Hillman G G, Maughan R L, Grignon D J, Yudelev M, Rubio J, Tekyi-Mensah S, Layer A, Che M, Forman J D
Department of Radiation Oncology, Barbara Ann Karmanos Cancer Institute at Wayne State University School of Medicine Detroit, Michigan 48201, USA.
Clin Cancer Res. 2001 Jan;7(1):136-44.
We have shown that implantation of human prostate carcinoma PC-3 cells in the prostates of nude mice led to the formation of prostate tumors with metastases to para-aortic lymph nodes. We found that day 6 prostate tumors were responsive to systemic injections of interleukin 2 (IL-2) therapy. We have now investigated the combination of primary tumor irradiation and IL-2 for metastatic prostate cancer in this preclinical tumor model. The effect of neutron radiation was compared with that of photon radiation. Advanced prostate tumors (approximately 0.4 cm) were irradiated, and a day later, mice were treated with systemic IL-2 for three weekly cycles. In separate experiments, mice were either sacrificed on day 30 to assess prostate tumor size and tumor histology or followed for survival. A dose-dependent inhibition of prostate tumor growth was caused either by photons or neutrons, but neutrons were more effective than photons with a relative biological effectiveness of 2. The tumor inhibition obtained with 250 cGy neutrons and 500 cGy photons was significant (>75%) and was further increased (> or = 90%) by addition of IL-2 therapy. In survival studies, the combination of radiation and IL-2 showed a significant survival advantage compared with untreated mice (P < or = 0.005) or radiation alone (P < or = 0.003) and an increase in median survival compared with IL-2 alone. Histologically, the combined regimen resulted in a greater degree of tumor destruction, inflammatory response, and vascular damage than that observed with each modality alone. After this combined treatment, no tumor was histologically detected in the para-aortic lymph nodes of these mice, and the lymph nodes were significantly smaller. These findings showed that primary tumor irradiation, either with neutrons or photons, enhanced IL-2 therapeutic effect for the treatment of advanced prostate cancer. This combined modality induced an antitumor response that controlled the growth of prostate tumors and their metastases.
我们已经证明，将人前列腺癌PC-3细胞植入裸鼠前列腺会导致前列腺肿瘤形成，并转移至主动脉旁淋巴结。我们发现，第6天的前列腺肿瘤对全身注射白细胞介素2（IL-2）治疗有反应。我们现在已经在这个临床前肿瘤模型中研究了原发性肿瘤照射与IL-2联合治疗转移性前列腺癌的效果。将中子辐射的效果与光子辐射的效果进行了比较。对晚期前列腺肿瘤（约0.4厘米）进行照射，一天后，对小鼠进行为期三个每周周期的全身IL-2治疗。在单独的实验中，在第30天处死小鼠以评估前列腺肿瘤大小和肿瘤组织学，或者对其进行生存跟踪。光子或中子均可引起剂量依赖性的前列腺肿瘤生长抑制，但中子比光子更有效，相对生物效应为2。250 cGy中子和500 cGy光子所获得的肿瘤抑制效果显著（>75%），并且通过添加IL-2治疗进一步提高（>或 = 90%）。在生存研究中，与未治疗的小鼠相比（P≤0.005）或与单独放疗相比（P≤0.003），放疗与IL-2联合治疗显示出显著的生存优势，并且与单独使用IL-2相比，中位生存期有所延长。组织学上，联合治疗方案导致的肿瘤破坏、炎症反应和血管损伤程度比单独使用每种治疗方式时更为严重。经过这种联合治疗后，在这些小鼠的主动脉旁淋巴结中未检测到组织学上的肿瘤，并且淋巴结明显更小。这些发现表明，无论是用中子还是光子进行原发性肿瘤照射，均可增强IL-2对晚期前列腺癌的治疗效果。这种联合治疗方式诱导了一种抗肿瘤反应，可控制前列腺肿瘤及其转移灶的生长。
