Neutralization of complement regulatory proteins CD55 and CD59 augments therapeutic effect of herceptin against lung carcinoma cells.
Human monoclonal anti-Her2/neu antibody (herceptin, also named trastuzumab) failed in the treatment of lung cancer when in combination with two chemotherapy agents gemcitabine and cisplatin, despite of its clinical benefit in women with Her2 positive breast cancer. The capacity of herceptin to activate human complement and complement-dependent cytotoxicity against tumor cells was investigated in a study of tumor immunotherapy. We found that the expression of membrane complement regulatory proteins (mCRPs), CD55 and CD59 on non-small cell lung cancer (NSCLC) cells was closely correlated with histological types, prognosis and preoperational adjutant chemotherapy of the disease. Herceptin-mediated complement cytotoxicity to two human lung carcinoma cell lines exerted stronger killing effect on tumor cells after the neutralization of mCPRs via their antibodies. Furthermore, treatment of herceptin combined with chemo-agents had advantages over chemotherapy alone, while CD55 and CD59 expression levels both declined remarkably in A549 and H157 cell lines after incubation with IC50 cisplatin for 72 h. Our data indicated that overexpression of mCRPs on tumor cells contributes to herceptin's acquisition of resistance to NSCLC, and its anticancer efficacy was enhanced when mCRPs were neutralized or cisplatin could be used to down-regulate their expression.
Zhao
Wei-Peng
WP
Cancer Institute of People's Liberation Army (PLA), Xinqiao Hospital, Third Military Medical University, Chongqing 400037, P.R. China.
Zhu
Bo
B
Duan
Yu-Zhong
YZ
Chen
Zheng-Tang
ZT
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology / Q000601:surgery; D000368:Aged; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D018958:CD55 Antigens / Q000276:immunology*; D018957:CD59 Antigens / Q000276:immunology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology / Q000601:surgery; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology / Q000601:surgery; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D003167:Complement Activation / Q000187:drug effects*; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology / Q000601:surgery; D008297:Male; D008875:Middle Aged; D013997:Time Factors; D000068878:Trastuzumab; D019139:Tumor Escape / Q000187:drug effects
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D018958:CD55 Antigens; D018957:CD59 Antigens; C051590:CD59 protein, human; D000068878:Trastuzumab; D002945:Cisplatin