title: Inhibiting tumor growth by targeting tumor vasculature with galectin-1 antagonist anginex conjugated to the cytotoxic acylfulvene, 6-hydroxylpropylacylfulvene.
abstract: Targeted delivery of therapeutic drugs promises to become the norm to treat cancer. Here, we conjugated the cytotoxic agent 6-hydroxypropylacylfulvene (HPAF) to anginex, a peptide that targets galectin-1, which is highly expressed in endothelial cells of tumor vessels. In a human ovarian cancer model in mice, the conjugate inhibited tumor growth better than equivalent doses of either compound alone. Immunofluorescence on tumor tissue demonstrated that the conjugate, like parent anginex, selectively targeted tumor vasculature and inhibited tumor angiogenesis. Increased activity from the conjugate further suggests that HPAF retains at least some of its normal cytotoxic activity when linked to anginex. More importantly perhaps is the observation that the conjugate abrogates apparent systemic toxicity from treatment with HPAF. This work contributes to the development of tumor vascular targeting agents against cancer in the clinic.
authors.affiliation: Department of Biochemistry, University of Minnesota, Minnesota, USA.
authors.forename: Ruud P M
authors.initials: RP
authors.lastname: Dings
authors.forename: Emily S
authors.initials: ES
authors.lastname: Van Laar
authors.forename: Melissa
authors.initials: M
authors.lastname: Loren
authors.forename: Jeremy
authors.initials: J
authors.lastname: Webber
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Waters
authors.forename: John R
authors.initials: JR
authors.lastname: Macdonald
authors.forename: Kevin H
authors.initials: KH
authors.lastname: Mayo
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002455:Cell Division / Q000187:drug effects; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects; D037483:Galectin 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D009369:Neoplasms / Q000098:blood supply* / Q000188:drug therapy / Q000473:pathology*; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D010455:Peptides; D011506:Proteins / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D012717:Sesquiterpenes / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D013141:Spiro Compounds / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D014407:Tumor Cells, Cultured; D014471:Umbilical Veins / Q000166:cytology
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D037483:Galectin 1; D010455:Peptides; D011506:Proteins; D012717:Sesquiterpenes; D013141:Spiro Compounds; C079422:acylfulvene; C111993:betapep-25 protein, synthetic