Combining doxorubicin and liposomal anti-HER-2/NEU antisense oligodeoxynucleotides to treat HER-2/NEU-expressing MDA-MB-435 breast tumor model.
This study assessed the in vivo therapeutic activity of an antisense molecule targeted against HER-2/neu expressing mRNA. Antisense activity was evaluated in female SCID/Rag2m mice bearing subcutaneous tumors derived from HER-2/neu-transfected MDA-MB-435 (MDA-MB-435(HER2)) cells, a transfected line derived from the human breast cancer MDA-MB-435 cell line. Animals were treated with free or liposome-encapsulated antisense. The area under the curve (AUC(0-24h)) of the liposomal formulated antisense was demonstrated to be more than 30-fold greater than that of free antisense following intravenous administration. Efficacy was determined by assessing changes in tumor growth rate as well as by an immunohistological end-point evaluating HER-2/neu expression. HER-2/neu protein expression was reduced in mice bearing HER-2/neu-transfected MDA-MB-435 tumors when treated with liposomal antisense. However, tumors in these mice grew at a faster rate than the control, a result that was interpreted to be a consequence of selection of a more rapidly proliferating HER-2/neu-negative subpopulation of cells. Effective control of the MDA-MB-435(HER2) tumors was achieved when antisense treatment was combined with doxorubicin. Tumors derived from animals treated with the combination of doxorubicin and the liposomal antisense against HER-2/neu exhibited no detectable levels of HER-2/neu expression. Antisense targeted against HER-2/neu mRNA was effective in reducing or eliminating HER-2/neu protein expression, and when combined wtih doxorubicin treatment was efficacious in the treatment of mice bearing HER-2/neu-overexpressing human xenograft tumors.
Waterhouse
Dawn N
DN
British Columbia Cancer Research Centre, Department of Advanced Therapeutics, Vancouver, Canada. dwater@bccancer.bc.ca
Gelmon
Karen A
KA
Masin
Dana
D
Bally
Marcel B
MB
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use*; D019540:Area Under Curve; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology; D004195:Disease Models, Animal; D015536:Down-Regulation; D004317:Doxorubicin / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D008081:Liposomes; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D009687:Nuclear Proteins; D016376:Oligonucleotides, Antisense / Q000627:therapeutic use*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D014407:Tumor Cells, Cultured
D000903:Antibiotics, Antineoplastic; D004268:DNA-Binding Proteins; D004317:Doxorubicin; D008081:Liposomes; D009687:Nuclear Proteins; D016376:Oligonucleotides, Antisense; D018719:Erb-b2 Receptor Tyrosine Kinases; C499311:RAG2 protein, human; C499308:Rag2 protein, mouse; C064655:V(D)J recombination activating protein 2