Enhanced anti-tumor effect of trastuzumab in combination with cisplatin.
The oncogenenic transmembrane tyrosine kinase receptor HER-2/neu is a promising target for treatment of HER-2-overexpressing cancers. The humanized anti-HER-2/neu antibody Trastuzumab is under clinical evaluation in combination with chemotherapy against breast cancer. The combination of Trastuzumab and cisplatin is expected to be active against HER-2 / neu-expressing tumors. We examined the mechanisms of this combination effect against human solid tumor cells in the presence of human peripheral blood mononuclear cells (PBMCs) using an in vitro MTT assay. The growth-inhibitory effects of cisplatin (CDDP) on the tumor cells were not significantly affected by Trastuzumab in the absence of effector cells. CDDP alone at a dose of less than 12.5 mM did not affect the viability of PBMCs, as determined by MTT assay, suggesting that PBMCs could exert antibody-dependent cell-mediated cytotoxicity (ADCC) at this CDDP concentration. The combination of Trastuzumab and CDDP showed higher cytotoxic effects against the tumor cells in the presence of PBMCs. The CDDP concentration required to inhibit tumor cell growth by 50% was reduced to approximately 20% by Trastuzumab in the presence of PBMCs at an effector/target ratio of 10. It may be important to select combined chemotherapeutic agents which do not diminish the ADCC activity of Trastuzumab via PBMCs. Both the expression of HER-2 / neu and the ADCC activity may be important determinants of the therapeutic benefit of the Trastuzumab/CDDP combination.
Naruse
Ichiro
I
Pharmacology Division, National Cancer Center Research Institute, Chuo-ku, Tokyo 104-0045.
Fukumoto
Hisao
H
Saijo
Nagahiro
N
Nishio
Kazuto
K
D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002945:Cisplatin / Q000008:administration & dosage* / Q000494:pharmacology; D004396:Coloring Agents / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006801:Humans; D020128:Inhibitory Concentration 50; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D013778:Tetrazolium Salts / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D013997:Time Factors; D000068878:Trastuzumab; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D004396:Coloring Agents; D013778:Tetrazolium Salts; D013844:Thiazoles; C022616:thiazolyl blue; D000068878:Trastuzumab; D002945:Cisplatin