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  • Title: Overcoming multidrug resistance in human carcinoma cells by an antisense oligodeoxynucleotide--doxorubicin conjugate in vitro and in vivo.
    Author: Ren Y, Wang Y, Zhang Y, Wei D.
    Journal: Mol Pharm; 2008; 5(4):579-87. PubMed ID: 18461970.
    Abstract:
    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.
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