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Does Paclitaxel (Taxol) Given after ¹¹¹In-Labeled Monoclonal Antibodies Increase Tumor-Cumulated Activity in Epithelial Cancers?

Authors' Affiliations: ¹ School of Medicine, University of California Davis, Davis and ² School of Medicine, University of California San Francisco, San Francisco, California

Requests for reprints: Gerald DeNardo, Radiodiagnosis and Therapy, Molecular Cancer Institute, 1508 Alhambra Boulevard, Room 3100, Sacramento, CA 95816. Phone: 916-734-3723; Fax: 916-451-2857; E-mail: gldenardo{at}ucdavis.edu.

Purpose: Paclitaxel synergized radiolabeled monoclonal antibodies, enhancing therapeutic effect in studies in mice with human xenografts. Paclitaxel was also observed to increase tumor uptake in imaging studies of ¹¹¹In-DOTA-Gly₃Phe-m170 in patients with breast and prostate cancers. Further evaluations of tissue-cumulated activities, therapeutic indices, and pharmacokinetics were done using data for patients with breast and prostate cancer and for mice with human breast cancer xenografts.

Experimental Design: In radioimmunotherapy trials, 12 patients with breast or prostate cancer were given two imaging doses (5 mCi each) of ¹¹¹In-DOTA-Gly₃Phe-m170 1 week apart. Five of these patients were given a single dose of paclitaxel i.v. (75 mg/m²) 2 days after the second dose of ¹¹¹In. In a subsequent study, athymic mice with human breast cancer xenografts were given ¹¹¹In-DOTA-Gly₃Phe-ChL6 alone, or in combination with daily paclitaxel i.p. (300 µg) one or more times. Pharmacokinetics were studied for at least 6 days in patients and 5 days in mice. Cumulated activities were determined for tumors and normal tissues.

Results: Tumor-cumulated activity for every patient in the paclitaxel-treated group increased for the second dose of ¹¹¹In-DOTA-Gly₃Phe-m170. The median ratio of cumulated activities in tumors for imaging dose 2 to those for dose 1 was 1.0 (0.8-1.3) in patients that were not given paclitaxel and 1.3 (1.2-1.4) in patients given paclitaxel. Normal tissue-cumulated activities were not different for the two doses. Mice given paclitaxel 1 day after ¹¹¹In-DOTA-Gly₃Phe-ChL6 also showed an increase in tumor-cumulated activity, 22.9 (± 1.3) versus 19.4 (± 3.3) µCi h/g/µCi (P = 0.05). Cumulated activities of normal tissues were similar for all groups of mice.

Conclusions: Paclitaxel given 1 to 2 days after ¹¹¹In-DOTA-Gly₃Phe-monoclonal antibody increased the tumor-cumulated activity in patients and in mice with epithelial cancers and did not alter cumulated activities in normal tissues.