Murata R, Siemann D W, Overgaard J, Horsman M R
Danish Cancer Society, Department of Experimental Clinical Oncology, Aarhus University Hospital, Nørrebrogade 44, Building 5, DK-8000 Aarhus C, Denmark.
Radiat Res. 2001 Nov;156(5 Pt 1):503-9. doi: 10.1667/0033-7587(2001)156[0503:itrbcr]2.0.co;2.
The interaction between 5,6-dimethylxanthenone-4-acetic acid (DMXAA) and radiation was investigated in two different mouse tumor models and a normal mouse tissue. C3H mouse mammary carcinomas transplanted in the feet of CDF1 mice and KHT mouse sarcomas growing in the leg muscles of C3H/HeJ mice were used. DMXAA was dissolved in saline and injected intraperitoneally. Tumors were irradiated locally in nonanesthetized mice, and response was assessed using tumor growth for the C3H mammary carcinoma and in vivo/in vitro clonogenic cell survival for the KHT sarcoma. DMXAA alone had an antitumor effect in both tumor types, but only at doses above 15 mg/kg. DMXAA also enhanced radiation damage, and again there was a threshold dose. No enhancement was seen in the C3H mammary carcinoma at 10 mg/kg and below, while in the KHT sarcoma, doses above 15 mg/kg were necessary. This enhancement of radiation damage was also dependent on the sequence of and interval between the treatments with DMXAA and radiation. Combining radiation with DMXAA at the maximum tolerated dose (i.e., the highest dose that could be injected without causing any lethality) of either 20 mg/kg (CDF1 mice) or 17.5 mg/kg (C3H/HeJ mice) gave an additive response when the two agents were administered simultaneously. Even greater antitumor effects were achieved when DMXAA was administered 1-3 h after irradiation. However, when administration of DMXAA preceded irradiation, the effect was similar to that seen for radiation alone, suggesting that appropriate timing is essential to maximize the utility of this agent. When such conditions were met, DMXAA was found to increase the tumor response significantly in the absence of an enhancement of radiation damage in normal skin, thus giving rise to therapeutic gain.
在两种不同的小鼠肿瘤模型和一种正常小鼠组织中研究了5,6-二甲基呫吨酮-4-乙酸（DMXAA）与辐射之间的相互作用。使用移植于CDF1小鼠足部的C3H小鼠乳腺癌以及生长在C3H/HeJ小鼠腿部肌肉中的KHT小鼠肉瘤。DMXAA溶解于盐水中并腹腔注射。在未麻醉的小鼠中对肿瘤进行局部照射，并使用C3H乳腺癌的肿瘤生长情况以及KHT肉瘤的体内/体外克隆形成细胞存活率来评估反应。单独使用DMXAA对两种肿瘤类型均有抗肿瘤作用，但仅在剂量高于15mg/kg时才有此作用。DMXAA还增强了辐射损伤，并且同样存在一个阈值剂量。在C3H乳腺癌中，10mg/kg及以下剂量未观察到增强作用，而在KHT肉瘤中，需要高于15mg/kg的剂量。这种辐射损伤的增强还取决于DMXAA与辐射治疗的顺序和间隔。当以20mg/kg（CDF1小鼠）或17.5mg/kg（C3H/HeJ小鼠）的最大耐受剂量（即注射后不会导致任何致死性的最高剂量）将辐射与DMXAA同时给药时，两种药物产生相加反应。当在照射后1 - 3小时给予DMXAA时，可实现更大的抗肿瘤效果。然而，当DMXAA在照射之前给药时，其效果与单独辐射时相似，这表明合适的给药时间对于最大化该药物的效用至关重要。当满足这些条件时，发现DMXAA在不增强正常皮肤辐射损伤的情况下显著增加肿瘤反应，从而产生治疗增益。
