Antitumor efficacy of trastuzumab in nude mice orthotopically xenografted with human pancreatic tumor cells expressing low levels of HER-2/neu.
The monoclonal antibody trastuzumab binds to the extracellular domain of HER-2/neu and induces clinical responses in breast tumors with HER-2 gene amplification and/or protein overexpression. Its role in other tumor types remains to be investigated. We evaluated the antitumor efficacy of trastuzumab in vitro and in nude mice implanted orthotopically with cells of 3 human pancreatic tumor lines expressing only low levels of HER-2/neu, as determined by flow cytometry. Although none of the 3 cell lines showed growth inhibition when cultured directly with trastuzumab, 2 of them, GER and PaCa3, were sensitive to lysis in antibody-dependent cellular cytotoxicity assay. This pattern of response was recapitulated in tumor-bearing mice repeatedly treated with trastuzumab, in which survival was significantly prolonged as compared with controls (P=0.03 for GER and 0.0008 for PaCa3). Incidence of metastases was also reduced, especially in liver. These preclinical results indicate that trastuzumab can exert an antitumor effect against orthotopic human pancreatic cancer xenografts with low-level HER-2/neu expression and that this effect correlates with the in vitro antibody-dependent cellular cytotoxicity susceptibility, suggesting a different role for HER-2/neu in the therapy of tumor types other than breast cancer.
Pratesi
Graziella
G
Preclinical Chemotherapy and Pharmacology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, Milan, Italy. graziella.pratesi@istitutotumori.it
Petrangolini
Giovanna
G
Tortoreto
Monica
M
Addis
Alessandro
A
Zunino
Franco
F
Calcaterra
Claudia
C
Merlo
Andrea
A
Tagliabue
Elda
E
Menard
Sylvie
S
Balsari
Andrea
A
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000920:Antibody-Dependent Cell Cytotoxicity; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D010190:Pancreatic Neoplasms / Q000737:chemistry / Q000188:drug therapy* / Q000473:pathology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis*; D000068878:Trastuzumab; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C508053:ERBB2 protein, human