RADIOACTIVE EGFR ANTIBODY CETUXIMAB IN MULTIMODAL CANCER TREATMENT: STABILITY AND SYNERGISTIC EFFECTS WITH RADIOTHERAPY

Purpose: Systemic therapies when added to whole brain radiotherapy have failed to improve the survival of patient h multiple brain metastases. The epidermal growth factor receptor antibody cetuximab is an attractive option, if it is able to cross the blood-brain barrier. This might be proven with molecular imaging if the radiolabeled antibody is stable long enough to be effective. This study investigated the stability of radiolabeled cetuximab (Erbitux) ((131)I-Erbi) and potential synergistic effects with radiotherapy in vitro. Methods and Materials: Two cell lines were investigated, A431 with numerous epidermal growth factor receptors, and JIMT without epidermal growth factor receptors. We labeled 0.4 mg cetuximab with 50 MBq of [(131)I] iodide. Stability was determined for 72 h. The cell cultures were incubated with (131)I-Erbi or cold cetuximab for 72 h. Uptake and cell proliferation were measured every 24 h after no radiotherapy or irradiation with 2, 4, or 10 Gy. Results: The radiolabeling yield of (131)I-Erbi was always >80%. The radiochemical purity was still 93.6% after 72 h. A431 cells showed a (131)I-Erbi uptake about 100-fold greater than the JIMT controls. After 48 h, the A431 cultures showed significantly decreased proliferation. At 72 h after irradiation, (131)I-Erbi resulted in more pronounced inhibition of cell proliferation than the cold antibody in all radiation dose groups. Conclusion: (131)I-Erbi was stable for <= 72 h. Radiotherapy led to increased tumor cell uptake of (131)I-Erbi. Radiotherapy and (131)I-Erbi synergistically inhibited tumor cell proliferation. These results provide the prerequisite data for a planned in vivo study of whole brain radiotherapy plus cetuximab for brain metastases. (C) 2009 Elsevier Inc.