The siRNA targeted to mdr1b and mdr1a mRNAs in vivo sensitizes murine lymphosarcoma to chemotherapy.
BACKGROUND
One of the main obstacles for successful cancer polychemotherapy is multiple drug resistance phenotype (MDR) acquired by tumor cells. Currently, RNA interference represents a perspective strategy to overcome MDR via silencing the genes involved in development of this deleterious phenotype (genes of ABC transporters, antiapoptotic genes, etc.).


METHODS
In this study, we used the siRNAs targeted to mdr1b, mdr1a, and bcl-2 mRNAs to reverse the MDR of tumors and increase tumor sensitivity to chemotherapeutics. The therapy consisting in ex vivo or in vivo application of mdr1b/1a siRNA followed by cyclophosphamide administration was studied in the mice bearing RLS40 lymphosarcoma, displaying high resistance to a wide range of cytostatics.


RESULTS
Our data show that a single application of mdr1b/1a siRNA followed by treatment with conventionally used cytostatics results in more than threefold decrease in tumor size as compared with the control animals receiving only cytostatics.


CONCLUSIONS
In perspective, mdr1b/1a siRNA may become a well-reasoned adjuvant tool in the therapy of MDR malignancies.
Patutina
Olga A
OA
Institute of Chemical Biology and Fundamental Medicine, Siberian Branch, Russian Academy of Sciences, Lavrentiev av, 8, Novosibirsk, 630090 Russia.
Mironova
Nadezda L
NL
Popova
Nelly A
NA
Kaledin
Vasily I
VI
Nikolin
Valery P
VP
Vlassov
Valentin V
VV
Zenkova
Marina A
MA
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics*; D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D003520:Cyclophosphamide / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D015316:Genetic Therapy / Q000379:methods*; D005838:Genotype; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D008297:Male; D051379:Mice; D008808:Mice, Inbred CBA; D010641:Phenotype; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism*; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden; D014407:Tumor Cells, Cultured; D000097202:ATP-Binding Cassette Sub-Family B Member 4
D018435:ATP Binding Cassette Transporter, Subfamily B; D018906:Antineoplastic Agents, Alkylating; D003520:Cyclophosphamide; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D000097202:ATP-Binding Cassette Sub-Family B Member 4; C095122:multidrug resistance protein 3
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