In vitro and in vivo effects of repifermin (keratinocyte growth factor-2, KGF-2) on human carcinoma cells
In vitro and in vivo effects of repifermin (keratinocyte growth factor-2, KGF-2) on human carcinoma cells
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DOI：
10.1007/s00280-002-0493-8
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发表时间：
2002-09-01
影响因子：
3
通讯作者：
Connolly, K
中科院分区：
文献类型：
--
作者：
Alderson, R;Gohari-Fritsch, S;Connolly, K
目的：reifermin（角质细胞生长因子-2，KGF-2）是一种选择性诱导上皮细胞增殖、分化和迁移的生长因子。本研究的目的是利用多种具有不同生长速度和KGF受体（KGFR）表达水平的人类癌细胞系，评估repifermin对体外肿瘤细胞增殖和体内肿瘤生长的影响。方法：在一系列血清条件下，采用alamarBlue和/或[H-3]-胸腺嘧啶掺入试验，评估repifermin对体外细胞增殖的潜在影响。通过将KGFR（+）癌皮下植入裸鼠体内，并通过静脉注射（i.v.）或腹腔注射（i.p）利匹费明或安慰剂，测量小鼠体内肿瘤生长情况。结果：在体外，在0.01 ~ 1000 ng/ml的浓度范围内，30种人癌细胞系均未表现出明显的增殖增加。体内实验结果显示，对接种了人KGFR（+）肿瘤(咽部（Detroit 562, FaDu）、结肠（cco -2）、唾腺（A-253）或舌部（SCC25, CAL 27）的胸腺裸鼠，单周期或多周期静脉注射利比费明（1mg /kg）均无显著的促肿瘤活性。此外，利匹弗明（0.2或2mg /kg）腹腔注射2周后，对卵巢（NIH:OVCAR-3, SK-OV 3, PA-1）、膀胱（scer）、表皮（a431）、肺（SW 900）、乳腺（MDA-MB-231）和子宫颈（SiHa）等8种人类肿瘤的生长均无影响。结论：Repifermin对KGFR（+）人上皮样肿瘤无体外和体内增殖作用。这种刺激肿瘤细胞生长的失败突出了repifermin特异性靶向正常上皮组织的能力。这对repifermin的安全性至关重要，因为它目前正在进行II期临床试验，用于治疗化疗或放疗引起的粘膜炎的癌症患者。
Purpose: Repifermin (keratinocyte growth factor-2, KGF-2) is a growth factor that selectively induces epithelial cell proliferation, differentiation and migration. The objective of this study was to assess the effect of repifermin on in vitro tumor cell proliferation and in vivo tumor growth using a variety of human carcinoma cell lines with differing growth rates and levels of KGF receptor (KGFR) expression. Methods: Potential effects of repifermin on in vitro cell proliferation were evaluated by alamarBlue and/or [H-3]-thymidine incorporation assays under a range of serum conditions. In vivo tumor growth was evaluated by implanting KGFR(+) carcinomas subcutaneously into nude mice and measuring tumor growth over time in mice injected intravenously (i.v.) or intraperitoneally (i.p.) with repifermin or placebo. Results: In vitro, none of the 30 human carcinoma cell lines tested demonstrated a substantial increase in proliferation in response to repifermin over the concentration range 0.01 to 1000 ng/ml. In vivo results showed no significant tumor growth-promoting activity when single- or multiple-cycle intravenous injections of repifermin (1 mg/kg) were given to athymic nude mice inoculated with human KGFR(+) tumors of the pharynx (Detroit 562, FaDu), colon (Caco-2), salivary gland (A-253) or tongue (SCC25, CAL 27). In addition, repifermin (0.2 or 2 mg/kg) injected i.p. for 2 weeks had no effect on the growth of eight other human carcinomas including those of the ovary (NIH:OVCAR-3, SK-OV 3, PA-1), bladder (SCaBER), epidermis (A 431), lung (SW 900), breast (MDA-MB-231) and cervix (SiHa). Conclusions: Repifermin had no in vitro or in vivo proliferative effects on KGFR(+) human epithelial-like tumors. This failure to stimulate tumor cell growth highlights the ability of repifermin to specifically target normal epithelial tissue. This is critical to the safety profile of repifermin, since it is currently in phase II clinical trials for the treatment of cancer patients with mucositis resulting from chemo- or radiotherapy.