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Insulin-like growth factor family and combined antisense approach in therapy of lung carcinoma

Background: Perturbation in a level of any peptide from insulin-like growth factor (IGF) family (ligands, receptors and binding proteins) seems to be implicated in lung cancer formation ; IGF ligands and IGF-I receptor through their mitogenic and antiapoptotic action, and the mannose 6-phosphate/insulin-like growth factor II receptor (M6-P/IGF-IIR) possibly as a tumor suppressor. Materials and Methods: To determine the identity, role and mutual relationship of IGF’s in lung cancer growth and maintenance we examined IGF’s gene (RT-PCR) and protein (immunohistochemistry) expression in 69 human lung carcinoma tissues. We also examined IGF-I receptor numbers (Scatchard analysis) and IGF-II production and release (Western blot) in IGF-II/IGF-IR mRNA positive and negative lung carcinomas. Finally, the potential role of IGF-IR and IGF-II as a growth promoting factors in lung cancer was studied using antisense oligodeoxynucleotides that specifically inhibit IGF-IR and IGF-II mRNA. Results: 32 tumors were positive for IGF-I, 39 for IGF-II, 48 for IGF-IR, and 35 for IGFBP-4 mRNA. Seventeen tumors were concomitantly positive for all four IGFs, whereas 34 were positive for IGF-II, IGF-IR, and IGFBP-4 mRNA. Elevated amount of IGF-II peptide was secreted into the growth medium of cell cultures established from five different IGF-II/IGF-IR mRNA positive lung cancer tissues. The cells expressed, also, elevated number of IGF-IR. Nine IGF-II negative and 19 IGF-II positive lung cancers of different stages were selected, and M6-P/IGF-II receptor was determined immunohistochemically. Most of the IGF-II negative tumors were strongly positive for M6-P/IGF-IIR. IGF-II positive tumors were mostly negative for M6-P/IGF-II receptors. Antisense oligodeoxynucleotides to IGF-II significantly inhibited, by 25-60%, the in Jasminka Pavelić vitro growth of all six-lung cancer cell lines. However, the best results (growth inhibition up to 80%) were achieved with concomitant antisense treatment (to IGF-IR and IGF-II). Conclusion: Our data suggest that lung cancer cells produce IGF-IR and IGF-II, which in turn stimulate their proliferation by autocrine mechanism. Cancer cell proliferation can be abrogated or alleviated by blocking mRNA activity of these genes indicating that antisense approach may represent and effective and practical cancer gene therapy strategy.

Insulin-like growth factors; lung carcinoma; therapy; antisense

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