Anti-alphav integrin monoclonal antibody intetumumab enhances the efficacy of radiation therapy and reduces metastasis of human cancer xenografts in nude rats.
We previously reported that intetumumab (CNTO 95), a fully human anti-αv integrin monoclonal antibody, is a radiosensitizer in mice with xenograft tumors. Because intetumumab does not cross-react with mouse integrins, but has cross-reactivity with rat integrins, we next studied the potential combined use of radiation therapy and intetumumab in human cancer xenograft models in nude rats to assess effects on both tumor cells and the tumor microenvironment. Nude rats bearing human head and neck cancer and non-small cell lung cancer (NSCLC) xenografts were treated with intetumumab and fractionated local tumor radiotherapy. Effects on tumor growth and metastasis, blood perfusion, oxygenation, and gastrointestinal toxicity were studied. Intetumumab alone had a moderate effect on tumor growth. When combined with fractionated radiation therapy, intetumumab significantly inhibited tumor growth and produced a tumor response rate that was significantly better than with radiation therapy alone. Treatment with intetumumab also significantly reduced lung metastasis in the A549 NSCLC xenograft model. The oxygenation and blood perfusion in xenograft tumors measured by microbubble-enhanced ultrasound imaging were substantially increased after treatment with intetumumab. The combined use of intetumumab and radiation therapy reduced the microvessel density and increased apoptosis in tumor cells and the tumor microenvironment. Toxicity studies showed that treatment with intetumumab did not cause the histopathologic changes in the lungs and did not sensitize the sensitive gastrointestinal epithelium to the effect of radiation therapy. Intetumumab can potentiate the efficacy of fractionated radiation therapy in human cancer xenograft tumors in nude rats without increased toxicity.
Ning
Shoucheng
S
Department of Radiation Oncology, Stanford University Medical Center, Stanford, California 94305-5152, USA.
Tian
Junqiang
J
Marshall
Deborah J
DJ
Knox
Susan J
SJ
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000098:blood supply / Q000188:drug therapy / Q000473:pathology / Q000532:radiotherapy / Q000556:secondary; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D006258:Head and Neck Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000473:pathology / Q000532:radiotherapy; D006801:Humans; D039564:Integrin alphaV / Q000276:immunology; D007413:Intestinal Mucosa / Q000187:drug effects / Q000473:pathology / Q000528:radiation effects; D008175:Lung Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000473:pathology / Q000532:radiotherapy / Q000556:secondary; D008297:Male; D009369:Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy*; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000528:radiation effects; D010100:Oxygen / Q000097:blood / Q000378:metabolism; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D051381:Rats; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D039564:Integrin alphaV; D011838:Radiation-Sensitizing Agents; C486839:intetumumab; D010100:Oxygen