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 prostate tumors, in athymic nude mice, produced by the intralesional injection of antisense oligonucleotides (oligos) directed against mRNAs encoding transforming growth factor-alpha (TGF-alpha) and its target, the epidermal growth factor receptor (EGFR). We now describe our experience with these oligos in treating additional mice with various doses and modes of administration. During prolonged treatment, a dose-response effect was observed, with the optimal dosage consisting of the combination of 400 micrograms of each oligo. Although responses varied, based upon amount and how oligos were administered, we found that tumors were best treated when initially less than 156 mm3. Intralesional inoculations produced necrosis and yielded responses, ranging from complete response (CR) or cure to partial responses (PR) in 9 of 12 tumors treated with full dose (400 micrograms of each oligo) and 1 of 1 treated with 800 micrograms of each oligo, against a large tumor. Included among the 9 positive responses with full-dose administration were 2 tumors that regressed (one completely). A single tumor treated with twice (2X) the normal dosage (800 micrograms of each oligo) also regressed. A single tumor treated with half (1/2) dose (200 micrograms of each) progressed similar to controls, as did 3 of 12 treated with the full dose. Limited experience with ALZET 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 period). It appears that multiple inoculations consisting of 400 micrograms of each oligo is most effective against these tumors, particularly when administered against tumors of <156 mm3 in initial size.