Animal Model of Drug‐Resistant Tumor Progression

Abstract

Experimental animal model of tumor progression based on mice lymphosarcoma (LS) and resistant lymphosarcoma (RLS) has been developed. LS tumor displays high sensitivity to cyclophosphamide, which is widely used in anticancer therapy. RLS tumor was derived from LS by passaging in mice receiving low concentration of cyclophosphamide (20 mg/kg) and display resistance to cyclophosphamide (up to dose 150 mg/kg). The primary cultures of LS and RLS tumors display different expression levels of the genes related to apoptosis and multiple drug-resistant phenotype: in RLS tumor high levels of mdr1b and bcl-2 genes and low level of p53 gene expression were found. A total of 10% of cells in RLS primary culture display multiple drug-resistant phenotype and survive even at high dose of cytostatics. Cultivation of RLS primary culture in the presence of increasing vinblastine concentrations gives RLS(40) cell culture, which exhibits high levels of mdr1a/1b genes expression as compared to RLS and 20-fold increase of resistance to cytostatics. Drug-resistant RLS(40) cells were transplanted into CBA mice and sensitivity of the tumors to anticancer drugs was tested. RLS(40) tumors were resistant to a number of cytostatics used in anticancer therapy (cyclophosphamide, cysplatin, vinblastine, rubomycinum). Thus, RLS(40) tumor can be used as model, which corresponds to tumor status observed in patients after one or several courses of chemotherapy and can be useful for testing conventional therapy alone or together with newly developed gene-targeted therapeutics.