Radiosensitivity of human pancreatic cancer cells in vitro and in vivo, and the effect of a new hypoxic cell sensitizer, doranidazole.
OBJECTIVE
A clinical study of the new 2-nitroimidazole nucleoside analogue doranidazole (PR-350) in combination with intraoperative radiotherapy is ongoing in Japan for localized unresectable pancreatic cancer. However, few data have been reported on the radiosensitivity and hypoxic fraction of human pancreatic cancers, and the efficacy of doranidazole against them. This study was undertaken to address these issues.


METHODS
In vitro, four established human pancreatic cancer cell lines (SUIT-2, PANC-1, MIA PaCa-2 and BxPC-3) and murine SCCVII tumor cells (for comparison) were used. These cells were treated with 0.4 or 1 mM doranidazole for 45 mm prior to and during aerobic or hypoxic irradiation, and the cell survival was determined using the colony assay. In vivo, Balb/c nude mice bearing the pancreatic cancers (about 200 mg) on their backs received whole-body irradiation either after cervical dislocation, without physical restraint or anesthesia, or 20 min after intravenous injection of 100 mg/kg (0.4 mmol/kg) or 250 mg/kg (1 mmol/kg) of doranidazole. Following irradiation, the in vivo-in vitro assay was performed. The hypoxic fraction was estimated by the paired survival curve method.


RESULTS
Regarding in vitro radiosensitivity, there were no characteristics common to the four pancreatic cancer cell lines. In vitro, doranidazole had no sensitizing effect under aerobic conditions, but under hypoxic conditions, its sensitizer enhancement ratio (SER) was 1.25-1.3 at 0. 4 mM and 1.4-1.55 at 1 mM against the four pancreatic cancer cell lines. These SERs were similar to those obtained in SCCVII cells. In vivo, the hypoxic fraction was 20% (95% CI, 11-38%) in SUIT-2, 14% (6.5-28%) in PANC-1, 10% (5.9-16%) in MIA PaCa-2, and 27% (15-46%) in BxPC-3 tumors. The SER of doranidazole was 1.15-1.3 at the dose of 100 mg/kg and 1.35-1.45 at 250 mg/kg.


CONCLUSIONS
The four xenografted human pancreatic cancers had hypoxic fractions of 10-27% (mean: 18%). Doranidazole had definite in vitro and in vivo effects on all pancreatic cancer cell lines.
Shibamoto
Y
Y
Department of Oncology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto 606-8507, Japan.
Kubota
T
T
Kishii
K
K
Tsujitani
M
M
D000818:Animals; D002470:Cell Survival; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D010179:Pancreas / Q000166:cytology / Q000187:drug effects / Q000528:radiation effects; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000532:radiotherapy*; D011836:Radiation Tolerance; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D012016:Reference Values; D012680:Sensitivity and Specificity; D014407:Tumor Cells, Cultured; D014916:Whole-Body Irradiation / Q000379:methods
D007093:Imidazoles; D011838:Radiation-Sensitizing Agents; C106738:doranidazole