Visit our Expo - Redox and Inflammation signaling 2012

Session XVII : Cell signaling in health and disease Poster XVII, 60
Animal model of tumor progression: a study of combined therapy to overcome the
multiple drug resistance syndromes of malignant cells
Marina Zenkova, Nadezda Mironova, Olga Shklyaeva, Ekaterina Andreeva, and
Valentin Vlassov
Institute of Chemical Biology and Fundamental Medicine SB RAS
8, Lavrentiev ave., 630090, Novisibirsk, Russian Federation E-mail:
marzen@niboch.nsc.ru
In this work we developed experimental animal model of tumor progression on the base of
mice lymphosarcomas LS and RLS. LS tumor displays high sensitivity to cyclophosphamide,
which is widely used in anticancer therapy to initiate apoptosis. RLS was derived from LS by
passaging at low concentration of cyclophosphamide in mice (10-20 mg/kg) and characterized
by resistance to high dose of cyclophosphamide (50-150 mg/kg).
The primary cultures (LS and RLS)) of these tumors were obtained and characterized by
differences in expression of the genes involved in formation of multiple drug resistant
phenotype. We show that RLS tumors are characterized by high level of mdr1b and bcl-2
genes expression as compared with LS and low level of p53 gene expression. The study of
RLS sensitivity to cytostatics revealed that about 10% of cells display MDR phenotype and
survive even at high dose of cytostatics. By cultivation of RLS on medium with increasing
vinblastine concentrations cell line RLS40 was obtained. RLS40 exhibited high levels of
mdr1a/1b genes expression as compared to RLS and 20-folds increase of resistance to
cytostatics. Drug resistant RLS40 cells were transplanted into CBA mice and sensitivity of
formed tumors (solid and ascetic) to anticancer drugs was tested. We show that RLS40
tumors were resistant to a number of cytostatics usually used in standard protocols of
antitumor therapy (cyclophosphamide, cysplatine, adriamicine, rubomicine and TNF): these
therapeutics have no effect on tumor growth. Thus, RLS40 tumor can be used as an animal
model of tumors which display high drug resistance and poor prognosis of treatment. This
model corresponds to tumor status observed in patients after one or several courses of
chemotherapy and can be used for testing combined conventional therapy and/or developing
gene-targeted therapeutics (siRNAs, antisense oligonucleotides, ribozymes) affecting
expression of mdr1a/1b and bcl-2 genes.
This work was supported by RAS programs Molecular and cellular biology and Science to
medicine, FCNTP grant RI-012/001/254.
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