Mutant sodium channel for tumor therapy.
Viral vectors have been used to deliver a wide range of therapeutic genes to tumors. In this study, a novel tumor therapy was achieved by the delivery of a mammalian brain sodium channel, ASIC2a, carrying a mutation that renders it constitutively open. This channel was delivered to tumor cells using a herpes simplex virus-1/Epstein-Barr virus (HSV/EBV) hybrid amplicon vector in which gene expression was controlled by a tetracycline regulatory system (tet-on) with silencer elements. Upon infection and doxycycline induction of mutant channel expression in tumor cells, the open channel led to amiloride-sensitive sodium influx as assessed by patch clamp recording and sodium imaging in culture. Within hours, tumor cells swelled and died. In addition to cells expressing the mutant channel, adjacent, noninfected cells connected by gap junctions also died. Intratumoral injection of HSV/EBV amplicon vector encoding the mutant sodium channel and systemic administration of doxycycline led to regression of subcutaneous tumors in nude mice as assessed by in vivo bioluminescence imaging. The advantage of this direct mode of tumor therapy is that all types of tumor cells become susceptible and death is rapid with no time for the tumor cells to become resistant.
Tannous
Bakhos A
BA
Department of Neurology, Molecular Neurogenetics Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02129, USA. btannous@hms.harvard.edu
Christensen
Adam P
AP
Pike
Lisa
L
Wurdinger
Thomas
T
Perry
Katherine F
KF
Saydam
Okay
O
Jacobs
Andreas H
AH
García-Añoveros
Jaime
J
Weissleder
Ralph
R
Sena-Esteves
Miguel
M
Corey
David P
DP
Breakefield
Xandra O
XO
D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics / Q000502:physiology; D004594:Electrophysiology; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics*; D018259:Herpesvirus 1, Human / Q000235:genetics; D004854:Herpesvirus 4, Human / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D018408:Patch-Clamp Techniques; D012964:Sodium / Q000378:metabolism; D015222:Sodium Channels / Q000235:genetics* / Q000502:physiology*
D015222:Sodium Channels; D012964:Sodium