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Yttrium-90-DOTA-Peptide-Chimeric L6 Radioimmunoconjugate: Efficacy and Toxicity in Mice Bearing p53 Mutant Human Breast Cancer Xenografts

Section of Radiodiagnosis and Therapy, Department of Internal Medicine, University of California Davis Medical Center, Sacramento; Brain Tumor Research Center, University of California San Francisco, San Francisco; and Department of Chemistry, University of California Davis, Davis, California

Correspondence: For correspondence or reprints contact: Sally J. DeNardo, MD, Molecular Cancer Institute, 1508 Alhambra Boulevard, Suite 3100, Sacramento, CA 95816.

ABSTRACT

The novel radioimmunoconjugate, ⁹⁰Y-DOTA-peptide-chimeric L6 (ChL6), was designed to reduce radiation to critical normal tissues with an exceptionally stable ⁹⁰Y chelate moiety and a biodegradable linker. Human breast cancer tumors (HBT 3477) in mice were treated with ⁹⁰Y-DOTA-peptide-ChLG to examine the effects of increasing dose on the therapeutic efficacy and toxicity of this new agent. Methods: Groups of athymic mice bearing HBT 3477 xenografts received 4.1- to 14.1-MBq doses of ⁹⁰Y-DOTA-peptide-ChL6 intravenously. The lethal dose (LD)_50/30, general well-being (weight loss), hematotoxicity and therapeutic efficacy were studied. Results: The LD_50/30 was 12.8 MBq, which corresponded to doses of 17.9 and 50.9 Gy to the total body and tumor (200 mm³), respectively. Deaths were associated with hematotoxicity; no deaths occurred at doses of 9.6 MBq or less. At sublethal doses, the rate of tumor response (cures + complete responses + partial responses) increased with increasing dose: 4.1 MBq, 27%; 5.9 MBq, 41%; 8.5 MBq, 69%; and 9.6 MBq, 79% (maximum tolerated dose, MTD). In mice receiving doses of 4.1–9.6 MBq, 6 of 74 (8%) of tumors were cured. Increasing the ⁹⁰Y dose led to smaller tumor size at nadir and longer tumor regrowth delay but no increase in cure. Although the HBT 3477 p53 gene was found to be mutant resulting in p53 protein not binding DMA breaks, tumors at MTD demonstrated evidence of apoptosis. Conclusion: In the human breast cancer athymic mouse model, ⁹⁰Y-DOTA-peptide-ChL6 had a high therapeutic index and LD_50/30 leading to a 79% response rate at the MTD. The evidence of apoptosis as a mechanism for this tumor response in p53 mutant breast cancer warrants further studies because these observations are relevant to the treatment of lethal breast cancer.

Key Words: yttrium-90 • breast carcinoma • radioimmunotherapy • apoptosis

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