Budach W, Taghian A, Freeman J, Gioioso D, Suit H D
Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston.
J Natl Cancer Inst. 1993 Jun 16;85(12):988-93. doi: 10.1093/jnci/85.12.988.
Irradiation of tumors causes the death of both parenchymal tumor cells as well as normal tissue stromal cells (e.g., endothelium, connective tissue). However, it has been difficult to distinguish the contributions to overall tumor response after irradiation from the two compartments. The development of the severe combined immunodeficient (SCID) mouse provides a model in which the contribution of stromal cell responses to ionizing radiation to overall tumor response can be defined, because its normal tissue cells are extremely radiosensitive. Therefore, the results of irradiation of tumors in radiation-sensitive (SCID) and radiation-resistant hosts can be compared, and the contribution of the normal tissue stroma clarified.
Our purpose was to investigate the effects of radiation-induced stromal cell damage on tumor cell death, using tumor growth delay (GD) and local control (complete and permanent regression of the irradiated tumor) as end points.
Tumor GD and local control experiments were performed in SCID, athymic, and C3H mice. Sixty SCID and 60 nude mice for each of three human tumor cell lines (HGL9, HSTS26, HCT15) and for each of five murine cell lines (FSC1, FSC2, FSM1, FSM2, E01) and 60 SCID and 60 C3H mice for the FSa2 spontaneous C3H sarcoma were studied. Neoplasms were produced by injection of 10(6) cells from in vitro tissue cultures into the flanks of donor mice; after tumors had grown, experimental neoplasms were produced by transplanting 2- to 3-mm fragments into recipient mice. Animals were randomly assigned to various groups when tumors reached average volumes of 120 mm3. Graded, single-dose x irradiations (15-115 Gy, dose rate about 7 Gy/min) were given under acutely hypoxic conditions. Tumors were scored one to two times per week until recurrence.
The x-ray doses needed to achieve local control in 50% of the animals (tumor control doses, TCD50) ranged from 45.1 to 58.0 Gy for human tumors and from 36.3 to 114.0 Gy for murine tumors. On average, the TCD50 values in SCID mice were only about 3.5% lower than values in nude or C3H mice. The amount of GD defined at 66% of the TCD50 for the various groups was, however, 27% longer in the SCID mice (P = .004).
While the three-fold higher radiation sensitivity of the normal tissue stromal cells in the SCID mice did not alter the percentage of tumors controlled by x irradiation in the SCID mouse hosts as compared with other hosts, there appear to be significant differences in GD. Radiation-induced stromal cell damage does not significantly contribute to tumor cell death; however, it can prolong the interval of tumor regression.
肿瘤照射会导致实质肿瘤细胞以及正常组织基质细胞（如内皮细胞、结缔组织）死亡。然而，一直难以区分这两个部分对照射后总体肿瘤反应的贡献。严重联合免疫缺陷（SCID）小鼠的培育提供了一个模型，在这个模型中，可以确定基质细胞对电离辐射的反应对总体肿瘤反应的贡献，因为其正常组织细胞对辐射极其敏感。因此，可以比较辐射敏感（SCID）宿主和辐射抗性宿主中肿瘤的照射结果，并阐明正常组织基质的贡献。
我们的目的是研究辐射诱导的基质细胞损伤对肿瘤细胞死亡的影响，以肿瘤生长延迟（GD）和局部控制（照射肿瘤的完全和永久性消退）为终点。
在SCID、无胸腺和C3H小鼠中进行肿瘤GD和局部控制实验。研究了三种人类肿瘤细胞系（HGL9、HSTS26、HCT15）和五种小鼠细胞系（FSC1、FSC2、FSM1、FSM2、E01）各60只SCID和60只裸鼠，以及FSa2自发C3H肉瘤的60只SCID和60只C3H小鼠。通过将体外组织培养的10⁶个细胞注射到供体小鼠的侧腹来产生肿瘤；肿瘤生长后，通过将2至3毫米的碎片移植到受体小鼠中来产生实验性肿瘤。当肿瘤达到平均体积120立方毫米时，将动物随机分配到各个组。在急性缺氧条件下给予分级单剂量X射线照射（15 - 115 Gy，剂量率约7 Gy/分钟）。每周对肿瘤进行一到两次评分，直至复发。
在50%的动物中实现局部控制所需的X射线剂量（肿瘤控制剂量，TCD50），人类肿瘤为45.1至58.0 Gy，小鼠肿瘤为36.3至114.0 Gy。平均而言，SCID小鼠中的TCD50值仅比裸鼠或C3H小鼠中的值低约3.5%。然而，在各个组中，以TCD50的66%定义的GD量在SCID小鼠中长27%（P = 0.004）。
虽然SCID小鼠中正常组织基质细胞的辐射敏感性高三倍，但与其他宿主相比，这并未改变SCID小鼠宿主中通过X射线照射控制的肿瘤百分比，然而在GD方面似乎存在显著差异。辐射诱导的基质细胞损伤对肿瘤细胞死亡没有显著贡献；然而，它可以延长肿瘤消退的间隔时间。
