Pierrefite-Carle V, Baqué P, Gavelli A, Mala M, Chazal M, Gugenheim J, Bourgeon A, Milano G, Staccini P, Rossi B
V. Pierrefite-Carle, B. Rossi, Unité INSERM 364, Faculté de Médecine, Nice, France.
J Natl Cancer Inst. 1999 Dec 1;91(23):2014-9. doi: 10.1093/jnci/91.23.2014.
The cytosine deaminase gene of Escherichia coli converts the nontoxic compound 5-fluorocytosine into 5-fluorouracil (5-FU), thereby acting as a suicide gene when introduced into cancer cells, killing the cells when they are exposed to 5-fluorocytosine. We analyzed the efficacy of using cytosine deaminase-bearing cancer cells as an autologous tumor vaccine in a rat model that mimics liver metastasis from colon carcinoma.
We introduced a plasmid vector containing the E. coli cytosine deaminase gene into a BDIX rat colon carcinoma cell line. Intrahepatic injection of the modified cells in syngeneic animals generates a single experimental liver "suicide tumor." We then analyzed the effect of 5-fluorocytosine treatment in terms of regression of cytosine deaminase-expressing cells in vivo as well as protection against wild-type cancer cells.
Treatment with 5-fluorocytosine induced regression of cytosine deaminase-expressing (CD+) tumors, with seven of 11 treated animals being tumor free at the end of 30 days and a statistically significant difference in tumor volumes between treated and control animals (two-sided P<.0001). Intrahepatic injection of CD+ cells followed by 5-fluorocytosine treatment rendered the treated animals resistant to challenge with wild-type tumor cells, with no (zero of seven) treated animals developing wild-type tumors in contrast to all (four of four) control animals. Moreover, in animals with established wild-type liver tumors, injection of CD+ tumor cells followed by 5-fluorocytosine treatment produced a statistically significant increase in survival time (two-sided P<.0001). In vivo immunodepletion and immunohistologic analysis of experimental tumors indicate that natural killer cells are the major immune component involved in this antitumor effect.
Taken together, these results suggest the potential use of suicide gene-modified tumor cells as therapeutic vaccines against liver metastasis from colon carcinoma.
大肠杆菌的胞嘧啶脱氨酶基因可将无毒化合物5-氟胞嘧啶转化为5-氟尿嘧啶（5-FU），因此当导入癌细胞时可作为一种自杀基因，使细胞在接触5-氟胞嘧啶时死亡。我们在一个模拟结肠癌肝转移的大鼠模型中分析了使用携带胞嘧啶脱氨酶的癌细胞作为自体肿瘤疫苗的疗效。
我们将含有大肠杆菌胞嘧啶脱氨酶基因的质粒载体导入BDIX大鼠结肠癌细胞系。在同基因动物中肝内注射修饰后的细胞可产生单个实验性肝脏“自杀肿瘤”。然后我们从体内表达胞嘧啶脱氨酶的细胞消退以及对野生型癌细胞的保护方面分析了5-氟胞嘧啶治疗的效果。
5-氟胞嘧啶治疗可诱导表达胞嘧啶脱氨酶（CD+）的肿瘤消退，11只接受治疗的动物中有7只在30天结束时无肿瘤，且治疗组和对照组动物的肿瘤体积存在统计学显著差异（双侧P<0.0001）。肝内注射CD+细胞后进行5-氟胞嘧啶治疗使治疗组动物对野生型肿瘤细胞的攻击具有抗性，与所有（4只中的4只）对照动物相比，没有（7只中的0只）接受治疗的动物发生野生型肿瘤。此外，在已建立野生型肝肿瘤的动物中，注射CD+肿瘤细胞后进行5-氟胞嘧啶治疗使生存时间有统计学显著增加（双侧P<0.0001）。对实验性肿瘤的体内免疫清除和免疫组织学分析表明，自然杀伤细胞是参与这种抗肿瘤作用的主要免疫成分。
综上所述，这些结果表明自杀基因修饰的肿瘤细胞有可能作为治疗结肠癌肝转移的治疗性疫苗。
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