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Section of Medicine Research Laboratories, Institute of Cancer Research, Belmont, Surrey [V. M. M., M. J. E., J. L. M.], Lung Unit, Royal Marsden Hospital, Sutton, Surrey [I. E. S.], Department of Cytopathology, Royal Marsden Hospital, Fulham Road, London [P. A. T.], and Department of Clinical Biochemistry, St. Lukes Hospitals, Guildford, Surrey [J. D. T.], United Kingdom; and Department of Pediatrics, University of North Carolina, Chapel Hill, North Carolina [J. J. V. W.]
We showed previously that insulin-like growth factor I (IGF-I) is detectable in small cell lung cancer (SCLC) tumor biopsies and cell lines and that recombinant human IGF-I stimulates DNA synthesis in SCLC cells. Here we report further studies on the role of IGF-I in 2 SCLC cell lines: HC12, classic; and ICR-SC17, variant. Immunoreactive IGF-I was detected in medium conditioned by HC12 but not ICR-SC17. Both HC12 and ICR-SC17 bound IGF-I with 100-fold greater affinity than insulin. Scatchard analysis revealed two classes of IGF-I binding site of high (Kd 0.1 nM, n = 2,300) and lower (Kd 3 nM, n = 28,000) affinity. In both cell lines [3H]thymidine incorporation was enhanced by recombinant human IGF-I, 100–1000 ng/ml. ICR-SC17 also showed growth enhancement as measured by increase in cell numbers. There was no response in HC12, probably due to endogenous IGF-I production. 125I-IGF-I binding and basal and IGF-I-stimulated mitogenesis were inhibited by monoclonal antibodies to IGF-I (SM1.20B, SM1.25) or the type I IGF receptor 
IR3 but not an isotypic control monoclonal antibody. Antiproliferative effects were manifest in [3H]thymidine incorporation assays in serum-free conditions and growth of serum-supplemented liquid cultures. We also tested fresh or newly cultured tumor cells obtained by fine needle aspiration of metastases in three previously untreated and four relapsed patients with SCLC. IGF-I binding sites were demonstrable on fresh SCLC cells, and specific binding was inhibited by SM1.20B. All seven samples showed stimulation of [3H]thymidine incorporation in the presence of recombinant human IGF-I, 100–500 ng/ml. As in cultured cells, basal and IGF-I-stimulated DNA synthesis was inhibited by monoclonal antibodies SM1.20B, SM1.25, and IR3 but not the isotypic control. These results confirm the findings of previous studies and suggest that IGF-I can function as an autocrine growth factor in SCLC in vitro and possibly also in vivo.
1 Supported by the T. K. Stubbins Fellowship of the Royal College of Physicians. To whom requests for reprints should be addressed, at Section of Medicine Research Laboratories, Institute of Cancer Research, 15, Cotswold Road, Belmont, Sutton SM2 5NG, United Kingdom.
2 Supported by the Alan Jay Lerner Research Fund.
Received 6/23/89.
Revised 11/13/89.
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