Yttrium-90-DOTA-peptide-chimeric L6 radioimmunoconjugate: efficacy and toxicity in mice bearing p53 mutant human breast cancer xenografts.

Abstract

UNLABELLED:

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-ChL6 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 DNA 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.

• Authors: S J DeNardo, D L Kukis, L A Miers, M D Winthrop, L A Kroger, Q Salako, S Shen, K R Lamborn, P H Gumerlock, C F Meares, G L DeNardo
• Journal: Journal of nuclear medicine : official publication, Society of Nuclear Medicine (J Nucl Med) Vol. 39 Issue 5 Pg. 842-9 (May 1998) ISSN: 0161-5505 [Print] United States
• PMID: 9591587 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antibodies, Monoclonal
• ChL6 monoclonal antibody
• Heterocyclic Compounds
• Oligopeptides
• Tumor Suppressor Protein p53
• Yttrium Radioisotopes
• yttrium-90-DOTA-peptide-chimeric L6
• Yttrium

Topics

• Adenocarcinoma (genetics, radiotherapy)
• Animals
• Antibodies, Monoclonal (therapeutic use)
• Apoptosis
• Breast Neoplasms (genetics, radiotherapy)
• Dose-Response Relationship, Radiation
• Female
• Heterocyclic Compounds (therapeutic use, toxicity)
• Humans
• Lethal Dose 50
• Mice
• Mice, Nude
• Neoplasm Transplantation
• Oligopeptides (therapeutic use, toxicity)
• Radioimmunotherapy (adverse effects)
• Transplantation, Heterologous
• Tumor Suppressor Protein p53 (genetics)
• Yttrium (therapeutic use, toxicity)
• Yttrium Radioisotopes (therapeutic use)