Holahan E V, Highfield D P, Holahan P K, Dewey W C
Radiat Res. 1984 Jan;97(1):108-31.
To quantitatively relate heat killing and heat radiosensitization, asynchronous or G1 Chinese hamster ovary (CHO) cells at pH 7.1 or 6.75 were heated and/or X-irradiated 10 min later. Since no progression of G1 cells into S phase occurred during the heat and radiation treatments, cell cycle artifacts were minimized. However, results obtained for asynchronous and G1 cells were similar. Hyperthermic radiosensitization was expressed as the thermal enhancement factor (TEF), defined as the ratio of the D0 of the radiation survival curve to that of the D0 of the radiation survival curve for heat plus radiation. The TEF increased continuously with increased heat killing at 45.5 degrees C, and for a given amount of heat killing, the amount of heat radiosensitization was the same for both pH's. When cells were heated chronically at 42.4 degrees C at pH 7.4, the TEF increased initially to 2.0-2.5 and then returned to near 1.0 during continued heating as thermal tolerance developed for both heat killing and heat radiosensitization. However, the shoulder (Dq) of the radiation survival curve for heat plus radiation did not manifest thermal tolerance; i.e., it decreased continuously with increased heat killing, independent of temperature, pH, or the development of thermotolerance. These results suggest that heat killing and heat radiosensitization have a target(s) in common (TEF results), along with either a different target(s) or a difference in the manifestation of heat damage (Dq results). For clinical considerations, the interaction between heat and radiation was expressed as (1) the thermal enhancement ratio (TER), which is the dose of X rays alone divided by the dose of X rays combined with heat to obtain an isosurvival, e.g., 10(-4), and (2) the thermal gain factor (TGF), the ratio of the TER at pH 6.75 to the TER at pH 7.4. Since low pH reduced the rate of development of thermal tolerance during heating at low temperatures, low pH enhanced heat killing more at 42-42.5 degrees C than at 45.5 degrees C where thermal tolerance did not develop. Therefore, the increase in the TGF after chronic heating at 42-42.5 degrees C was greater than after acute heating at 45.5 degrees C, due primarily to the increase in heat killing causing an even greater increase in heat radiosensitization. These findings agree with animal experiments suggesting that in the clinic, a therapeutic gain for tumor cells at low pH may be greater for temperatures of 42-42.5 degrees C than of 45.5 degrees C.
为了定量关联热杀伤和热放射增敏作用，将处于pH 7.1或6.75的异步或G1期中国仓鼠卵巢（CHO）细胞加热，并在10分钟后进行X射线照射。由于在加热和辐射处理过程中G1期细胞没有进入S期，细胞周期假象被最小化。然而，异步细胞和G1期细胞得到的结果相似。热放射增敏作用用热增强因子（TEF）表示，定义为辐射存活曲线的D0与加热加辐射的辐射存活曲线的D0之比。在45.5℃时，随着热杀伤增加，TEF持续升高，并且对于给定的热杀伤量，两种pH值下的热放射增敏量相同。当细胞在pH 7.4条件下于42.4℃长期加热时，随着热耐受的发展，TEF最初升高至2.0 - 2.5，然后在持续加热过程中恢复到接近1.0，热耐受同时针对热杀伤和热放射增敏。然而，加热加辐射的辐射存活曲线的坪区（Dq）并未表现出热耐受；即，它随着热杀伤增加而持续降低，与温度、pH或热耐受的发展无关。这些结果表明，热杀伤和热放射增敏有共同的靶点（TEF结果），同时存在不同的靶点或热损伤表现的差异（Dq结果）。出于临床考虑，热与辐射之间的相互作用表示为：（1）热增强比（TER），即单独的X射线剂量除以与热联合使用以获得等存活（例如存活分数为10⁻⁴）的X射线剂量；（2）热增益因子（TGF），即pH 6.75时的TER与pH 7.4时的TER之比。由于低pH降低了低温加热过程中热耐受的发展速率，在42 - 42.5℃时，低pH比在不产生热耐受的45.5℃时更能增强热杀伤。因此，在42 - 42.5℃长期加热后TGF的增加大于在45.5℃急性加热后，这主要是由于热杀伤增加导致热放射增敏进一步大幅增加。这些发现与动物实验结果一致，表明在临床上，对于肿瘤细胞，在低pH条件下，42 - 42.5℃时的治疗增益可能大于45.5℃时。
