michael      V. Talabaev; Yuri      E. Demidchik; Sergei      K. Petkevich; Vladimir      V. Kazbanov; Tatiana      A. Gurinovich; Margarita      O. Roeva; Dmitry      G. Grigoriev; Alexei      V. Kletskov; Vladimir      N.Kalunov

doi:10.2174/157340612799278298

Abstract

Neuroepithelial tumor cells were cultured in vitro. The biopsy material was taken from 93 children at removal of the brain tumors during neurosurgical operations. The individual features of the cells sensitivity of primary cultures in respect to protocol-approved chemotherapy drugs and changes in the Interleukin-6 (Il-6) level in the culture medium after the application of chemotherapy were established. The initial level of Il-6 exceeded 600.0 pg/ml in the cultural medium with histologically verified pilomyxoid astrocytoma cells, and ranged from 100.0 to 200.0 pg/ml in the medium at cultivation of ganglioneuroblastoma and pilocytic astrocytoma. A decrease in the Il-6 level in the medium culture of primary tumors cells was observed after the application of chemotherapeutic agents on the cells of pilomyxoid astrocytoma, astrocytomas, and pilocytic desmoplastic/nodular medulloblastoma. The production of Il-6 increased after application of cytostatic drugs on the cells of oligoastrocytomas. A decrease in Il-6 level after application of Cisplatin and Methotrexate and a 5-10 fold increase in the level of Il-6 after application of Etoposide, Carboplatin, Cytarabine, and Gemcitabine were registered in the medium with ganglioneuroblastoma. To improve the cytotoxic action of chemotherapeutic agents, the combined application of cytostatics with heterocyclic compounds was carried out. A computer modeling of ligand-protein complexes of carbamide using the Dock 6.4 and USF Chimera program packages was performed with molecular mechanics method. Special attention was drawn to the ability of several isoxazole heterocycles and isothiazolyl to inhibit the tyrosine kinase. It was proved in vitro that the joint application of chemotherapeutic agents and heterocyclic compounds could reduce the concentration of the cytostatic factor by 10 or more times, having maintained the maximum cytotoxic effect. It was assumed that the target amplification of cytotoxic action of chemotherapeutic agents had prospects for reducing toxic side effects of chemotherapy in vivo, which would be carried out only after the preclinical studies.

Keywords: Biopsy, cytostatic, glioma, heterocycles, Interleukin-6, primary cell culture, pilomyxoid astrocytoma, astrocytomas, pilocytic desmoplastic, nodular medulloblastoma