SLT-VEGF reduces lung metastases, decreases tumor recurrence, and improves survival in an orthotopic melanoma model.
SLT-VEGF reduces lung metastases, decreases tumor recurrence, and improves survival in an orthotopic melanoma model.
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DOI：
10.3390/toxins2092242
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发表时间：
2010-09
期刊：
影响因子：
4.2
通讯作者：
Hamby CV
中科院分区：
文献类型：
--
作者：
Ackerman R;Backer JM;Backer M;Skariah S;Hamby CV
SLT-VEGF是由志贺样毒素（Shiga-like toxin，SHG）A亚单位与人血管内皮生长因子（VEGF）融合而成的重组细胞毒素。它对过表达VEGF受体-2（VEGFR-2/KDR/Flk 1）的肿瘤内皮细胞具有高度细胞毒性，并抑制乳腺癌和前列腺癌皮下模型中原发性肿瘤的生长，并抑制胰腺癌原位模型中的转移性播散。我们在原位黑色素瘤模型中检测了SLT-VEGF在限制肿瘤生长和转移方面的功效，该模型使用接种了高转移性IV线Cl 1培养的人黑色素瘤细胞的NCR无胸腺裸鼠。当皮内注射1 × 106个细胞/小鼠后一周肿瘤变得可触及时，开始每周两次注射SLT-VEGF。尽管从肿瘤血管系统中选择性地去除过表达VEGFR-2的内皮细胞，但SLT-VEGF治疗不影响肿瘤生长。然而，原发性肿瘤切除后，继续SLT-VEGF治疗导致更少的肿瘤复发（p = 0.007），降低肺转移的发生率（p = 0.038），并提高生存率（p = 0.002）。这些结果表明，SLT-VEGF在肿瘤发展的非常早期阶段是有效的，此时选择性杀死VEGFR-2过表达的内皮细胞仍然可以防止进一步的进展。我们推测，SLT-VEGF可能是一种有前途的辅助治疗，以抑制或预防侵袭性原发性黑色素瘤病灶切除后转移灶的生长。
SLT-VEGF is a recombinant cytotoxin comprised of Shiga-like toxin (SLT) subunit A fused to human vascular endothelial growth factor (VEGF). It is highly cytotoxic to tumor endothelial cells overexpressing VEGF receptor-2 (VEGFR-2/KDR/Flk1) and inhibits the growth of primary tumors in subcutaneous models of breast and prostate cancer and inhibits metastatic dissemination in orthotopic models of pancreatic cancer. We examined the efficacy of SLT-VEGF in limiting tumor growth and metastasis in an orthotopic melanoma model, using NCR athymic nude mice inoculated with highly metastatic Line IV Cl 1 cultured human melanoma cells. Twice weekly injections of SLT-VEGF were started when tumors became palpable at one week after intradermal injection of 1 × 106 cells/mouse. Despite selective depletion of VEGFR-2 overexpressing endothelial cells from the tumor vasculature, SLT-VEGF treatment did not affect tumor growth. However, after primary tumors were removed, continued SLT-VEGF treatment led to fewer tumor recurrences (p = 0.007), reduced the incidence of lung metastasis (p = 0.038), and improved survival (p = 0.002). These results suggest that SLT-VEGF is effective at the very early stages of tumor development, when selective killing of VEGFR-2 overexpressing endothelial cells can still prevent further progression. We hypothesize that SLT-VEGF could be a promising adjuvant therapy to inhibit or prevent outgrowth of metastatic foci after excision of aggressive primary melanoma lesions.
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DOI：
10.1038/nrc2442
发表时间：
2008-08
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
通讯作者：
--
影响因子：
3
作者：
Chang, Yong S.;Adnane, Jalila;Wilhelm, Scott
通讯作者：
Wilhelm, Scott
影响因子：
4.7
作者：
Backer, MV;Backer, JM
通讯作者：
Backer, JM
影响因子：
82.9
作者：
Backer, Marina V.;Levashova, Zoya;Backer, Joseph M.
通讯作者：
Backer, Joseph M.
影响因子：
5.7
作者：
Vallera, Daniel A.;Oh, Seunguk;Frankel, Arthur E.
通讯作者：
Frankel, Arthur E.