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Enhanced Antitumor Activity of Combination Radioimmunotherapy (¹³¹I-labeled Monoclonal Antibody A33) with Chemotherapy (Fluorouracil)¹

New York Branch, Ludwig Institute for Cancer Research [E. B., C. W., L. J. O., S. W.], Department of Surgery [J. T., A. M. C.], and Department of Epidemiology and Biostatistics [T-J. Y.], Memorial Sloan-Kettering Cancer Center, New York, New York 10021

Monoclonal antibody (mAb) A33 reacts with an antigen expressed by > 95% of colon cancer and normal colon epithelial cells. An earlier Phase I trial of ¹³¹I-labeled mAb A33 (¹³¹I-mAb A33) demonstrated bone marrow suppression as the dose-limiting toxicity, and although modest antitumor effects were seen, no normal colon toxicity was observed. In this study, a nude mouse model was used to test whether combinations of low-dose ¹³¹I-mAb A33 (0.1 mCl) and chemotherapy [5-fluorouacil (5-FU) or 5-FU + leucovorin, doxorubicin, or carmustine] enhance the antitumor effects, compared to ¹³¹I-mAb A33 alone or either drug regimen alone. 5-FU was administered either at 30 mg/kg/day for 5 days or at 75 mg/kg/day on days 1 and 5. In assessing the reduction in tumor volumes over the first 28 days of the experiment, 5-FU treatment (with or without leucovorin) in combination with ¹³¹I-mAb A33 showed a statistically significant additive antitumor effect compared to ¹³¹I-mAb A33 alone or to chemotherapy alone. When long-term survival was used as an end point, 38% of the mice treated with 5-FU and ¹³¹I-mAb A33 were disease free at 276 days compared to none from any other group, suggesting a synergistic effect. These data indicate that Phase II clinical trials combining radiolabeled antibody therapy with 5-FU-based treatments are warranted.

¹ This study was supported in part by funds provided by Prof. E. Bodner, Chairman, Second Department of Surgery, University of Innsbruck, Innsbruck, Austri, and Grant CA-08748 from the National Cancer Institute.

² To whom requests for reprints should be addressed, at Ludwig Institute for Cancer Research, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021-6007.

Received 7/29/96. Accepted 4/ 7/97.

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