Imaging progress of herpes simplex virus type 1 thymidine kinase suicide gene therapy in living subjects with positron emission tomography.
Molecular imaging of a suicide transgene's expression will aid the development of efficient and precise targeting strategies, and imaging for cancer cell viability may assess therapeutic efficacy. We used the PET reporter probe, 9-(4-[18F]fluoro-3-(hydroxymethyl)butyl)guanine ([18F]FHBG) to monitor the expression of a mutant Herpes Simplex Virus 1 thymidine kinase (HSV1-sr39tk) in C6 glioma tumors implanted subcutaneously in nude mice that were repetitively being treated with the pro-drug Ganciclovir (GCV). [18F]-Fluorodeoxyglucose ([18F]FDG), a metabolic tracer, was used to assess tumor cell viability and therapeutic efficacy. C6 glioma tumors stably expressing the HSV1-sr39tk gene (C6sr39) accumulated [18F]FHBG prior to GCV treatment. Significant declines in C6sr39 tumor volumes and [18F]FHBG and [18F]FDG accumulation were observed following 2 weeks of GCV treatment. However, 3 weeks after halting GCV treatment, the tumors re-grew and [18F]FDG accumulation increased significantly; in contrast, tumor [18F]FHBG concentrations remained at background levels. Therefore, [18F]FHBG can be used to detect tumors expressing HSV1-sr39tk, susceptible to regression in response to GCV exposure, and the effectiveness of GCV therapy in eradicating HSV1-sr39tk-expressing cells can be monitored by [18F]FHBG scanning. [18F]FHBG and [18F]FDG imaging data indicate that exposure of C6sr39 tumors to GCV causes the elimination of [18F]FHBG-accumulating C6sr39 cells and selects for re-growth of tumors unable to accumulate [18F]FHBG.
Yaghoubi
Shahriar S
SS
Department of Molecular & Medical Pharmacology, UCLA School of Medicine, Los Angeles, California 90095-1770, USA.
Barrio
Jorge R
JR
Namavari
Mohammad
M
Satyamurthy
Nagichettiar
N
Phelps
Michael E
ME
Herschman
Harvey R
HR
Gambhir
Sanjiv S
SS
D000818:Animals; D045744:Cell Line, Tumor; D003952:Diagnostic Imaging / Q000379:methods*; D005462:Fluorine Radioisotopes; D019788:Fluorodeoxyglucose F18; D015774:Ganciclovir / Q000627:therapeutic use; D015870:Gene Expression; D041722:Genes, Transgenic, Suicide / Q000235:genetics*; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics / Q000627:therapeutic use*; D005910:Glioma / Q000188:drug therapy / Q000235:genetics / Q000628:therapy*; D006147:Guanine / Q000031:analogs & derivatives*; D018259:Herpesvirus 1, Human / Q000235:genetics* / Q000378:metabolism; D007091:Image Processing, Computer-Assisted; D051379:Mice; D008819:Mice, Nude; D049268:Positron-Emission Tomography; D051381:Rats; D013937:Thymidine Kinase / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use*; D013997:Time Factors; D014183:Transplantation, Heterologous
C113308:9-(4-fluoro-3-hydroxymethylbutyl)guanine; D005462:Fluorine Radioisotopes; D019788:Fluorodeoxyglucose F18; D006147:Guanine; D013937:Thymidine Kinase; D015774:Ganciclovir