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Autocrine Tumor Cell Growth-inhibiting Activities from Human Malignant Melanoma

Department of Neurology, Cell Biology, and Neurochemistry Laboratories [U. B., R. A., M. G., C. B., R. M.], Institute of Genetics and Microbiology [C. B.], and Institute of Physiological Chemistry [J. H.], Julius-Maximilians-University, Würzburg, Josef-Schneider Strasse 11, D 8700 Federal Republic of Germany

Autocrine-secreted tumor cell growth-inhibiting activities were isolated from supernatants of a malignant melanoma cell line, HTZ 19-dM, established from a central nervous system melanoma metastasis. HTZ 19-dM was characterized by cyto- and immunocytochemistry and karyotyping; cells were propagated in defined serum-free tissue culture medium for up to 8 months. Supernatants were ultrafiltrated, dialyzed, lyophilized, and purified by Bio-Gel P-10 gel permeation chromatography, leading to three active fraction pools, MIA_I [melanoma-inhibiting activity (MIA), 2 kDa), MIA_II (M_r 11,500–17,000) and MIA_III (proteins at the cutoff of Bio-Gel P-10) inhibiting growth of 19-dM cells with 50% inhibitory concentrations of 0.79 µg/ml (MIA_I), 0.13 µg/ml (MIA_II), and 16.7 µg/ml (MIA_II). MIA_II could be further purified by reverse phase high pressure liquid chromatography; the main activity displayed a 50% inhibitory concentration of 0.33 µg/ml. On sodium dodecyl sulfate-polyacrylamide gel electrophoresis one major band (molecular weight about 14,000) and two minor bands (up to M_r 17,000) were identified. Macromolecular synthesis was inhibited in 19-dM cells up to >99.5%; tumor stem cell colony formation was reduced by 99.89%; the inhibitory effect of MIA_II was irreversible, nonsaturable, and partially antagonized by a serum factor (depending on purification stage). MIA_II was heat stable (3 min at 100°C) and trypsin labile. The effect of MIA_II on allogeneic neuroectodermal tumors was also investigated; proliferation of two of three malignant melanomas and two of four glioblastomas was inhibited up to 85.2%; proliferation of a neuroblastoma cell line could be inhibited to 33.8%, whereas normal fibroblasts and low grade gliomas were not influenced in their proliferation.

¹ To whom requests for reprints should be addressed.

Received 3/ 9/89. Revised 6/22/89. Accepted 7/ 6/89.

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