Vascular endothelial growth factor expression is closely related to irinotecan-mediated inhibition of tumor growth and angiogenesis in neuroblastoma xenografts
Vascular endothelial growth factor expression is closely related to irinotecan-mediated inhibition of tumor growth and angiogenesis in neuroblastoma xenografts
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DOI：
10.1111/j.1349-7006.2008.00790.x
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发表时间：
2008-06-01
期刊：
影响因子：
5.7
通讯作者：
Kaneko, Michio
中科院分区：
文献类型：
--
作者：
Kaneko, Setsuko;Ishibashi, Makiko;Kaneko, Michio
在本研究中，伊立替康（CPT-11）不仅对化学敏感的神经母细胞瘤（NB）异种移植物SK-N-ASnu和TNB 9非常有效，而且对多药耐药NB异种移植物TS-N-2nu也非常有效。SK-N-ASnu和TNB 9对低剂量每日CPT-11治疗的反应显著高于间歇性给予三分之一的半数致死剂量。对于TS-N-2nu，两种治疗方案之间的肿瘤生长抑制无显著差异。单独用CPT-11治疗不能完全消除小鼠中的肿瘤生长。对于TNB 9，肿瘤再生长似乎是由于在治疗期间不能使基质中的宿主血管消退以及在整个治疗期间不能抑制宿主来源的血管内皮生长因子（VEGF）表达。在多药耐药的TS-N-2nu中，CPT-11的低剂量治疗不能抑制VEGF，并且神经毒性阳性肿瘤细胞逃避凋亡，生长停滞于G（0）/G（1）期。这些发现表明TS-N-2nu对CPT-11的不完全反应性的机制。我们的数据表明，减少VEGF基因和蛋白质的表达是密切相关的肿瘤生长抑制和抑制血管生成的CPT-11在NB异种移植。我们的研究结果进一步表明，基质来源的VEGF的持久性阻断剂将需要与CPT-11组合以完全抑制化学敏感性NB的生长，并且需要以更高剂量施用CPT-11以抑制多药耐药NB的生长。
In the present study, irinotecan (CPT-11) was highly effective not only against the chemosensitive neuroblastoma (NB) xenografts SK-N-ASnu and TNB9, but also against the multidrug-resistant NB xenograft TS-N-2nu. SK-N-ASnu and TNB9 were significantly more responsive to low-dose daily CPT-11 treatment than to intermittent administration of one-third of the median lethal dose. For TS-N-2nu, there was no significant difference in tumor growth inhibition between the two treatment schedules. Treatment with CPT-11 alone could not completely abolish tumor growth in mice. For TNB9, tumor regrowth seemed to result from an inability to regress host vessels in the stroma during treatment and an inability to suppress host-derived vascular endothelial growth factor (VEGF) expression throughout therapy. In the multidrug-resistant TS-N-2nu, VEGF was not suppressed by low-dose therapy with CPT-11, and neurofilament-positive tumor cells escaped from apoptosis and were growth arrested at G(0)/G(1) phase. These findings suggest a mechanism for the incomplete responsiveness of TS-N-2nu to CPT-11. Our data demonstrate that diminished VEGF gene and protein expression is closely correlated with tumor growth inhibition and inhibition of angiogenesis by CPT-11 in NB xenografts. Our results further suggest that a persistent blocker of stroma-derived VEGF will need to be combined with CPT-11 to completely inhibit the growth of chemosensitive NB, and that administration of CPT-11 at higher doses will be required to inhibit the growth of multidrug-resistant NB.