Tumor necrosis factor alpha sensitizes low epidermal growth factor receptor (EGFR)-expressing carcinomas for anti-EGFR therapy.
Analysis of 1,060 xenotransplants derived from cancer cell lines as wel as spontaneously occurring tumors from the larynx, pharynx, mammary gland, uterine cervix, and vulva revealed that tumor regression induced by treatment with monoclonal antibodies (EMD 55900 and EMD 72000 against the epidermal growth factor receptor (EGFR) could be enhanced by tumor necrosis factor alpha (TNF-alpha) treatment in vivo. Moreover, tumor that primarily do not respond to antibody treatment can be made suscep tible by additional TNF-alpha treatment. To investigate the in vivo effects of monoclonal antibodies, we treated tumors derived from cell lines (A431 and Detroit 562) as well as spontaneously occurring squamous cell carci nomas and adenocarcinomas (transplanted on NMRI-nu/nu mice) gener ally with EMD 55900 (40 microg/g mouse) and its humanized version EMD 72000 (40 microg/g mouse). When treated with EMD 55900 and EMD 72000 carcinomas with an EGFR concentration of > or = 70 fmol/mg protein showed significant reduction in tumor size compared with untreated controls. The degree of tumor regression correlated with the EGFR concentration of the tumor. In mice treated with TNF-alpha (0.5 microg/g mouse) and EMD 55900 72000 simultaneously, we observed enhanced antitumor effects up to complete tumor eradication. Carcinomas with an EGFR concentration <70 fmol/mg protein could be made susceptible to treatment with EMD 55900 and EMD 72000 by simultaneous treatment with TNF-alpha, resulting in a significant reduction in tumor size.
Hambek
M
M
Department of Otorhinolaryngology School of Medicine, J. W. Goethe University, Frankfurt, Germany.
Solbach
C
C
Schnuerch
H G
HG
Roller
M
M
Stegmueller
M
M
Sterner-Kock
A
A
Kiefer
J
J
Knecht
R
R
D000230:Adenocarcinoma / Q000276:immunology / Q000378:metabolism / Q000628:therapy*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000276:immunology / Q000378:metabolism / Q000628:therapy; D002294:Carcinoma, Squamous Cell / Q000276:immunology / Q000378:metabolism / Q000628:therapy*; D002455:Cell Division / Q000187:drug effects; D004357:Drug Synergism; D066246:ErbB Receptors / Q000096:biosynthesis / Q000276:immunology*; D005260:Female; D006801:Humans; D007822:Laryngeal Neoplasms / Q000276:immunology / Q000378:metabolism / Q000628:therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010610:Pharyngeal Neoplasms / Q000276:immunology / Q000378:metabolism / Q000628:therapy; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D002583:Uterine Cervical Neoplasms / Q000276:immunology / Q000378:metabolism / Q000628:therapy; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; D014409:Tumor Necrosis Factor-alpha; D066246:ErbB Receptors