Although many thyroid cancers carry a favorable prognosis, there is a subgroup of patients with more aggressive histologies. Current therapies offer no significant survival benefit to patients with anaplastic thyroid carcinomas, which are considered fatal. Oncolytic herpes simplex viruses (HSVs) have potent antitumor effects against a variety of human malignancies. We assessed the activity of a replication-competent, attenuated, oncolytic HSV (NV1023) against 7 different thyroid cancers, including one papillary (NPA-187), one follicular (WRO82-1), one medullary (DRO81-1) and 4 anaplastic (DRO90-1, ARO, KAT-4C and KAT-18) cell lines. Only the follicular WRO82-1 line was resistant to NV1023 infection and cell lysis at a concentration of 5 viral pfu per cell (MOI 5). All other cell lines at MOI 5 demonstrated >95% infection in vitro at day 2 by X-gal staining and >88% cell death at day 4 by cytotoxicity assays. Even at MOI 0.1, 4 of these lines displayed complete cell death by day 7. Viral proliferation assays revealed that all of the non-follicular cell lines supported logarithmic viral replication. Flank tumors of NPA-187, DRO81-1, DRO90-1 and ARO in athymic nude mice were treated with NV1023 (2 x 10(7) pfu). All NPA-187 tumors completely regressed following a single dose. DRO81-1 tumors demonstrated partial response with a single dose and significant improvement with 3 serial doses. ARO and DRO90-1 tumors showed a significant response following either single injection (54 22 and 292 138 mm;, respectively) or 3 serial injections (33 14 and 241 68 mm 3, respectively) compared to saline injections (472 193 and 1,257 204 mm;, respectively) at day 20. These data suggest that herpes oncolytic therapy may be effective for the treatment of aggressive thyroid carcinomas and merits further investigation. (C) 2004 Wiley-Liss, Inc.