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

我们研究了辐射和emitefur的联合作用，emitefur是一种新开发的抗癌剂，由5-氟尿嘧啶（5-FU）的掩蔽形式和5-FU降解的有效抑制剂组成，在小鼠肿瘤中。对12.5和25 mg/kg剂量的Emitefur单独或与单次（15 Gy）、5次（每次4 Gy）或10次（每次2.8 Gy）照射联合使用肿瘤生长延迟试验对SCCVII肿瘤进行评估，并与4次（每次5 Gy）照射联合使用体内体外试验对EMT6肿瘤进行评估。除10组分外，12.5 mg/kg放射物的抗肿瘤和增强辐射作用均不显著。另一方面，单独或与辐射联合给予25毫克/公斤放射物的多次剂量会产生明显的效果。这种组合所带来的生长延迟的增加至少是累加的。4份5 Gy剂量加25mg/kg剂量的放射物对EMT6肿瘤的作用低于4份7.5…More Gy剂量的放射物对SCCVII肿瘤的作用与5份6 Gy剂量的作用相似，10份2.8 Gy剂量加25mg/kg剂量的放射物对SCCVII肿瘤的作用远高于10份4.2 Gy剂量的放射物。即使在临床相关的剂量水平下，Emitefur单独或与辐射联合使用似乎也具有显著的抗肿瘤作用，尽管阈值剂量存在于12.5至25mg /kg之间。该化合物的进一步临床研究是必要的。我们还研究了抗肿瘤前药5-FU OFU001[1 -（2'-氧丙基）-5-氟尿嘧啶]的放射化学反应性和生物学效应。用高效液相色谱法测定好氧或缺氧辐照后OFU001溶解于磷酸盐缓冲液中5-FU的释放量。为了研究其体外抗肿瘤作用，将化合物溶解在培养基中，在好氧和缺氧条件下照射，SCCVII细胞在培养基中培养1 ~ 6小时。低氧照射时化合物释放5-FU的g值为1.8，好氧照射时化合物释放5-FU的g值为0.1。在缺氧条件下辐照15-30 Gy的OFU001对SCCVII细胞有细胞毒性作用，而在有氧条件下辐照的化合物几乎没有细胞毒性。我们的研究提示了利用这一思路开发新的辐射激活抗肿瘤前药的可能性。此外，我们还分析了食管癌和肺癌放化疗联合治疗的临床结果。这些研究是在南斯拉夫克拉古耶瓦茨大学医院进行的，分析显示了非常有希望的结果，似乎优于单独放射治疗所获得的结果。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