c-Kit-targeting immunotherapy for hereditary melanoma in a mouse model
c-Kit-targeting immunotherapy for hereditary melanoma in a mouse model
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DOI：
10.1158/0008-5472.can-03-2532
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发表时间：
2004-02-01
期刊：
影响因子：
11.2
通讯作者：
Nakashima, L
中科院分区：
文献类型：
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作者：
Kato, M;Takeda, K;Nakashima, L
在RET转基因小鼠品系304/B6中研究了e-Kit在黑色素瘤发展中的作用，其中黑色素瘤自发发展。在Wv/Wv-RET（304/B6）转基因小鼠中，c-Kit功能严重受损，黑色素瘤的发展受到强烈抑制。尽管44只原始RET转基因小鼠中有31只在出生后12个月内死于快速生长的黑色素瘤，但44只Wv/Wv-RET转基因小鼠中只有8只发展缓慢生长的黑色素细胞肿瘤，平均无瘤期大大延长，其中2只在晚期死于黑色素瘤。甚至Wv/+-RET转基因小鼠在出生后12个月内也有明显延长的无肿瘤期和明确降低的肿瘤死亡频率（61例中的6例）。这些小鼠皮肤中的黑色素产生没有受到强烈的损害，表明c-Kit影响这些小鼠中黑色素瘤的发展，对黑色素产生的影响很小。RET转基因小鼠出生后不久皮肤中的c-Kit表达得到促进，并且c-Kit在肿瘤的良性而非恶性阶段以高水平表达。在出生后不久向RET转基因小鼠中单次注射抗c-Kit抗体（ACK 2）引起对黑色素瘤发展的令人惊讶的持久抑制，大大延长了无肿瘤期，并且28只ACK 2治疗的RET转基因小鼠在12个月大时没有一只死于肿瘤。黑色素生成所需的c-Kit功能在ACK 2处理的RET转基因小鼠中也被抑制了异常长的时间。这些结果表明，c-Kit可以是黑色素瘤治疗的独特靶分子。
The role of e-Kit in the development of melanoma was studied in line 304/B6 of RET-transgenic mice, in which melanoma spontaneously develops. In Wv/Wv-RET (304/B6)-transgenic mice, in which c-Kit function was severely impaired, development of melanoma was strongly suppressed. Although 31 of the 44 original RET-transgenic mice died of rapidly growing melanoma within 12 months after birth, only 8 of the 44 Wv/Wv-RET-transgenic mice developed slowly growing melanocytic tumors with a greatly prolonged mean tumor-free period, 2 of which died of melanoma at a late stage. Even Wv/+-RET-transgenic mice had a clearly prolonged tumor-free period and definitely reduced frequency (6 of 61) of tumor death within 12 months after birth. Melanin production in the skin of these mice was not strongly impaired, suggesting that c-Kit affects the development of melanomas in these mice with only minor effects in melanin production. c-Kit expression in skin soon after birth was promoted in RET-transgenic mice, and c-Kit was expressed at high levels at the benign but not malignant stage of the tumor. A single injection of anti-c-Kit antibody (ACK2) into RET-transgenic mice soon after birth caused a surprisingly long-lasting suppression of development of melanoma, greatly prolonging the tumor-free period, and none of the 28 ACK2-treated RET-transgenic mice died from tumors at 12 months of age. The c-Kit function needed for melanin production was also suppressed for an unusually long time in ACK2-treated, RET-transgenic mice. These results suggest that c-Kit can be a unique target molecule for melanoma treatment.