A specific vascular endothelial growth factor receptor tyrosine kinase inhibitor enhances the antiproliferative effect of trastuzumab in human epidermal growth factor receptor 2 overexpressing breast cancer cell lines.
BACKGROUND
Trastuzumab has been found to have potent antiproliferative effects in human epidermal growth factor receptor 2 (HER-2)-overexpressing human breast tumors. Inhibition of vascular endothelial growth factor receptor (VEGFR), a protein often overexpressed in breast carcinoma, has been shown to induce apoptosis.


METHODS
Breast carcinoma cell lines were cultured with increasing doses of trastuzumab and/or a VEGFR tyrosine kinase inhibitor (TKI). Growth inhibition and apoptosis were assessed after 5 days and 48 hours of treatment, respectively. Combination index values were calculated to determine the effectiveness of this drug combination.


RESULTS
A dose-dependent growth inhibition was shown in all cell lines tested with the VEGFR TKI, whereas trastuzumab was effective only in the HER-2-positive cells. A synergistic interaction was shown in the HER-2-overexpressing cell lines, accompanied by an increase in apoptosis.


CONCLUSIONS
The combination of trastuzumab and a VEGFR TKI may be of therapeutic value in select breast cancer patients.
Kim
Elizabeth M H
EM
Department of Surgery, Providence Hospital and Medical Centers, Southfield, MI 48075, USA. drlizkim@hotmail.com
Lobocki
Catherine
C
Dubay
Linda
L
Mittal
Vijay K
VK
D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005260:Female; D006801:Humans; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors; D000068878:Trastuzumab
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D018719:Erb-b2 Receptor Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor; D000068878:Trastuzumab