Oral lactoferrin inhibits growth of established tumors and potentiates conventional chemotherapy
Oral lactoferrin inhibits growth of established tumors and potentiates conventional chemotherapy
复制标题
DOI：
10.1002/ijc.20271
复制
发表时间：
2004-09
影响因子：
6.4
通讯作者：
A. Varadhachary;J. Wolf;K. Petrak;B. O'Malley;M. Spadaro;C. Curcio;G. Forni;F. Pericle
中科院分区：
文献类型：
--
作者：
A. Varadhachary;J. Wolf;K. Petrak;B. O'Malley;M. Spadaro;C. Curcio;G. Forni;F. Pericle
在这项工作中，我们研究了单独口服重组人乳铁蛋白（rhLF）以及与化疗联合使用对荷瘤小鼠的抗癌活性。当通过口服管饲法以 1,000 mg/kg (2.9 g/m2) 每天两次连续 8 天施用 rhLF 时，T 细胞免疫功能低下的 nu/nu 小鼠中鳞状细胞癌 (O12) 肿瘤的生长抑制了 80% (p < 0.001)。在同基因、免疫功能正常的 BALB/c 小鼠中观察到类似的活性，其中口服 rhLF（1,000 mg/kg，2.9 g/m2，每天一次）可阻止乳腺癌 TUBO 的生长。口服 rhLF（200 mg/kg，0.57 g/m2）也单独使用或与顺铂（5 mg/kg）联合使用，在同基因小鼠模型中治疗头颈鳞状细胞癌。与安慰剂相比，口服 rhLF 或顺铂单一疗法分别抑制了 61% 或 66% 的肿瘤生长。接受两种疗法的小鼠表现出 79% 的生长抑制，与单独使用每种药物相比，具有统计学上的显着改善。然后我们证明，给荷瘤小鼠或初始小鼠口服 rhLF（300 mg/kg，0.86 g/m2）会导致（i）肠道中 IL-18 的产生显着增加，（ii）全身 NK 细胞激活和（iii）循环 CD8+ T 细胞扩增。这些数据表明，口服 rhLF 是一种免疫调节剂，可作为单药和联合化疗有效对抗癌症，通过刺激肠道肠细胞中的 IL-18 和其他细胞因子发挥其全身作用。已对 211 人进行口服 rhLF 治疗，未发生任何严重的药物相关不良事件。因此，rhLF有望成为一种安全且耐受性良好的新型免疫调节抗癌药物。 © 2004 Wiley-Liss, Inc.
In this work, we investigated the anticancer activity of orally administered recombinant human lactoferrin (rhLF) alone and in combination with chemotherapy in tumor‐bearing mice. rhLF inhibited the growth of squamous cell carcinoma (O12) tumors in T cell–immunocompromised nu/nu mice by 80% when administered at 1,000 mg/kg (2.9 g/m2) by oral gavage twice daily for 8 days (p < 0.001). Similar activity was observed in syngeneic, immunocompetent BALB/c mice, where orally administered rhLF (1,000 mg/kg, 2.9 g/m2 once daily) halted the growth of mammary adenocarcinoma TUBO. Oral rhLF (200 mg/kg, 0.57 g/m2) was also used alone and in combination with cis‐platinum (5 mg/kg) to treat head‐and‐neck squamous cell carcinoma in a syngeneic murine model. Monotherapy with oral rhLF or cis‐platinum caused 61% or 66% tumor growth inhibition over placebo, respectively. Mice receiving both therapies showed 79% growth inhibition, a statistically significant improvement over each drug alone. We then demonstrated that administration of oral rhLF (300 mg/kg, 0.86 g/m2) to tumor‐bearing or naive mice resulted in (i) significantly increased production of IL‐18 in the intestinal tract, (ii) systemic NK cell activation and (iii) circulating CD8+ T‐cell expansion. These data suggest that oral rhLF is an immunomodulatory agent active against cancer as a single agent and in combination chemotherapy, exerting its systemic effect through stimulation of IL‐18 and other cytokines in the gut enterocytes. rhLF has been administered orally to 211 people without a single serious drug‐related adverse event. Thus, rhLF shows promise as a safe and well‐tolerated novel immunomodulatory anticancer agent. © 2004 Wiley‐Liss, Inc.