Effect of MDR1 phosphorothioate antisense oligodeoxynucleotides in multidrug-resistant human tumor cell lines and xenografts.
The effect of MDR1 antisense phosphorothiate oligodeoxynucleotides (S-ODNs) on resistant phenotype was investigated in multidrug-resistant human colon carcinoma and breast carcinoma cells in vitro and in vivo. Drug resistance in human colon carcinoma (SW620 Ad300) and breast carcinoma (MCF-7/INT500, MCF-7/AD150 and MCF-7/TH) cell lines is predominantly due to overexpression of P-glycoprotein (P-gp) resulting in decreased daunorubicin (DNR) accumulation. Two MDR1 antisense S-ODNs, one complementary to the initial 15 bases of first exon (S-ODN I) and the other a loop forming sequence (S-ODN II) complementary to bases from 993-1007 of MDR1 gene, were tested for enhancing the doxorubicin (DOX) cytotoxicity in vitro and the efficiency of chemotherapy in human tumor xenografts. MDR1 antisense S-ODN I reduced the DOX IC50 value 9-fold in multidrug-resistant SW620 Ad300 human colon carcinoma cells and 7 to 10-fold in breast carcinoma cells in vitro. The increase in DOX cytotoxicity correlated with a significant reduction of MDR1 mRNA in antisense S-ODN I-treated SW620 Ad300 cells. Even though the P-gp level was reduced at the end of the third day in antisense S-ODN I-treated cells, the rate of reduction was only partial compared to mRNA. The combination treatment of MDR1 antisense S-ODN I or II for three days and DOX for four days significantly controlled tumor growth rate in human tumors developed in nude mice. Our results suggest that MDR1 antisense S-ODN treatment can increase the efficiency of chemotherapy by suppressing gene expression and resistant phenotype.
Ramachandran
Cheppail
C
Department of Radiation Oncology, University of Miami School of Medicine, Research Institute, Miami, Children's Hospital, Miami, FL, USA. cheppail.ramachandran@mch.com
Wellham
Larry L
LL
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects / Q000235:genetics; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004317:Doxorubicin / Q000494:pharmacology*; D018432:Drug Resistance, Multiple; D004357:Drug Synergism; D019450:Genes, MDR / Q000235:genetics*; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D016376:Oligonucleotides, Antisense / Q000235:genetics / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D004317:Doxorubicin