Fujiwara K, Modest E J, Welander C E, Wallen C A
Department of Radiology, Bowman Gray School of Medicine of Wake Forest University, Winston-Salem, North Carolina 27103.
Cancer Res. 1989 Nov 15;49(22):6285-9.
Ether lipid (EL) analogues of platelet activating factor are known to have a cell membrane-mediated antitumor activity. Although previous studies demonstrated additive interactions with EL and conventional DNA-interacting chemotherapeutic agents, little is known about the interaction of EL with heat. In this study, the cytotoxic interaction of one EL analogue, ET-18-OMe, with heat was measured at two different temperatures, 42 and 44 degrees C, using BG-1 human ovarian carcinoma cells. When the number of colonies, greater than or equal to 40 microns in diameter, was counted as a function of incubation time, the rate of colony formation was suppressed by treatment with ET-18-OMe alone at doses greater than or equal to 2.0 microM or with heat alone. The combination of ET-18-OMe with heat inhibited the colony formation of the slowest growing fraction of the heated cells. The dose-response curve for BG-1 cells after continuous exposure to ET-18-OMe alone was exponential with a small shoulder (Dq = 0.25 microM). The T0 value (the time to reduce survival on the exponential portion of the curve by a factor of 1/e) of the 44 degrees C dose-response curve (30 min) was reduced to half (15 min) by the addition of 0.25 to 1.0 microM ET-18-OMe, but increased again to 24 min when heat was combined with ET-18-OMe concentrations greater than or equal to 2.0 microM. The thermotolerant tail seen in the dose-response curve after continuous heating at 42 degrees C was removed by adding as little as 0.25 microM ET-18-OMe. Isobologram analysis for the combined treatments with 44 degrees C heat and ET-18-OMe at surviving fractions of 0.5, 0.3, 0.1, and 0.01 showed that the treatments were supraadditive at low concentrations (less than 0.5 microM) of ET-18-OMe and additive at moderate concentrations (0.5 to 1.0 microM) of ET-18-OMe. Similarly, the interaction of ET-18-OMe with 42 degrees C heat at surviving fractions of 0.3 and 0.1 was supraadditive at low concentrations (less than 0.5 microM) of the ET-18-OMe and additive with moderate concentrations (0.5 to 1.5 microM) of ET-18-OMe. Because the greatest interaction of ET-18-OMe and heat occurred at clinically achievable doses of both agents, this combination of agents should be considered for use in clinical trials.
已知血小板活化因子的醚脂（EL）类似物具有细胞膜介导的抗肿瘤活性。尽管先前的研究表明EL与传统的DNA相互作用化疗药物具有相加作用，但关于EL与热的相互作用却知之甚少。在本研究中，使用BG-1人卵巢癌细胞在42和44摄氏度这两个不同温度下测量了一种EL类似物ET-18-OMe与热的细胞毒性相互作用。当将直径大于或等于40微米的集落数量作为孵育时间的函数进行计数时，单独用剂量大于或等于2.0微摩尔/升的ET-18-OMe处理或单独加热均可抑制集落形成率。ET-18-OMe与热的联合处理抑制了受热细胞中生长最慢部分的集落形成。单独连续暴露于ET-18-OMe后，BG-1细胞的剂量反应曲线呈指数形式且有一个小的肩部（Dq = 0.25微摩尔/升）。44摄氏度剂量反应曲线（30分钟）的T0值（使曲线指数部分的存活率降低1/e的时间）通过添加0.25至1.0微摩尔/升的ET-18-OMe降低至一半（15分钟），但当热与浓度大于或等于2.0微摩尔/升的ET-18-OMe联合时又增加至24分钟。在42摄氏度连续加热后的剂量反应曲线中出现的热耐受尾部通过添加低至0.25微摩尔/升的ET-18-OMe而消除。对44摄氏度热与ET-18-OMe在存活分数为0.5、0.3、0.1和0.01时的联合处理进行等效线分析表明，在低浓度（小于0.5微摩尔/升）的ET-18-OMe下处理具有超相加作用，而在中等浓度（0.5至1.0微摩尔/升）的ET-18-OMe下具有相加作用。同样，在存活分数为0.3和0.1时，ET-18-OMe与42摄氏度热的相互作用在低浓度（小于0.5微摩尔/升）的ET-18-OMe下具有超相加作用，而在中等浓度（0.5至1.5微摩尔/升）的ET-18-OMe下具有相加作用。由于ET-18-OMe与热之间最大的相互作用发生在两种药物临床可达到的剂量下，因此应考虑将这种药物组合用于临床试验。
