The combination of adenoviral HSV TK gene therapy and radiation is effective in athymic mouse glioblastoma xenografts without increasing toxic side effects.
OBJECTIVE
In mouse models of prostate and breast cancer therapeutic effects are enhanced when adenoviral HSV TK gene therapy is combined with ionizing radiation. In the present study, we adopted this approach for the treatment of human glioblastoma xenografts in an athymic mouse model and assessed treatment results as well as toxic side effects.


METHODS
About 72 nude mice received intracerebral inoculations of 2 x 10(5) U87deltaEGFR cells. On day 7 after tumor implantation the study population was randomized into six treatment arms: (1) intratumoral buffer inoculation on day 7, (2) intratumoral adenoviral vector injection (2 x 10(9) vp) on day 7, (3) single dose radiation (2.1 Gy) on day 9, (4) adenoviral injection + radiation, (5) adenoviral injection + ganciclovir (GCV) (20 microg/g twice daily from day 8 to 17), (6) adenoviral injection + GCV + radiation. On day 21 half of the animals were sacrificed for histological evaluation of the brain tumors, the other half was assessed for survival.


RESULTS
This study showed significantly prolonged median survival time of 5 days for the GCV treated groups. The addition of radiation decreased the frequency of neurological symptoms and delayed the onset of deficits without altering the expression of thymidine kinase in the tumor cells.


CONCLUSIONS
We conclude that adenoviral HSV TK gene therapy in combination with adjuvant radiotherapy does not generate increased toxic side effects in glioblastoma treatment. The prolonged survival time of animals receiving gene therapy and the reduced occurrence of neurological symptoms in irradiated mice constitute promising features of the combined treatment.
Nestler
Ulf
U
Molecular Neuro-Oncology Laboratory, Department of Radiation Oncology, Massachusetts General Hospital East, Charlestown, MA, USA. ulf.nestler@neuro.med.uni-giessen.de
Wakimoto
Hiroaki
H
Siller-Lopez
Fernando
F
Aguilar
Laura K
LK
Chakravarti
Arnab
A
Muzikansky
Alona
A
Stemmer-Rachamimov
Anat
A
Chiocca
E Antonio
EA
Aguilar-Cordova
Estuardo
E
Hochberg
Fred H
FH
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D005260:Female; D015774:Ganciclovir / Q000494:pharmacology; D015316:Genetic Therapy / Q000009:adverse effects; D005909:Glioblastoma / Q000628:therapy*; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008819:Mice, Nude; D011878:Radiotherapy / Q000009:adverse effects; D018139:Simplexvirus / Q000235:genetics*; D013937:Thymidine Kinase / Q000235:genetics / Q000378:metabolism; D014183:Transplantation, Heterologous
D000998:Antiviral Agents; D013937:Thymidine Kinase; D015774:Ganciclovir