Shinohara H, Killion J J, Kuniyasu H, Kumar R, Fidler I J
Department of Cell Biology, The University of Texas M.D. Anderson Cancer Center, Houston 77030, USA.
Clin Cancer Res. 1998 Sep;4(9):2053-63.
The induction of severe diarrhea limits the usefulness of the DNA topoisomerase I inhibitor irinotecan (CPT-11) in the treatment of advanced colon cancer. We investigated whether oral administration of the new synthetic bacterial lipopeptide, JBT 3002, encapsulated in phospholipid liposomes could prevent damage to the intestinal epithelium and lamina propria and thus allow for the parenteral administration of high-dose irinotecan to mice with established syngeneic CT-26 colon cancer liver metastases. Treatment of mice with four daily i.p. injections of 100 mg/kg irinotecan was effective against liver metastases but also resulted in loss of body weight and early death. Histopathological examination of the intestines after this treatment revealed loss of villi, epithelial vacuolation, decrease in the number of cells in the crypts in S-phase, increase in the number of apoptotic cells, and reduction in the number of lymphocytes in the lamina propria. In contrast, treatment of mice with the same irinotecan regimen after oral administration of JBT 3002 produced highly significant inhibition of liver metastases without detectable damage to the intestines. Studies that used irinotecan administered once a week for 3 weeks after pretreatment with oral JBT 3002 demonstrated significantly intensified eradication of established CT-26 liver metastases compared with treatment with once-weekly irinotecan alone. Histological studies revealed that the liver metastases in mice treated with oral JBT 3002 and i.p. irinotecan contained a higher number of macrophages than metastases in mice treated with either drug alone. In vitro studies revealed that irinotecan produced direct antiproliferative effects but JBT 3002 did not. Tumor cells exposed to both irinotecan and macrophages activated by JBT 3002 were highly susceptible to lysis. These data show that oral administration of JBT 3002 can prevent irinotecan-induced gastrointestinal toxic effects and maintain the integrity of the lamina propria, thus allowing for intensification of irinotecan therapy against liver metastases from colon cancer.
严重腹泻的诱导限制了DNA拓扑异构酶I抑制剂伊立替康（CPT - 11）在晚期结肠癌治疗中的应用。我们研究了口服包裹在磷脂脂质体中的新型合成细菌脂肽JBT 3002是否能预防肠道上皮和固有层的损伤，从而使高剂量伊立替康能够经肠胃外给药至已建立同基因CT - 26结肠癌肝转移的小鼠。每天腹腔注射4次100 mg/kg伊立替康治疗小鼠对肝转移有效，但也导致体重减轻和早期死亡。该治疗后对肠道进行组织病理学检查发现绒毛缺失、上皮空泡化、S期隐窝细胞数量减少、凋亡细胞数量增加以及固有层淋巴细胞数量减少。相比之下，口服JBT 3002后用相同伊立替康方案治疗小鼠，对肝转移产生了高度显著的抑制作用，且未检测到对肠道的损伤。在口服JBT 3002预处理后每周一次使用伊立替康治疗3周的研究表明，与单独每周一次使用伊立替康治疗相比，已建立的CT - 26肝转移的根除显著增强。组织学研究显示，口服JBT 3002和腹腔注射伊立替康治疗的小鼠肝转移灶中的巨噬细胞数量高于单独使用任何一种药物治疗的小鼠转移灶。体外研究表明，伊立替康产生直接抗增殖作用，但JBT 3002没有。暴露于伊立替康和由JBT 3002激活的巨噬细胞的肿瘤细胞极易被裂解。这些数据表明，口服JBT 3002可以预防伊立替康诱导的胃肠道毒性作用并维持固有层的完整性，从而允许强化伊立替康对结肠癌肝转移的治疗。
