Uncoupling of 2-fluoro-2-deoxyglucose transport and phosphorylation in rat hepatoma during gene therapy with HSV thymidine kinase

Abstract

This animal study investigates the application of positron poration into the tumour DNA was determined after i.v. emission tomography (PET) with tracers of tumour metabadministration of 3 H-thymidine. An uncoupling of FDG olism for monitoring suicide gene therapy with herpes simtransport and phosphorylation was found with enhanced K 1 plex virus thymidine kinase (HSVtk). After transplantation and k 2 values and a normal k 3 after 2 days of GCV treatof HSVtk-expressing Morris hepatoma cells into ACI rats, ment. The increase in FDG transport normalized after 4 dynamic PET measurements of 18 F-labeled 2-fluoro-2-days whereas the phosphorylation rate k 3 increased. deoxyglucose (FDG) uptake were performed in animals 2 Quantification using the metabolic rate or the SUV showed days (n = 7) and 4 days (n = 5) after the onset of therapy congruent but less sensitive results compared with the with 100 mg ganciclovir (GCV)/kg body weight as well as modeling approach. The thymidine incorporation into the after administration of sodium chloride (n = 8). The arterial DNA of the tumours declined to 10.5% of the controls after FDG plasma concentration was measured dynamically in 4 days of GCV treatment. The data indicate that PET an extracorporeal loop and the rate constants for FDG with 18 FDG and 11 C-thymidine may be applied for monitortransport (K 1 , k 2 ) and FDG phosphorylation (k 3 ) were caling of gene therapy with the HSVtk/GCV suicide system. culated using a three-compartment model modified for hetIncreased transport rates are evidence of stress reactions erogeneous tissues. Also, quantification using the metaearly after therapy. The measurement of thymidine incorbolic rate of FDG turnover and the standardized uptake poration into the tumour DNA can be used as an indicator value (SUV) was done. Furthermore, the thymidine incorof therapy efficacy.

Imaging-Guided Gene Therapy of Experimental Gliomas

“…Some authors have reported noninvasive imaging follow-up of suicide gene therapy in experimental models, but these studies were usually done on tumors grown from stably transfected cell lines (33)(34)(35)(36). Few studies used molecular imaging-guided followup after transduction of therapeutic genes in vivo using adenoviral (37,38) and lentiviral vectors (39).…”

Tumor-specific gene expression using regulatory elements of the glucose transporter isoform 1 gene

“…This effect has been observed in former in vivo experiments. 39 In conclusion, the in vitro and in vivo assays performed so far indicate that the GLUT1 promoter shows high activity in tumor cells and no significant activity in nontumor cells. When GLUT1 is used as the regulatory element for HSVtk, a cytotoxic effect after GCV treatment is restricted to tumor tissue, a fact that makes GLUT1 a promising regulatory element for use in a tumor-specific gene therapy.…”

MIA (melanoma inhibitory activity) promoter mediated tissue-specific suicide gene therapy of malignant melanoma

“…Therefore, after failure of the ex vivo gene transfer the approach using a stable HSVtk expressing melanoma cell line was chosen to demonstrate the in vivo efficiency of the HSVtk/GCV system under control of the MIA promoter for therapy of malignant melanoma. Since other studies showed that HSVtk expression controlled by unspecific promoters lead to disappearance of the tumor, 52 a similar experiment with stable CMV-HSVtktransduced melanoma cells was not performed. In the future, the in vivo transduction efficiency has to be improved, in order to achieve a therapeutically sufficient enzyme activity after a single or a repeated application of virus particles.…”