Identification of a small topoisomerase I-binding peptide that has synergistic antitumor activity with 9-aminocamptothecin.
The topoisomerase I (top1)-targeted camptothecin class of anticancer drugs is important in the treatment of several types of cancers. This class of drug inhibits the top1 enzyme during its catalytic DNA relaxation cycle, stabilizing the transient covalent top1-DNA complex by simultaneous noncovalent interactions with DNA and top1. We examined top1 using phage display because of the significance of this known top1-directed drug action. Several peptides that bind top1 were discovered and these were examined for top1 affinity, top1 catalytic and cleavage complex effects, and cytotoxic effects in cultured cell lines and in an in vivo tumor model. Although several peptides exhibited nanomolar and low-micromolar affinity for top1, none had cytotoxic effects when administered alone. However, in combination with 9-aminocamptothecin, one 15-mer peptide (SAYAATVRGPLSSAS) had synergistic cytotoxic effects with 9-aminocamptothecin both in the cytotoxicity assay and in nude mouse xenograft human tumor models. This report details the investigation of this peptide.
Department of Pharmacology and Toxicology, University of Utah, 30 South 2000 East Room 201, Salt Lake City, UT 84112, USA.
Christopher D
CD
Pond
Kathryn M
KM
Marshall
Louis R
LR
Barrows
D000595:Amino Acid Sequence; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000627:therapeutic use; D004247:DNA / Q000737:chemistry / Q000187:drug effects; D004264:DNA Topoisomerases, Type I / Q000737:chemistry; D004357:Drug Synergism; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D009841:Oligonucleotides / Q000737:chemistry / Q000302:isolation & purification / Q000627:therapeutic use; D019151:Peptide Library; D010455:Peptides / Q000737:chemistry / Q000302:isolation & purification / Q000627:therapeutic use*; D059004:Topoisomerase I Inhibitors; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D009841:Oligonucleotides; D019151:Peptide Library; D010455:Peptides; C510479:T1BP2 peptide; D059004:Topoisomerase I Inhibitors; C080125:9-aminocamptothecin; D004247:DNA; D004264:DNA Topoisomerases, Type I; D002166:Camptothecin