Samel S, Keese M, Lux A, Jesnowski R, Prosst R, Saller R, Hafner M, Sturm J, Post S, Löhr M
Department of Surgery, University Hospital Mannheim, University of Heidelberg, Germany.
Cancer Gene Ther. 2006 Jan 1;13(1):65-73. doi: 10.1038/sj.cgt.7700849.
The prognosis of peritoneal spread from gastrointestinal cancer and subsequent malignant ascites is poor, and current medical treatments available are mostly ineffective. Targeted chemotherapy with intraperitoneal prodrug activation may be a beneficial new approach. L293 cells were genetically modified to express the cytochrome P450 enzyme 2B1 under the control of a cytomegalovirus immediate early promoter. This CYP2B1 enzyme converts ifosfamide to its active cytotoxic compounds. The cells are encapsulated in a cellulose sulfate formulation (Capcell). Adult Balb/c mice were inoculated intraperitoneally with 1 x 10(6) colon 26 cancer cells, previously transfected with GFP to emit a stable green fluorescence, by injection into the left lower abdominal quadrant. Two or five day's later animals were randomly subjected to either i.p. treatment with ifosfamide alone or ifosfamide combined with microencapsulated CYP2B1-expressing cells. Peritoneal tumor volume and tumor viability were assessed 10 days after tumor inoculation by means of fluorescence microscopy, spectroscopy and histology. Early i.p. treatment with ifosfamide and CYP2B1 cells resulted in a complete response. Treatment starting on day 5 and single-drug treatment with ifosfamide resulted in a partial response. These results suggest that targeted i.p. chemotherapy using a combination of a prodrug and its converting enzyme may be a successful treatment strategy for peritoneal spread from colorectal cancer.
胃肠道癌腹膜转移及随后的恶性腹水预后较差，目前可用的医学治疗大多无效。腹膜内前体药物激活的靶向化疗可能是一种有益的新方法。L293细胞经过基因改造，在巨细胞病毒立即早期启动子的控制下表达细胞色素P450酶2B1。这种CYP2B1酶将异环磷酰胺转化为其活性细胞毒性化合物。细胞被包裹在硫酸纤维素制剂（Capcell）中。成年Balb/c小鼠通过向左下腹象限注射，腹膜内接种1×10(6)个先前用绿色荧光蛋白转染以发出稳定绿色荧光的结肠26癌细胞。两天或五天后，动物被随机分为单独腹腔注射异环磷酰胺或异环磷酰胺联合微囊化表达CYP2B1细胞的治疗组。在肿瘤接种10天后，通过荧光显微镜、光谱学和组织学评估腹膜肿瘤体积和肿瘤活力。早期腹腔注射异环磷酰胺和CYP2B1细胞导致完全缓解。第5天开始治疗和异环磷酰胺单药治疗导致部分缓解。这些结果表明，使用前体药物及其转化酶联合进行靶向腹腔化疗可能是治疗结直肠癌腹膜转移的成功策略。
