%0 Journal Article
%T The Toxic Effects of Polychemotherapy onto the Liver Are Accelerated by the Upregulated MDR of Lymphosarcoma
%A Alexandra V. Sen'kova
%A Nadezhda L. Mironova
%A Olga A. Patutina
%A Tatyana A. Ageeva
%A Marina A. Zenkova
%J ISRN Oncology
%D 2012
%R 10.5402/2012/721612
%X Antitumor therapy of hematological malignancies is impeded due to the high toxicity of polychemotherapy toward liver and increasing multiple drug resistance (MDR) of tumor cells under the pressure of polychemotherapy. These two problems can augment each other and significantly reduce the efficiency of antineoplastic therapy. We studied the combined effect of polychemotherapy and upregulated MDR of lymphosarcoma RLS40 onto the liver of experimental mice using two treatment schemes. Scheme 1 is artificial: the tumor was subjected to four courses of polychemotherapy while the liver of the tumor-bearing mice was exposed to only one. This was achieved by threefold tumor retransplantation taken from animals subjected to chemotherapy into intact animals. Scheme 2 displays Ħ°real-lifeĦħ status of patients with MDR malignancies: both the tumor and the liver of tumor-bearing mice were subjected to three sequential courses of polychemotherapy. Our data show that the strengthening of MDR phenotype of RLS40 under polychemotherapy and toxic pressure of polychemotherapy itself has a synergistic damaging effect on the liver that is expressed in the accumulation of destructive changes in the liver tissue, the reduction of the regeneration capacity of the liver, and increasing of Pgp expression on the surface of hepatocytes. 1. Introduction Despite the significant progress in the therapy of hematological malignancies there are several problems that impede the use of the polychemotherapy for treatment of this group of diseases. The first one is the high intrinsic toxicity of multiple chemotherapies [1, 2] that may lead to the multiple-organ failure in particular liver dysfunction. The next is the strengthening of multidrug resistance (MDR) of tumor cells by cytostatic agents that are often characterized by the MDR phenotype even at baseline [3¨C5]. These two problems can augment each other and can significantly reduce the efficiency of antineoplastic therapy. The resistance of tumor cells to chemotherapy can be a result of various processes: from active ATP-dependent transport of cytotoxic agents out of the cells executed by P-glycoprotein, the member of subfamily B of ABC-transporters [6, 7], to disorders in the apoptosis, mutations or downregulation of p53 gene, impairing its proapoptotic function, and/or overexpression of bcl-2 gene causing insensitivity of cells to proapoptotic stimuli [8¨C10]. Studies of pharmacokinetics of antitumor drugs suggest that they undergo biotransformation in the liver with the formation of toxic metabolites, which may cause hepatocyte damage
%U http://www.hindawi.com/journals/isrn.oncology/2012/721612/