title: Prodrug chemotherapeutics bypass p-glycoprotein resistance and kill tumors in vivo with high efficacy and target-dependent selectivity.
abstract: Doxorubicin intercalates into DNA, causes double-strand breaks, and leads to apoptotic death. Limitations to the efficacy and therapeutic index of doxorubicin include poor tumor selectivity, high systemic toxicity, and the development of resistance, especially p-glycoprotein (p-gp)-mediated. We chemically coupled doxorubicin to a monoclonal antibody directed to the insulin-like growth factor-1 receptor, a receptor highly overexpressed in most tumors and validated as a tumor target. The prodrug conjugate bounded to tumor cells selectively, and accumulated efficiently and only in receptor-expressing cells. The conjugate was processed to release free doxorubicin inside target cells leading to selective toxicity, had >200-fold improved therapeutic index, and in vivo reduced tumor load with no systemic toxicity. Importantly, the prodrug conjugate is not subject to p-gp efflux and can bypass resistance in vivo. Our studies define a strategy to develop improved and more selective anticancer agents.
authors.affiliation: Department of Pharmacology and Therapeutics, McGill University, 3655 Drummond Ave., 1320 Montréal, QC, Canada H3G 1Y6.
authors.forename: Veronique
authors.initials: V
authors.lastname: Guillemard
authors.forename: H
authors.initials: H
authors.lastname: Uri Saragovi
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000818:Animals; D000906:Antibodies / Q000276:immunology / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000493:pharmacokinetics / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D000922:Immunotoxins / Q000276:immunology / Q000493:pharmacokinetics / Q000494:pharmacology; D051379:Mice; D008819:Mice, Nude; D011355:Prodrugs / Q000494:pharmacology*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000906:Antibodies; D000970:Antineoplastic Agents; D000922:Immunotoxins; D011355:Prodrugs; D004317:Doxorubicin