title: Hypoxia imaging predicts success of hypoxia-induced cytosine deaminase/5-fluorocytosine gene therapy in a murine lung tumor model.
abstract: Tc-99m-HL91 is a hypoxia imaging biomarker. The aim of this study was to investigate the value of Tc-99m-HL91 imaging for hypoxia-induced cytosine deaminase (CD)/5-fluorocytosine (5-FC) gene therapy in a murine lung tumor model. C57BL/6 mice were implanted with Lewis lung carcinoma cells transduced with the hypoxia-inducible promoter-driven CD gene (LL2/CD) or luciferase gene (LL2/Luc) serving as the control. When tumor volumes reached 100 mm(3), pretreatment images were acquired after injection of Tc-99m-HL91. The mice were divided into low and high hypoxic groups based on the tumor-to-non-tumor ratio of Tc-99m-HL91. They were injected daily with 5-FC (500 mg kg(-1)) or the vehicle for 1 week. When tumor volumes reached 1000 mm(3), autoradiography and histological examinations were performed. Treatment with 5-FC delayed tumor growth and enhanced the survival of mice bearing high hypoxic LL2/CD tumors. The therapeutic effect of hypoxia-induced CD/5-FC gene therapy was more pronounced in high hypoxic tumors than in low hypoxic tumors. This study provides the first evidence that Tc-99m-HL91 can serve as an imaging biomarker for predicting the treatment responses of hypoxia-regulated CD/5-FC gene therapy in animal tumor models. Our results suggest that hypoxia imaging using Tc-99m-HL91 has the predictive value for the success of hypoxia-directed treatment regimens.
authors.affiliation: Department of Nuclear Medicine, National Cheng Kung University, College of Medicine and Hospital, Tainan, Taiwan.
authors.forename: B-F
authors.initials: BF
authors.lastname: Lee
authors.forename: C-H
authors.initials: CH
authors.lastname: Lee
authors.forename: N-T
authors.initials: NT
authors.lastname: Chiu
authors.forename: C-C
authors.initials: CC
authors.lastname: Hsia
authors.forename: L-H
authors.initials: LH
authors.lastname: Shen
authors.forename: A-L
authors.initials: AL
authors.lastname: Shiau
mesh_terms: D000818:Animals; D000963:Antimetabolites / Q000627:therapeutic use* / Q000633:toxicity; D001835:Body Weight; D018827:Carcinoma, Lewis Lung / Q000000981:diagnostic imaging / Q000235:genetics / Q000628:therapy*; D015687:Cell Hypoxia; D002460:Cell Line; D043525:Cytosine Deaminase / Q000235:genetics* / Q000378:metabolism; D005437:Flucytosine / Q000627:therapeutic use* / Q000633:toxicity; D015316:Genetic Therapy; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015609:Organotechnetium Compounds; D010091:Oximes; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals; D047368:Tumor Burden / Q000235:genetics
chemical_list: D000963:Antimetabolites; D015609:Organotechnetium Compounds; D010091:Oximes; D019275:Radiopharmaceuticals; C105527:technetium Tc 99m 4,9-diaza-3,3,10,10-tetramethyldodecan-2,11-dione dioxime; D005437:Flucytosine; D043525:Cytosine Deaminase