9-(4-fluoro-3-hydroxymethylbutyl)guanine and Breast-Neoplasms

To study the in vitro accumulation of (18)F-FHBG, its in vivo distribution and (18)F-FHBG PET-CT imaging for reporter gene (HSV1-tk) in nude mice with a xenograft of breast adenocarcinoma.. The in vitro uptake of (18)F-FHBG in tumor cells of T47D and T47D-tk and the distribution of (18)F-FHBG in normal Kunming mice and nude mice with breast adenocarcinoma xenograft were detected by well-type gamma counter. Reporter gene PET-CT imaging with (18)F-FHBG was performed in nude mice with a xenograft of breast adenocarcinoma. And the expression location of HSV1-tk gene could be monitored by observing the in vitro and in vivo accumulation of (18)F-FHBG.. The in vitro uptake of (18)F-FHBG in T47D-tk cells (143.67 dpm/10(4) +/- 5.82 dpm/10(4) cells) was significantly higher than that in T47D cells (2.23 dpm/10(4) +/- 0.23 dpm/10(4) cells) at 60 and 120 min post-injection (P < 0.001) and reaches a plateau at 60 min. In normal Kunming mice, (18)F-FHBG was mainly distributed in liver, intestine, kidney and bladder while there was no obvious radioactive accumulation in brain. (18)F-FHBG accumulated at a significantly higher level in T47D-tk tumors than in T47D tumors and its accumulation yielded the best image effect at 2 h by PET-CT imaging in nude mice.. The in vitro uptake of (18)F-FHBG in T47D-tk cells is significantly higher than that in T47D cells. (18)F-FHBG is mainly excreted by digestive tract and urinary tract in mice. It agrees with the expression pattern of HSV1-tk gene. (18)F-FHBG can determine the localization of HSV1-tk gene expression in an efficient way. This study will offer a monitoring method and scientific base for (18)F-FHBG reporter gene imaging and HSV1-tk gene therapy in tumors.

Topics: Adenocarcinoma; Animals; Breast Neoplasms; Cell Line, Tumor; Female; Fluorine Radioisotopes; Genes, Reporter; Genetic Therapy; Guanine; Humans; Mice; Mice, Inbred BALB C; Mice, Inbred Strains; Mice, Nude; Neoplasm Transplantation; Positron-Emission Tomography

2'-Deoxy-2'-fluoro-5-methyl-1-beta-D-arabinofuranosyluracil (FMAU), 9-(4-fluoro-3-hydroxy-methyl-butyl)guanine (FHBG) and 9-[(3-fluoro-1-hydroxy-2-propoxy)methyl]-guanine (FHPG) have been evaluated in a human breast cancer model as potential radiotracers for PET imaging of HSV1-tk gene expression. In vitro accumulation of [14C]FMAU, [18F]FHBG, and [18F]FHPG in HSV1-tk-expressing cells was 14- to 16-fold (p <.001), 9- to 13-fold (p <.001), and 2- to 3-fold (p <.05) higher than tk-negative control cells, respectively, between 30 and 240 min. Accumulation of FMAU and FHBG in vector-transduced cells was 10- to 14-fold and 6- to 10-fold higher than wild-type cells, respectively. At 2 hr, uptake of [(14)C]FMAU in tkpositive cells was 6.3-fold and 60-fold higher than [18F]FHBG and [18F]FHPG, respectively. In vivo, tumor uptake of [14C]FMAU in HSV1-tk-expressing cells was 3.7-fold and 5.5-fold (p <.001) higher than tk-negative control cells at 1 and 2 hr, respectively. Tumor uptake of [18F]FHBG was 4.2-fold and 12.6-fold higher (p <.001) than tk-negative cells at the same time points. Incorporation of [14C]FMAU in tk-positive tumor was 18-fold and 24-fold higher (p <.001) than [18F]FHBG at 1 and 2 hr, respectively. Micro-PET images support the biodistribution results and indicate that both [18F]FMAU and [18F]FHBG are useful for imaging HSV1-tk expression in breast cancer. Although FMAU demonstrates higher total incorporation (%dose/g) in tumor tissue compared with the other tracers, FHBG is superior in terms of specific accumulation in transfected cells at later time points.

Topics: Animals; Arabinofuranosyluracil; Breast Neoplasms; Carbon Radioisotopes; Diagnostic Imaging; Female; Ganciclovir; Gene Expression Regulation, Neoplastic; Gene Expression Regulation, Viral; Guanine; Herpesvirus 1, Human; Humans; Mice; Mice, Nude; Models, Biological; Neoplasm Transplantation; Positron-Emission Tomography; Radiopharmaceuticals; Thymidine Kinase; Time Factors; Tissue Distribution; Tumor Cells, Cultured