| Budget Amount *help |
¥3,900,000 (Direct Cost: ¥3,900,000)
Fiscal Year 1998: ¥1,700,000 (Direct Cost: ¥1,700,000)
Fiscal Year 1997: ¥2,200,000 (Direct Cost: ¥2,200,000)
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| Research Abstract |
We investigated the combined effect of radiation and emitefur, a newly developed anticancer agent consisting of a masked form of 5-fluorouracil (5-FU) and a potent inhibitor of 5-FU degradation, in murine tumors. Emitefur at doses of 12.5 and 25 mg/kg was evaluated either alone or in combination with single (15 Gy), 5-fraction (4 Gy each) or 10-fraction (2.8 Gy each) irradiation using a tumor growth delay assay for SCCVII tumors and in combination with 4-fraction (5 Gy each) irradiation using an in vivo-in vitro assay for EMT6 tumors. The antitumor and radiation-enhancing effects of 12.5 mg/kg emitefur were not significant in any except the 10-fraction experiment. On the other hand, multiple doses of 25 mg/kg emitefur given either alone or in combination with radiation produced marked effects. The increase in growth delay afforded by this combination was at least additive. The effect of 4 fractions of 5 Gy with 25 mg/kg emitefur in EMT6 tumors was lower than that of 4 fractions of 7.5
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Gy, but the effect of 5 fractions of 4 Gy with this dose of emitefur in SCCVII tumors was similar to the effect of 5 fractions of 6 Gy, and the effect of 10 fractions of 2.8 Gy with 25mg/kg emitefur was much higher than that of 10 fractions of 4.2 Gy. Emitefur given either alone or in combination with radiation appeared to have a significant antitumor effect even at clinically relevant dose levels, although a threshold dose exists between 12.5 and 25 mg/kg. Further clinical studies of this compound are warranted.
We also investigated the radiation chemical reactivity and biological effects of an antitumor prodrug of 5-FU, OFU001 [1 -(2'-oxopropyl)-5-fluorouracil]. Release of 5-FU from OFU001 dissolved in phosphate buffer following aerobic or hypoxic irradiation was measured by high-performance liquid chromatography. To investigate in vitro antitumor effect, the compound dissolved in culture medium was irradiated under both aerobic and hypoxic conditions and SCCVII cells were cultured with the medium for 1 to 6 h. The compound released 5-FU at a G-value of 1.8 following hypoxic irradiation but at 0.1 following aerobic irradiation. OFU001 irradiated at 15-30 Gy under hypoxic conditions had cytotoxic effect against SCCVII cells, whereas the compound irradiated under aerobic conditions showed little cytotoxicity. Our study suggested the possibility of developing new radiation-activating antitumor prodrugs using this idea.
Furthermore, weanalyzed the clinical results of combined radiotherapy and chemotherapy for esophageal and lung cancers. The studies had been performed at University Hospital, Kragujevac, Yugoslavia The analyses showed very promising results which appeared to be superior to those obtained by radiotherapy alone. Less
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