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Interaction of an -Melanocyte-stimulating Hormone-Diphtheria Toxin Fusion Protein with Melanotropin Receptors in Human Melanoma Metastases¹

Division of Endocrinology, Diabetes, Metabolism and Molecular Medicine [J. B. T., M. L. E., S. R.] and Hematology-Oncology, Department of Medicine [M. B. A.]; Department of Surgical Oncology [T. J. S.], Tufts University School of Medicine and New England Medical Center Hospitals, Boston, Massachusetts 02111; and the Evans Department of Clinical Research and Department of Medicine, The University Hospital, Boston University Medical Center [Z. W., J. R. M.], Boston, Massachusetts 02118

A hybrid toxin targeted to melanotropin receptors and selectively cytotoxic to melanoma cell lines in vitro has recently been developed. The toxin, a recombinant fusion protein (designated DAB₃₈₉-MSH), contains the peptide sequences of -melanocyte-stimulating hormone (-MSH) and the catalytic (cytotoxic; Fragment A) and lipophilic (part of Fragment B) domains of diphtheria toxin. In the present study, binding of DAB₃₈₉-MSH to melanotropin receptors in biopsy specimens of human and mouse melanoma metastases was assessed by measuring its ability to inhibit binding of a radiolabeled, superpotent analogue of -MSH (¹²⁵I-[Nle⁴,D-Phe⁷]--MSH; ¹²⁵I-NDP-MSH) and comparing its potency in this system with those of the established ligands NDP-MSH and -MSH. Radioligand binding to tissue sections in vitro was localized and quantified by autoradiography and image analysis. DAB₃₈₉-MSH inhibited binding of ¹²⁵I-NDP-MSH to experimental murine B16-F1C23 melanoma metastasis tissue and to melanoma metastases of three patients. In both mouse and human melanoma tissues, concentration-response relationships for DAB₃₈₉-MSH-mediated inhibition of ¹²⁵I-NDP-MSH binding were parallel, and its maximal effects were comparable in magnitude, to those of NDP-MSH and -MSH. Half-maximal peptide concentrations for inhibition of ¹²⁵I-NDP-MSH binding to mouse melanoma tissue sections were: NDP-MSH, 0.63 nM; -MSH, 3.14 nM; and DAB₃₈₉-MSH, 10.1 nM. In human melanoma tissues, the respective half-maximal peptide concentrations for inhibition of ¹²⁵I-NDP-MSH binding to mouse melanoma tissue sections were: NDP-MSH, 1.80 nM; -MSH, 2.43 nM; and DAB₃₈₉-MSH, 11.9 nM. Taken together, these results suggest that NDP-MSH, -MSH, and DAB₃₈₉-MSH bind to a common melanotropin receptor in human metastatic melanoma cells. Since previous work has shown that melanotropin receptors are detectable in melanoma metastases of about 80% of human patients, malignant melanoma cells of many patients may be susceptible to killing by the melanotropin receptor-targeted cytotoxin DAB₃₈₉-MSH.

¹ This work was supported in part by Grants RD-285 from the American Cancer Society (J. B. T.), 1RO1-MH-44694 from the National Institute of Mental Health (J. B. T.), and CA-41746 and UO1-CA-48626 from the National Cancer Institute (J. R. M.).

² To whom requests for reprints should be addressed, at Box 268, Division of Endocrinology, Diabetes, Metabolism and Molecular Medicine, New England Medical Center Hospital, 750 Washington Street, Boston, MA 02111.

³ Present address: Department of Immunology, Washington University School of Medicine, St. Louis, MO 63110.

Received 10/25/91. Accepted 2/24/92.

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