Siemann D W, Maddison K, Wolf K, Hill S A, Keng P C
Cancer Res. 1985 Jan;45(1):198-202.
The effect of combining the radiosensitizer misonidazole (MISO) with 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) prior to radiation on the response of various KHT sarcoma cell subpopulations was evaluated. Centrifugal elutriation was used to obtain homogeneous populations of cells with respect to their cell cycle position from suspensions prepared directly from treated solid KHT tumors. Survival in these subpopulations was determined using an in vivo to in vitro cloning assay. In situ treatment consisted of either (a) CCNU (3.0 mg/kg) plus MISO (1.0 mg/g), (b) radiation (15 Gy) alone, or (c) CCNU plus MISO preceding the radiation by 24 hr. In the latter protocol, one treatment effectively eliminated those cells being preferentially spared by the other. The CCNU-MISO followed by radiation combination not only reduced the treatment resistance due to hypoxia and cell cycle position but also left all cell subpopulations in the tumor equally sensitive to the treatment. To determine the nature of the interaction between these agents in detail, the extent of cell killing following such a treatment regimen was evaluated using isoeffect plot (isobologram) analysis. KHT sarcoma-bearing C3H mice were treated with various doses of CCNU either alone or in simultaneous combination with a 1.0-mg/g dose of MISO 24 hr prior to receiving a range of radiation doses. Combining CCNU and radiation led to significantly enhanced tumor cell killing. When evaluated by isoeffect plot analysis, the data points resulting from this combination fell well below the envelope of additivity, indicating that a supraadditive interaction between these two agents had occurred in the tumor cells. An even greater interaction was observed in the KHT sarcomas when MISO was combined with CCNU prior to irradiation. The findings of effective elimination of treatment-resistant subpopulations along with a supraadditive tumor cell kill offer, at least in part, an explanation for the previously described therapeutic advantage observed for the CCNU-MISO-radiation protocol.
评估了在放疗前将放射增敏剂米索硝唑（MISO）与1-(2-氯乙基)-3-环己基-1-亚硝基脲（CCNU）联合使用对各种KHT肉瘤细胞亚群反应的影响。采用离心淘析法从直接取自经处理的实体KHT肿瘤的悬液中获得细胞周期位置均一的细胞群体。使用体内到体外克隆试验确定这些亚群中的细胞存活率。原位治疗包括：（a）CCNU（3.0mg/kg）加MISO（1.0mg/g）；（b）单独放疗（15Gy）；或（c）在放疗前24小时给予CCNU加MISO。在后者的方案中，一种治疗有效地消除了另一种治疗优先保留的细胞。先给予CCNU-MISO然后放疗的联合治疗不仅降低了由于缺氧和细胞周期位置导致的治疗抗性，而且使肿瘤中的所有细胞亚群对治疗同样敏感。为了详细确定这些药物之间相互作用的性质，使用等效线图（等高线图）分析评估了这种治疗方案后的细胞杀伤程度。携带KHT肉瘤的C3H小鼠在接受一系列辐射剂量之前，单独或在同时给予1.0mg/g剂量的MISO 24小时后，用不同剂量的CCNU进行治疗。联合使用CCNU和放疗导致肿瘤细胞杀伤显著增强。通过等效线图分析评估时，这种联合产生的数据点远低于相加性包络线，表明这两种药物在肿瘤细胞中发生了超相加相互作用。当在照射前将MISO与CCNU联合使用时，在KHT肉瘤中观察到更大的相互作用。有效消除治疗抗性亚群以及超相加性肿瘤细胞杀伤的结果至少部分解释了先前描述的CCNU-MISO-放疗方案的治疗优势。
