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Latent Transformed Growth-inhibiting Factor in Human Malignant Effusions¹

Departments of Medicine, Harvard Medical School and Massachusetts General Hospital (Gastrointestinal Unit), Boston, Massachusetts 02114

An inhibitor of soft agar colony formation by a human breast carcinoma-derived cell line was found to be present in latent form in the majority of cytology-positive human malignant effusions. Prior to dialysis, addition of human malignant effusions resulted in <10% alteration in efficiency of colony formation by the BT-20 human breast carcinoma cell line (mean efficiency 1 colony/4.3 cells plated at 14 days; mean colony diameter >0.8 mm). After dialysis (membrane cutoff of 3500 molecular weight), 58 of 70 malignant effusions from patients with a variety of epithelial cell carcinomas resulted in 71% mean inhibition of colony formation (range 19.1–98% inhibition). Similar inhibition of anchorage-independent growth was observed for a human colon cancerderived cell line (HCT-15) but not for polyoma and murine sarcoma virus-transformed rodent fibroblast lines. The malignant effusion-related transformed cell growth-inhibiting factor (TGIF) was sensitive to heat, sulfhydryl reduction, and protease treatment. TGIF-containing effusion resulted in parallel inhibition of thymidine incorporation in sensitive cell types in vitro. TGIF was precipitable in 28–34% ammonium sulfate with reconstitution of activity after resolubilization. TGIF was partially purified by chromatography on Biogel A-0.5 and Biogel P-100 which yielded two peaks of inhibitory activity. The predominant species had an approximate molecular weight of 110,000 and could be recovered as a single species from DEAE-cellulose at relatively high salt concentrations (0.4 M NaCl). A smaller amount of inhibitory activity was recovered from Biogel P-100 or Biogel P-60 with an apparent molecular weight of 55,000. The higher molecular-weight TGIF which appears to be a dimer of the M_r 55,000 protein is distinguishable from previously described growth-promoting and -inhibiting factors.

¹ Supported by a grant from the NIH (RO1-AM34422) and a Research Career Development Award (D. K. P.) (K04-AM01257).

² To whom requests for reprints should be addressed.

Received 6/29/87. Revised 9/29/87. Accepted 10/15/87.

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