title: Cell surface density of p185(c-erbB-2) determines susceptibility to anti-p185(c-erbB-2)-ricin A chain (RTA) immunotoxin therapy alone and in combination with anti-p170(EGFR)-RTA in ovarian cancer cells.
abstract: Approximately 30% of ovarian and breast cancers overexpress p185(c-erbB-2) with as many as 10(6) receptors/cell. Normal cells have as few as 10(4) receptors/cell. We have examined the susceptibility of SKOv3 human ovarian cancer cells to anti-c-erbB2 antibodies and immunotoxins as a function of c-erbB-2 density on the cell surface. A panel of SKOv3 clones that expressed different densities of p185(c-erbB-2) receptor were generated through transfection with the c-erbB-2 gene. A significant correlation was found between p185(c-erbB-2) density and susceptibility to killing by anti-p185(c-erbB-2)-ricin A chain (anti-p185(c-erbB-2)-RTA) immunotoxins. With 10(5) copies/cell of p185(c-erbB-2), <10% of clonogenic ovarian cancer cells could be eliminated, whereas in clones that expressed 10(6) copies/cell of p185(c-erbB-2), 99.9% of clonogenic tumor cells were killed. In cell lines that overexpressed p185(c-erbB-2) and also expressed p170(EGFR), anti-p185(cerbB-2)-RTA and anti-p170(EGFR)-RTA immunotoxins exerted synergistic cytotoxicity. Treatment with the two immunotoxins could eliminate 99.99% of clonogenic cells. Importantly, tumor cells that had survived first treatment with anti-p185(c-erbB2)-RTA alone still retained sensitivity to repeat treatment with the same immunotoxin and also proved susceptible to the synergistic cytotoxicity of anti-p185(cerbB-2)-RTA in combination with anti-p170(EGFR)-RTA. Growth characteristics of the clones expressing various levels of p185(c-erbB-2) were also studied. No correlation was found between p185(c-erbB-2) expression levels and the rate of anchorage-dependent growth, anchorage-independent growth, or in vivo growth in nude mice.
authors.affiliation: Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710, USA.
authors.forename: G S
authors.initials: GS
authors.lastname: Dean
authors.forename: L
authors.initials: L
authors.lastname: Pusztai
authors.forename: F J
authors.initials: FJ
authors.lastname: Xu
authors.forename: K
authors.initials: K
authors.lastname: O'Briant
authors.forename: K
authors.initials: K
authors.lastname: DeSombre
authors.forename: M
authors.initials: M
authors.lastname: Conaway
authors.forename: C M
authors.initials: CM
authors.lastname: Boyer
authors.forename: J
authors.initials: J
authors.lastname: Mendelsohn
authors.forename: R C
authors.initials: RC
authors.lastname: Bast
mesh_terms: D000818:Animals; D004357:Drug Synergism; D066246:ErbB Receptors / Q000032:analysis* / Q000276:immunology; D005260:Female; D006801:Humans; D000922:Immunotoxins / Q000627:therapeutic use*; D051379:Mice; D010051:Ovarian Neoplasms / Q000628:therapy*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis* / Q000276:immunology; D012276:Ricin / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured
chemical_list: D066246:ErbB Receptors; D000922:Immunotoxins; D018719:Erb-b2 Receptor Tyrosine Kinases; D012276:Ricin