Ex Vivo and In Vivo IGF-I Antisense RNA Strategies for Treatment of Cancer in Humans

Two technical approaches to gene therapy for cancer utilize ex vivo and in vivo gene transfer methodology. This paper focuses on applicability and use of each of these approaches using an IGF-I antisense RNA strategy of treatment. Insulin-like growth factor I (IGF-I) and IGF-II have pivotal roles in cell proliferation and development (for review see 1–4). The preponderance of peptide synthesis and activity occur during fetal development. Protein synthesis is down-regulated in most mature tissues except for adult liver. However, many cancers produce and secrete IGF-I and/or IGF-II and also express IGF-I receptor. These include: astrocytomas, glioblastoma multiforme, sarcomas, thyroid adenomas, hepatocellular cancer, small cell cancer of the lung, and carcinomas of breast, colon, and prostate gland. The initiation and/or early growth of these tumors may be dependent upon changes in these mitogenic peptides or their receptors. Kaleko et. al. (1990) showed that overexpression of human IGF-I receptor in mice fibroblasts promotes colony formation in soft agar for cells grown in 10% serum supplemented with IGF-I. Trojan, Ilan, and colleagues demonstrated in 1992 that inhibition of IGF-I expression by an IGF-I antisense RNA strategy of gene therapy inhibits tumor formation and causes regression and cure of wild-type C6 glioblastoma in rats (6). They further showed that tumor was infiltrated with CD8 lymphocytes as the process resolved, suggesting that the treatment may act through an immunogenic mechanism (7). Resnicoff, Baserga, and colleagues showed that down-regulation of the IGF-I receptor in rat C6 glioblastoma cells by an antisense strategy also prevents tumor formation and/or causes regression of tumors induced by wild type C6 cells (8–9).