Synergy of a herpes oncolytic virus and paclitaxel for anaplastic thyroid cancer.
OBJECTIVE
Novel therapeutic regimens are needed to improve the dismal outcomes of patients with anaplastic thyroid cancer (ATC). Oncolytic herpes simplex virus have shown promising activity against human ATC. We studied the application of oncolytic herpes simplex virus (G207 and NV1023) in combination with currently used chemotherapeutic drugs (paclitaxel and doxorubicin) for the treatment of ATC.


RESULTS
All four agents showed dose-response cytotoxicity in vitro for the human ATC cell lines KAT4 and DRO90-1. G207, combined with paclitaxel, showed synergistic cytotoxicity. Chou-Talalay combination indices ranged from 0.56 to 0.66 for KAT4, and 0.68 to 0.74 for DRO90-1 at higher affected fractions. Paclitaxel did not enhance G207 viral entry and early gene expression or G207 viral replication. Paclitaxel combined with G207 compared with single-agent treatment or controls showed significantly increased microtubule acetylation, mitotic arrest, aberrant chromatid separation, inhibition of metaphase to anaphase progression, and apoptosis. A single i.t. injection of G207 combined with biweekly i.p. paclitaxel injections in athymic nude mice bearing KAT4 flank tumors showed significantly reduced mean tumor volume (74 +/- 38 mm(3)) compared with G207 alone (388 +/- 109 mm(3)), paclitaxel alone (439 +/- 137 mm(3)), and control (520 +/- 160 mm(3)) groups at 16 days. There was no morbidity in vivo attributable to therapy.


CONCLUSIONS
Mechanisms of paclitaxel antitumoral activity, including microtubule acetylation, mitotic block, and apoptosis, were enhanced by G207, which also has direct oncolytic effects. Combination of G207 and paclitaxel therapy is synergistic in treating ATC and holds promise for patients with this fatal disease.
Lin
Shu-Fu
SF
Department of Surgery and Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Gao
Sizhi Paul
SP
Price
Daniel L
DL
Li
Sen
S
Chou
Ting-Chao
TC
Singh
Paramjeet
P
Huang
Yu-Yao
YY
Fong
Yuman
Y
Wong
Richard J
RJ
D000107:Acetylation; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002277:Carcinoma / Q000188:drug therapy / Q000628:therapy* / Q000821:virology; D002470:Cell Survival / Q000187:drug effects; D003131:Combined Modality Therapy; D004317:Doxorubicin / Q000008:administration & dosage; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008938:Mitosis; D050130:Oncolytic Virotherapy; D050504:Oncolytic Viruses / Q000235:genetics*; D017239:Paclitaxel / Q000008:administration & dosage; D018139:Simplexvirus / Q000502:physiology*; D013964:Thyroid Neoplasms / Q000188:drug therapy / Q000628:therapy* / Q000821:virology; D014779:Virus Replication
D004317:Doxorubicin; D017239:Paclitaxel