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

Sally J. DeNardo, David L. Kukis, Laird A. Miers, Michelle D. Winthrop, Linda A. Kroger, Qansy Salako, Sui Shen, Kathleen R. Lamborn, Paul H. Gumerlock, Claude F. Meares, Gerald L. DeNardo

    Research output: Contribution to journalArticle

    42 Citations (Scopus)

    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- 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.

    Original languageEnglish (US)
    Pages (from-to)842-849
    Number of pages8
    JournalJournal of Nuclear Medicine
    Volume39
    Issue number5
    StatePublished - May 1998

    Fingerprint

    Immunoconjugates
    Heterografts
    Breast Neoplasms
    Maximum Tolerated Dose
    Lethal Dose 50
    Neoplasms
    Peptides
    Nude Mice
    Apoptosis
    DNA Breaks
    p53 Genes
    yttrium-90-DOTA-peptide-chimeric L6
    Protein Binding
    Weight Loss
    Therapeutics
    Radiation

    Keywords

    • Apoptosis
    • Breast carcinoma
    • Radioimmunotherapy
    • Yttrium-90

    ASJC Scopus subject areas

    • Radiological and Ultrasound Technology

    Cite this

    Yttrium-90-DOTA-peptide-chimeric L6 radioimmunoconjugate : Efficacy and toxicity in mice bearing p53 mutant human breast cancer xenografts. / DeNardo, Sally J.; Kukis, David L.; Miers, Laird A.; Winthrop, Michelle D.; Kroger, Linda A.; Salako, Qansy; Shen, Sui; Lamborn, Kathleen R.; Gumerlock, Paul H.; Meares, Claude F.; DeNardo, Gerald L.

    In: Journal of Nuclear Medicine, Vol. 39, No. 5, 05.1998, p. 842-849.

    Research output: Contribution to journalArticle

    DeNardo, SJ, Kukis, DL, Miers, LA, Winthrop, MD, Kroger, LA, Salako, Q, Shen, S, Lamborn, KR, Gumerlock, PH, Meares, CF & DeNardo, GL 1998, 'Yttrium-90-DOTA-peptide-chimeric L6 radioimmunoconjugate: Efficacy and toxicity in mice bearing p53 mutant human breast cancer xenografts', Journal of Nuclear Medicine, vol. 39, no. 5, pp. 842-849.
    DeNardo, Sally J. ; Kukis, David L. ; Miers, Laird A. ; Winthrop, Michelle D. ; Kroger, Linda A. ; Salako, Qansy ; Shen, Sui ; Lamborn, Kathleen R. ; Gumerlock, Paul H. ; Meares, Claude F. ; DeNardo, Gerald L. / Yttrium-90-DOTA-peptide-chimeric L6 radioimmunoconjugate : Efficacy and toxicity in mice bearing p53 mutant human breast cancer xenografts. In: Journal of Nuclear Medicine. 1998 ; Vol. 39, No. 5. pp. 842-849.
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    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- 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.",
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    AU - Kukis, David L.

    AU - Miers, Laird A.

    AU - Winthrop, Michelle D.

    AU - Kroger, Linda A.

    AU - Salako, Qansy

    AU - Shen, Sui

    AU - Lamborn, Kathleen R.

    AU - Gumerlock, Paul H.

    AU - Meares, Claude F.

    AU - DeNardo, Gerald L.

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