Anti-insulin-like growth factor-I activity of a novel polysulphonated distamycin A derivative in human lung cancer cell lines.
1. The purpose of this study was to investigate the antiproliferative effect and the modulation of the mitogenic insulin-like growth factor-I (IGF-I) system by FCE 26644 and FCE 27784, two polyanionic sulphonated distamycin A derivative compounds, on two human non-small cell lung cancer (N-SCLC) cell lines. 2. For cell growth studies the colorimetric MTT and the thymidine incorporation assays were performed; the presence of IGF-I and IGF-binding proteins in conditioned media was revealed by radioimmunoassay and Western ligand blot, respectively. Variations at the IGF-I-receptor level were tested by binding studies on cell monolayers. 3. A significant concentration- and time-dependent cytostatic activity of FCE 26644 (IC50 approximately 200 micrograms ml-1 at 72 h) compared to its analogue FCE 27784 (IC50 > 800 micrograms ml-1) was observed in both cell lines studied. The IGF-I-stimulated proliferation of the IGF-I-responsive A549 cell line was abolished by 24 h of FCE 26644 treatment whereas FCE 27784 was inactive. FCE 26644 increased (4 to 6 fold) the secretion of IGF-I-like material and reduced the IGF-I binding (IC50 > 100 micrograms ml-1) in both A549 and Ca-Lu-1 cell lines. FCE 26644 (100 micrograms ml-1) did not affect the KD (approximately 0.5 nM) but reduced the Bmax and the number of receptor sites (50%). 4. Our findings demonstrate that the ability to down-regulate the cell proliferation of N-SCLC cell lines, shown by FCE 26644, depends at least partially, on interference with the "IGF-I mitogenic system'.
de Cupis
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A
Department of Preclinical Oncology, Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy.
Ciomei
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M
Pirani
P
P
Ferrera
A
A
Ardizzoni
A
A
Favoni
R E
RE
D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism / Q000473:pathology*; D002455:Cell Division / Q000187:drug effects; D017077:Culture Media, Conditioned; D004273:DNA, Neoplasm / Q000096:biosynthesis; D004214:Distamycins / Q000494:pharmacology*; D006801:Humans; D018969:Insulin-Like Growth Factor Binding Proteins / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology*; D011863:Radioimmunoassay; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D017077:Culture Media, Conditioned; D004273:DNA, Neoplasm; D004214:Distamycins; C085720:FCE 26644; C105963:FCE 27784; D018969:Insulin-Like Growth Factor Binding Proteins; D007334:Insulin-Like Growth Factor I; C030000:stallimycin