Antitumor efficacy of cytotoxic drugs and the monoclonal antibody 806 is enhanced by the EGF receptor inhibitor AG1478 Journal Article
| Authors: | Johns, T. G.; Luwor, R. B.; Murone, C.; Walker, F.; Weinstock, J.; Vitali, A. A.; Perera, R. M.; Jungbluth, A. A.; Stockert, E.; Old, L. J.; Nice, E. C.; Burgess, A. W.; Scott, A. M. |
| Article Title: | Antitumor efficacy of cytotoxic drugs and the monoclonal antibody 806 is enhanced by the EGF receptor inhibitor AG1478 |
| Abstract: | Blockade of epidermal growth factor receptor (EGFR) signaling with specific inhibitors of the EGFR tyrosine kinase retards cellular proliferation and arrests the growth of tumor xenografts. AG1478, an inhibitor of the EGFR tyrosine kinase, is used in laboratory studies; however, its therapeutic potential has not been elucidated. Therefore, we evaluated an aqueous form of AG1478 for its antitumor activity in mice bearing human xenografts expressing the WT EGFR or a naturally occurring ligand-independent truncation of the EGFR [delta2-7 (de2-7) EGFR or EGFRvIII]. Parenteral administration of soluble AG1478 blocked phosphorylation of the EGFR at the tumor site and inhibited the growth of A431 xenografts that overexpress the WT EGFR and glioma xenografts expressing the de2-7 EGFR. Strikingly, even subtherapeutic doses of AG1478 significantly enhanced the efficacy of cytotoxic drugs, with the combination of AG1478 and temozolomide displaying synergistic antitumor activity against human glioma xenografts. AG1478 was also examined in combination with mAb 806, an anti-EGFR antibody that was raised against the de2-7 EGFR but unexpectedly also binds a subset of the EGFR expressed in cells exhibiting amplification of the EGFR gene. The combination of AG1478 and mAb 806 displayed additive, and in some cases synergistic, antitumor activity against tumor xenografts overexpressing the EGFR. Here, we demonstrate that different classes of inhibitors to the EGFR can have synergistic antitumor activity in vivo. These results establish the antitumor efficacy of the EGFR inhibitor AG1478 and provide a rationale for its clinical evaluation in combination with both chemotherapy and other EGFR therapeutics. |
| Keywords: | signal transduction; controlled study; protein expression; unclassified drug; human cell; carcinoma, squamous cell; cytotoxic agent; cancer combination chemotherapy; cancer growth; dose response; drug efficacy; drug potentiation; antineoplastic agents; temozolomide; glioma; cell proliferation; animals; mice; cell survival; gene overexpression; enzyme inhibition; gene amplification; epidermal growth factor receptor; receptor, epidermal growth factor; antineoplastic activity; cytotoxicity; tumor xenograft; tumor cells, cultured; protein tyrosine kinase; monoclonal antibody; drug synergism; mice, nude; head and neck neoplasms; enzyme inhibitors; transplantation, heterologous; growth inhibition; 4 (3 chloroanilino) 6,7 dimethoxyquinazoline; tyrphostins; monoclonal antibody 806; humans; human; priority journal; article |
| Journal Title: | Proceedings of the National Academy of Sciences of the United States of America |
| Volume: | 100 |
| Issue: | 26 |
| ISSN: | 0027-8424 |
| Publisher: | National Academy of Sciences |
| Date Published: | 2003-12-23 |
| Start Page: | 15871 |
| End Page: | 15876 |
| Language: | English |
| DOI: | 10.1073/pnas.2036503100 |
| PUBMED: | 14676326 |
| PROVIDER: | scopus |
| PMCID: | PMC307660 |
| DOI/URL: | |
| Notes: | Export Date: 12 September 2014 -- Source: Scopus |
Altmetric
Citation Impact
BMJ Impact Analytics
Related MSK Work