Enhanced local tumour control after single or fractionated radiation treatment using the hypoxic cell radiosensitizer doranidazole.

Objective: This study was designed to assess the potential of the nitroaromatic radiosensitizer doranidazole to preferentially enhance radiation-induced local control in a murine tumour.

Methods: A C3H mammary carcinoma grown in the right rear foot of female CDF1 mice was used and treated when at 200 mm(3) in size. Doranidazole was dissolved in saline and injected intravenously.

X irradiation combined with TNF alpha-related apoptosis-inducing ligand (TRAIL) reduces hypoxic regions of human gastric adenocarcinoma xenografts in SCID mice.

Our previous study showed that X irradiation induced the expression of death receptor DR5 on the cell surface in tumor cell lines under not only normoxia but also hypoxia. X irradiation combined with TNF alpha-related apoptosis-inducing ligand (TRAIL), which is the ligand of DR5, induced apoptosis in vitro (Takahashi et al., (2007) Journal of Radiation Research, 48: 461-468).

Enhancement of cell death by TNF alpha-related apoptosis-inducing ligand (TRAIL) in human lung carcinoma A549 cells exposed to x rays under hypoxia.

Our previous study showed that ionizing radiation induced the expression of death receptor DR5 on the cell surface in tumor cell lines and that the death receptor of the TNF alpha-related apoptosis-inducing ligand TRAIL enhanced the apoptotic pathway (Hamasu et al., (2005) Journal of Radiation Research, 46:103-110). The present experiments were performed to examine whether treatment with TRAIL enhanced the cell killing in tumor cells exposed to ionizing radiation under hypoxia, since the presence of radioresistant cells in hypoxic regions of solid tumors is a serious problem in radiation therapy for tumors.

Initial evaluation of dynamic human imaging using 18F-FRP170 as a new PET tracer for imaging hypoxia.

Unlabelled: 18F-FRP170, 1-(2-fluoro-1-[hydroxymethyl]ethoxy)methyl-2-nitroimidazole, is a new hypoxia imaging agent for positron emission tomography. This compound was synthesized by 18F-labeling of RP170, which was developed as a new hydrophilic 2-nitroimidazole analog. In the present study, we analyzed dynamic whole-body imaging in healthy volunteers and dynamic tumor imaging in three patients with lung cancer.

Effect of a hypoxic cell sensitizer doranidazole on the radiation-induced apoptosis of mouse L5178Y lymphoma cells.

We investigated the sensitizing effect of the 2-nitroimidazole analogue doranidazole, a new hypoxic radiosensitizer, on radiation-induced apoptosis in L5178Y cells. Apoptosis was assessed by checking DNA ladder formation, the presence of sub-G1 peaks in flow cytometry, and chromatin condensation. A radiosensitizing effect of doranidazole was also confirmed by a soft-agar colony assay of surviving cells.

Radiation-chemical properties of the hypoxic cell radiosensitizer doranidazole (PR-350).

This study was performed to confirm the radiation-chemical properties of the 2-nitroimidazole derivative doranidazole, (+/-)-(2RS,3SR)-3-[(2-nitroimdazol-1-yl)-methoxy]butane-1,2,4-triol [CAS 137339-64-1], PR-350, which was synthesized as a hypoxic cell radiosensitizer with low toxicity. Radiation-chemical experiments using doranidazole showed that (1) unlike O2, it had high reactivity toward not only hydrated electrons (eaq-), but also hydroxyl radicals (.OH), (2) the reduced intermediates of doranidasole had no ability to induce immediate strand breaks of colE1 plasmid DNA, (3) doranidazole enhanced radiation-induced DNA strand breaks of colE1 plasmid DNA in the aqueous state, whereas it did not enhance the base alteration, such as 8-oxo-deoxyguanosine, (4) it enhanced the radiation-induced formation of strand breaks with 3'-phosophate and 3'-phosphoglycolate termini, and (5) it was bound to DNA after irradiation.

Imaging of ischemic but viable myocardium using a new 18F-labeled 2-nitroimidazole analog, 18F-FRP170.

Unlabelled: RP170, 1-(2-hydroxy-1-[hydroxymethyl]ethoxy)methyl-2-nitroimidazole, is a new hypoxic radiosensitizer. We recently succeeded in labeling this compound with 18F to make 18F-FRP170, 1-(2-fluoro-1-[hydroxymethyl]ethoxy)methyl-2-nitroimidazole. In this study, we attempted to visualize the ischemic but viable myocardium of rats as hot-spot images using 18F-FRP170.