Overcoming multidrug resistance in human carcinoma cells by an antisense oligodeoxynucleotide--doxorubicin conjugate in vitro and in vivo.
Multidrug resistance (MDR), a major obstacle to successful cancer chemotherapy, may be induced by amplification of the MDR1 gene and overexpression of the P-glycoprotein (P-gp), which acts as drug efflux pump decreasing intracellular drug accumulation. In this study, an antisense oligodeoxynucleotide--doxorubicin conjugate was used to overcome MDR in a human carcinoma-resistant cell line, both in vitro and in vivo, through downregulation of P-gp expression and mRNA levels. Compared with the unmodified antisense-oligodeoxynucleotide (AS-ODN), the conjugate markedly inhibited P-gp expression and mRNA levels. With in vitro treatment with the conjugate, the intracellular accumulation of doxorubicin (DOX) was increased 4.4-fold compared to treatment with DOX alone; by contrast, a 2.2-fold increase was observed when treated with AS-ODN alone. In the in vivo studies, it was approximately 3.5-fold higher compared to the control group treatment with DOX alone and 2.1-fold higher than found with AS-ODN. The weight of tumors formed was markedly decreased after conjugate treatment as compared to either treatments with AS-ODN or DOX alone. Furthermore, treatment with combinations of the agents appeared to be well tolerated. These results suggest that a strategy using the conjugate in combination with antitumor drugs may comprise a powerful treatment for MDR.
Ren
Yuhong
Y
State Key Laboratory of Bioreactor Engineering, Institute of Biochemistry, East China University of Science and Technology, Shanghai, China. yhren@ecust.edu.cn
Wang
Yong
Y
Zhang
Yufei
Y
Wei
Dongzhi
D
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D002277:Carcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000737:chemistry* / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D020319:Oligodeoxyribonucleotides, Antisense / Q000737:chemistry*; D012333:RNA, Messenger / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D020319:Oligodeoxyribonucleotides, Antisense; D012333:RNA, Messenger; D004317:Doxorubicin