Anti‐insulin‐like growth factor‐I activity of a novel polysulphonated distamycin A derivative in human lung cancer cell lines

Abstract

1 The purpose of this study was to investigate the antiproliferative eect 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 signi®cant concentration-and time-dependent cytostatic activity of FCE 26644 (IC 50 &200 mg ml 71 at 72 h) compared to its analogue FCE 27784 (IC 50 4800 mg ml 71) 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 (IC 50 4100 mg ml 71 ) in both A549 and Ca-Lu-1 cell lines. FCE 26644 (100 mg ml 71 ) did not aect the K D (&0.5 nM) but reduced the B max and the number of receptor sites (50%). 4 Our ®ndings 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'.

Responsiveness to hormone, growth factor and drug treatment of a human breast cancer cell line: Comparison between early and late cultures

“…On the contrary, MCF-7 E cells proved to be much more affected than MCF-7 L cells when treated with the steroidal antiestrogen (> sixfold of Bm~ reduction). As expected, on the basis of the action mechanisms of both ICI 182,780 and PNU145156E (6,8), K D values remained unchanged.…”

“…On the contrary, as previously mentioned, the mechanism of action of PNU145156E is not dependent on the presence of ER. The distamycin A derivative, like other polysulfonated corapounds, is able to counteract growth factor activity by capturing the mitogenic peptide, thereby preventing its binding to the cell surface receptor (6,32).…”

“…Taking into account the different mechanisms of action of the drugs being studied (6,8), two different experimental procedures of radio-receptor assay (RRA) were chosen.…”

“…More recently, in the search for more effective and less toxic drugs with a mechanism of action similar to that of suramin, a series of polyanionic naphthalene derivatives of distamycin A has been synthesized (1). Among these, the compound identified as PNU145156E (formerly FCE26644) proved active in inhibiting the growth factor activity with different experimental approaches (2,6,25).…”

Small cell lung cancer: from molecular biology to novel therapeutics

“…Several agents that inhibit angiogenesis have been created for the purpose of inhibiting new capillary formation around tumors and thus inhibiting tumor growth. Agents include suramin FCE 26644 (142), angiostatin (143), endostatin, and TNP-470 (144). Clinical trials need to be conducted to determine the significance of these agents in treating patients with SCLC.…”