1-(4--hydroxy-2--butenoxy)methyl-2-nitroimidazole and Pancreatic-Neoplasms

RK-28 is one of the new hypoxic cell radiosensitizers being developed in Japan and has been tested clinically. To reduce its toxicity and increase its sensitizing activity, intratumoral injection of RK-28 was performed during intraoperative radiation therapy for pancreatic cancer. This report presents the results of pharmacokinetic studies performed in 10 of the 17 patients who were administrated intravenous or intratumoral RK-28 during intraoperative radiation therapy. No adverse effects were noted following intravenous or intratumoral injection of the drug. Pharmacokinetic studies demonstrated several metabolites of RK-28 in both serum and tumor tissues. After intratumoral injection, the tumor drug concentration ranged from 123 micrograms/g to 9,292 micrograms/g just after intraoperative radiation therapy (30-50 min after injection of the compound), while the serum concentration ranged from 4.1 to 9.8 micrograms/ml. The tumor drug concentration was 23.3 micrograms/g at 45 min after intravenous injection of RK-28. Thus, intratumoral injection of RK-28 was superior to intravenous administration in this pharmacokinetic study. The combination of intraoperative radiation therapy and intratumoral injection of RK-28 appears to be a feasible treatment method.

Topics: Adult; Aged; Aged, 80 and over; Female; Humans; Male; Middle Aged; Misonidazole; Pancreatic Neoplasms; Radiation-Sensitizing Agents

The radiosensitivity of pancreatic cancer, optimum dose of irradiation and the effect of 1-[(4'-Hydroxy-2'-Butenoxy) Methyl]-2-Nitrosoimidazole (RK-28) on irradiation were investigated using an experimental pancreatic cancer of hamster and the following results were obtained: i) The mean lethal dose (Do) and the 50% tumor control dose (TCD50) against the pancreatic cancer were 3.5 Gy and 73.7 +/- 6.9 Gy, respectively. These results indicate that the pancreatic cancer is resistant to irradiation, which could be explained by the existence of hypoxic cells consisting of 35% of the tumor. ii) The dose of intraoperative irradiation (10-40 Gy) seemed to be insufficient to bring long-term anti-tumor effect and long-term survival since that dose resulted in only temporary regression of the tumor. iii) The hypoxic cell sensitizer (RK28), which is known to specifically enhance the sensitivity of hypoxic cells to irradiation, lowered TCD50 of the pancreatic cancer to 53.8 +/- 1.57Gy. Therefore, RK-28 was effective in the treatment of the experimental pancreatic cancer (the enhancement ratio: 1.37). When combined with 30 or 40 Gy of irradiation, which is applicable to intraoperative irradiation, RK-28 induced a longer period of tumor suppression and a higher tumor regression ratio than irradiation alone. These results indicate that RK-28 significantly increases the effect of intraoperative irradiation and this combination therapy could possibly induce remarkable effect on tumor regression and long-term survival.

Topics: Adenocarcinoma; Animals; Cell Division; Combined Modality Therapy; Cricetinae; Intraoperative Care; Mesocricetus; Misonidazole; Pancreatic Neoplasms; Radiation-Sensitizing Agents; Radiotherapy Dosage