Cao S, Black J D, Troutt A B, Rustum Y M
Grace Cancer Drug Center, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.
Cancer Res. 1998 Aug 1;58(15):3270-4.
Irinotecan (CPT-11) is a chemotherapeutic agent that is active in the treatment of a variety of solid tumor malignancies. Diarrhea represents the most common dose-limiting toxicity that is independent of the schedule of administration. A rat model with dose-limiting toxicity profiles that are similar to those observed in patients treated with CPT-11 was developed and used to evaluate the role of interleukin 15 (IL-15) in the modulation of the therapeutic selectivity of CPT-11 in normal rats and rats bearing advanced colorectal cancer. The maximum tolerated dose and lethal dose (LD) of CPT-11 by i.v. push daily x 3 were 150 and 200 mg/kg/day, respectively. CPT-11 at the LD induced a 93-100% incidence of severe diarrhea and an 86-100% incidence of lethality in treated animals. IL-15, a cytokine with multiple mechanisms of action, was used at a 100 or 400 microg/kg/dose with different schedules of administration (3, 8, and 11 doses, i.p.) to protect against CPT-11-induced toxicity. IL-15 offered complete and sustained selective protection against CPT-11-induced delayed diarrhea and lethality. IL-15 also moderately potentiated the antitumor activity of CPT-11 in rats bearing advanced colorectal cancer. Morphological examination of rat intestinal tissues after treatment with LD of CPT-11 revealed dramatic protection of duodenal and colonic tissue architecture by IL-15. CPT-11 alone produced serious damage to duodenal villi and colonic crypts. The results clearly demonstrated the ability of IL-15 to provide significant protection from CPT-11-induced intestinal toxicity with maintenance of antitumor activity, resulting in an increase in the therapeutic index of CPT-11. The clinical relevance of the results obtained in this model system needs to be confirmed.
伊立替康（CPT-11）是一种化疗药物，对多种实体瘤恶性肿瘤的治疗有效。腹泻是最常见的剂量限制性毒性反应，且与给药方案无关。我们建立了一种大鼠模型，其剂量限制性毒性特征与接受CPT-11治疗的患者相似，并用于评估白细胞介素15（IL-15）在调节CPT-11对正常大鼠和晚期结直肠癌大鼠治疗选择性中的作用。通过每日静脉推注×3给药，CPT-11的最大耐受剂量和致死剂量（LD）分别为150和200mg/kg/天。LD剂量的CPT-11可使治疗动物出现严重腹泻的发生率达到93%-100%，致死率达到86%-100%。IL-15是一种具有多种作用机制的细胞因子，以100或400μg/kg/剂量采用不同给药方案（腹腔注射，3、8和11剂）用于预防CPT-11诱导的毒性。IL-15对CPT-11诱导的迟发性腹泻和致死性提供了完全且持续的选择性保护。IL-15还适度增强了CPT-11对晚期结直肠癌大鼠的抗肿瘤活性。用LD剂量的CPT-11治疗后对大鼠肠道组织进行形态学检查发现，IL-15对十二指肠和结肠组织结构有显著保护作用。单独使用CPT-11会对十二指肠绒毛和结肠隐窝造成严重损伤。结果清楚地表明，IL-15能够在维持抗肿瘤活性的同时，为CPT-11诱导的肠道毒性提供显著保护，从而提高CPT-11的治疗指数。该模型系统中获得的结果的临床相关性有待证实。
