msh--4-nle-7-phe-alpha- and Neoplasm-Metastasis

In this study we have compared the effects of different pro-opiomelanocortin (POMC) peptides on melanogenesis and metastasis and their relationship to MSH receptor expression in B16F1 melanoma cells. All peptides, apart from beta-endorphin, increased melanogenesis and the order of potency was Nle4DPhe7-alpha-MSH greater than alpha-MSH greater than ACTH[1-39] greater than des-acetyl alpha-MSH greater than ACTH[1-24]. A similar order of potency was found for metastasis, except for ACTH [1-24], which had a relatively greater effect on metastasis. These findings suggest that the effects on melanogenesis and metastasis are mediated via the same receptor. The results of ligand binding studies also indicated the presence of a single receptor with a KD value for Nle4DPhe7-alpha-MSH of 62 +/- 16pM. This was consistent with crosslinking studies using [125I] Nle4DPhe7-alpha-MSH which produced a single 50-55 kD band on analysis by SDS-PAGE. However, the relative binding affinities of the different peptides, measured by displacement of [125I]-Nle4DPhe7-alpha-MSH, did not closely correlate with the relative potencies in stimulating melanogenesis and metastasis. This suggests that receptor activation and the subsequent biological response is not determined solely by binding affinity.

Topics: Adrenocorticotropic Hormone; alpha-MSH; Animals; Cosyntropin; Gene Expression Regulation, Neoplastic; Melanins; Melanoma, Experimental; Mice; Mice, Inbred C57BL; Neoplasm Metastasis; Neoplasm Proteins; Neoplasm Transplantation; Peptide Fragments; Protein Binding; Receptors, Pituitary Hormone; Tumor Cells, Cultured

Melanocyte stimulating hormone (alpha-MSH, alpha-melanotropin),Ac-Ser-Tyr-Ser-Met-Glu-His-Phe-Arg-Trp-Gly-Ly-Pro-Va l-NH2, regulates melanogenesis within epidermal melanocytes of many animals. An MSH analogue ([Nle4,D-Phe7]alpha-MSH) that exhibits superpotency and prolonged biological activity has been synthesized, biologically characterized, and is presently in clinical trials to determine its possible clinical use in tanning of the skin. It also has potential for the diagnosis, localization, and chemotherapy of melanoma. The effects of this analogue on the growth, metastatic behavior, and invasive potential of a melanotic variant of Cloudman S-91 murine melanoma are reported here. In an intracutaneous murine model of melanoma cell tumor growth, the analogue did not increase primary tumor growth (size) after the period of administration of the peptide hormone analogue and did not affect spontaneous lung metastases. Survival times for the control and melanotropin-treated groups were similar, suggesting that overall tumor burden was not affected by treatment with the hormone analogue. Last, melanoma cell invasion through a human amniotic basement membrane in vitro was not enhanced compared to untreated cells.

Topics: alpha-MSH; Amino Acid Sequence; Animals; Cell Division; Female; Humans; Melanocyte-Stimulating Hormones; Melanoma; Mice; Mice, Inbred DBA; Molecular Sequence Data; Neoplasm Invasiveness; Neoplasm Metastasis; Tumor Cells, Cultured