| Co-Investigator(Kenkyū-buntansha) |
KOKUBO Masaki Kyoto University, Graduate School of Medicine, Assistant Professor, 医学研究科, 助手 (90283605)
SASAI Keisuke Kyoto University, Graduate School of Medicine, Associate Professor, 医学研究科, 助教授 (20225858)
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| Budget Amount *help |
¥3,800,000 (Direct Cost: ¥3,800,000)
Fiscal Year 2000: ¥1,800,000 (Direct Cost: ¥1,800,000)
Fiscal Year 1999: ¥2,000,000 (Direct Cost: ¥2,000,000)
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| Research Abstract |
We investigated the radiosensitivity and hypoxic fraction of human pancreatic cancer cells xenografted in nude mice, and the efficacy of a new hypoxic cell radiosensitizer doranidazole against them. Although a clinical study of doranidazole in combination with intraoperative radiotherapy is ongoing in Japan for localized unresectable pancreatic cancer, few data have been reported on these issues.
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 min 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) o
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r 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.
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.
In summary, the four xenografted pancreatic cancers had hypoxic fractions of 10-27% (mean : 18%). These results might suggest that the use of a hypoxic cell sensitizer is reasonable in intraoperative radiotherapy for unresectable pancreatic cancer. Doranidazole had definite in vitro and in vivo effects on all pancreatic cancer cell lines, but the SERs were not high enough. Dose escalation should be investigated in future clinical studies. Less
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