Radiosensitivity of human pancreatic cancer cells in vitro and in vivo, and the effect of a new hypoxic cell sensitizer, doranidazole

Background and purpose: A clinical study of the new 2-nitroimidazole nucleo side analogue doranidazole (PR-350) in combination with intraoperative radi otherapy is ongoing in Japan for localized unresectable pancreatic cancer. However, few data have been reported on the radiosensitivity and hypoxic fr action of human pancreatic cancers, and the efficacy of doranidazole agains t them. This study was undertaken to address these issues. Materials and methods: In vitro, four established human pancreatic cancer c ell lines (SUIT-2, PANC-1, MIA PaCa-2 and BxPC-3) and murine SCCVII tumor c ells (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 re ceived whole-body irradiation either after cervical dislocation, without ph ysical restraint or anesthesia, or 20 min after intravenous injection of 10 0 mg/kg (0.4 mmol/kg) or 250 mg/kg (1 mmol/kg) of doranidazole. Following i rradiation, 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 ha d no sensitizing effect under aerobic conditions, but under hypoxic conditi ons, 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 w as 20% (95% CI, 11-38%) in SUIT-2, 14% (6.5-28%) in PANC-1, 10% (5.9-16%) i n MIA PaCa-2, and 27% (15-46%) in BxPC-3 tumors. The SER of doranidazole wa s 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 frac tions of 10-27% (mean: 18%). Doranidazole had definite in vitro and in vivo effects on all pancreatic cancer cell lines. (C) 2000 Elsevier Science Ire land Ltd. All rights reserved.