ANTISENSE OLIGONUCLEOTIDE INTRALESIONAL THERAPY FOR HUMAN PC-3 PROSTATE TUMORS CARRIED IN ATHYMIC NUDE-MICE

Previously we reported hemorrhagic necrosis in human-derived PC-3 pros tate tumors, in athymic nude mice, produced by the intralesional injec tion of antisense oligonucleotides (oligos) directed against mRNAs enc oding transforming growth factor-alpha (TGF-alpha) and its target, the epidermal growth factor receptor (EGFR). We now describe our experien ce with these oligos in treating additional mice with various doses an d modes of administration. During prolonged treatment, a dose-response effect was observed, with the optimal dosage consisting of the combin ation of 400 mu g of each oligo. Although responses varied, based upon amount and how oligos were administered, we found that tumors were be st treated when initially less than 156 mm(3). Intralesional inoculati ons produced necrosis and yielded responses, ranging from complete res ponse (CR) or cure to partial responses (PR) in 9 of 12 tumors treated with full dose (400 mu g of each oligo) and 1 of 1 treated with 800 m u g of each oligo, against a large tumor. Included among the 9 positiv e responses with full-dose administration were 2 tumors that regressed (one completely). A single tumor treated with twice (2X) the normal d osage (800 mu g of each oligo) also regressed. A single tumor treated with half (1/2) dose (200 mu g of each) progressed similar to controls , as did 3 of 12 treated with the full dose. Limited experience with A LZET diffusion pumps gave CR (1 of 3) or PR (2 of 3) in 100% of tumors treated (including one mouse cured of multiple tumors in a five day p eriod). It appears that multiple inoculations consisting of 400 mu g o f-each oligo is most effective against these tumors, particularly when administered against tumors of <156 mm(3) in initial size. (C) 1996 W iley-Liss, Inc.