Tumor necrosis factor-α augmented tumor response in B16BL6 melanoma-bearing mice treated with stealth liposomal doxorubicin (DOXIL®) correlates with altered DOXIL® pharmacokinetics
Tumor necrosis factor-α augmented tumor response in B16BL6 melanoma-bearing mice treated with stealth liposomal doxorubicin (DOXIL®) correlates with altered DOXIL® pharmacokinetics
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DOI：
10.1002/ijc.11703
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发表时间：
2004-04-10
影响因子：
6.4
通讯作者：
Ten Hagen, TLM
中科院分区：
文献类型：
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作者：
Brouckaert, P;Takahashi, N;Ten Hagen, TLM
肿瘤坏死因子- α （tumor necrosis factor- α， TNF）治疗实体瘤的应用受到其严重、危及生命的毒性的限制。因此，只有低剂量的细胞因子才能全身应用，这导致肿瘤反应差。先前已经证明，在所谓的孤立灌注系统中给予高剂量TNF，当与化疗联合使用时，可显着改善肿瘤反应。TNF似乎对肿瘤相关的脉管系统有主要的影响。在这些高浓度下，TNF诱导内皮细胞死亡，导致肿瘤血管床完全塌陷。引人注目的是，仅凭这种作用不足以诱导肿瘤反应，但必须添加化疗药物才能获得抗肿瘤作用。我们发现TNF本身没有抗肿瘤作用，但主要通过增加血管渗漏来增强肿瘤内的药物积累。似乎是血管渗漏增加，而不是内皮细胞死亡，解释了TNF和联合用药之间的相互作用。我们假设在低剂量环境下TNF可以诱导肿瘤积累化疗药物，从而改善肿瘤反应。我们证明，游离TNF对B16BL6黑色素瘤小鼠中共给药Doxil（(R)）的药代动力学有很强的影响，导致肿瘤中药物积累的强烈增强和肿瘤反应的改善。与游离TNF相比，Stealth（(R)）脂质体TNF与Doxil（(R)）联合注射可产生类似或不太明显的肿瘤反应。这些结果表明，全身应用临床耐受剂量的TNF可能改善药物分布和肿瘤反应，并可能在许多抗癌治疗中有用。(C) 2004 Wiley-Liss, Inc。
The application of tumor necrosis factor-alpha (TNF) for the treatment of solid tumors is limited by its severe, life-threatening, toxicity. Therefore, only low dosages of this cytokine can be applied systemically, which results in poor tumor response. It has been demonstrated previously that administration of high-dose TNF in a so-called isolated perfusion system markedly improved tumor response when combined with chemotherapy. It appeared that TNF had a major impact specifically on the tumor-associated vasculature. At these high concentrations, endothelial cell death is induced by TNF, resulting in complete collapse of the tumor vascular bed. Strikingly, this effect alone is not enough to induce a tumor response, but addition of a chemotherapeutic drug is mandatory to obtain an anti-tumor effect. We showed that TNF has no anti-tumor effect by itself but augmented drug accumulation mainly in the tumor, most likely by enhancing vascular leakage. It seems that enhanced vascular leakage but not endothelial cell death, explains the interaction between TNF and the co-administered drug. We hypothesized that in a low-dose setting TNF could induce tumor accumulation of chemotherapeutic drugs and consequently improve tumor response. We demonstrate that free TNF has a strong effect on the pharmacokinetics of co-administered Doxil((R)) in B16BL6 melanoma-bearing mice, resulting in strongly augmented drug accumulation in the tumor and improved tumor response. Co-injection of Stealth((R)) liposomal TNF with Doxil((R)) resulted in comparable or less pronounced tumor responses as compared to free TNF. These results imply that systemic application of clinically tolerable doses of TNF may improve drug distribution and tumor response and could be useful in a number of anti-cancer therapies. (C) 2004 Wiley-Liss, Inc.