Studies on the optimal combination therapy with radiation and new anticancer agents

我们研究了辐射和艾米氟的联合作用，艾米氟是一种新开发的抗癌药物，由掩蔽形式的5-氟尿嘧啶(5-FU)组成，并有效地抑制了5-FU的降解。对于SCCVII肿瘤，采用肿瘤生长延迟法评价12.5和25 mg/kg剂量的依米替夫，对于EMT6肿瘤，采用体内体外试验，评价12.5和25 mg/kg剂量的依米替夫单独或与单次(15GY)、5次(每次4GY)或10次(每次2.8GY)照射联合照射的效果。除10组分实验外，12.5 mg/kg组小鼠的抗肿瘤和辐射增强作用均不显著。另一方面，单独或与辐射联合使用多次剂量的25毫克/公斤的艾美氟产生了显著的效果。这种组合带来的增长延迟增加至少是相加的。放射剂量为25 mg/kg的4次5GyEMT6肿瘤的疗效低于4次7.5…的疗效2.8Gy25 mg/kg照射10次的疗效明显高于4.2Gy10次照射的疗效。即使在临床相关的剂量水平上，单独给予或与放射联合给予依米特氟似乎也有显著的抗肿瘤作用，尽管阈值剂量存在于12.5至25 mg/kg之间。我们还考察了抗肿瘤前药5-FU-OFU001[1-(2‘-氧丙基)-5-氟尿嘧啶]的放射化学反应和生物学效应。用高效液相色谱法测定在有氧或低氧照射后，OFU001在磷酸盐缓冲液中的5-FU释放量。为研究化合物的体外抗肿瘤作用，将溶解于培养液中的化合物分别在有氧和低氧条件下照射1~6h，低氧照射后5-FU释放G值为1.8，有氧照射后G值为0.1。OFU001在低氧条件下照射15-30Gy时对SCCVII细胞有杀伤作用，而在有氧条件下照射对SCCVII细胞几乎没有细胞毒作用。我们的研究提出了利用这一理念开发新的辐射激活抗肿瘤前药的可能性。此外，我们还分析了放化疗联合治疗食管癌和肺癌的临床效果。这些研究是在南斯拉夫克拉古耶瓦克的大学医院进行的。分析显示，非常有希望的结果似乎优于仅通过放射治疗获得的结果。较少

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 … More 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