Ivan Doina, Niveiro Maria, Diwan A Hafeez, Eton Omar, Kim Kevin B, Lacey Carol, Gonzalez Cipriano, Prieto Victor G
Department of Pathology, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030-4009, USA.
J Cutan Pathol. 2006 Apr;33(4):280-5. doi: 10.1111/j.0303-6987.2006.00432.x.
Protein tyrosine kinase (PTK) inhibition has been identified as a promising strategy in the development of new selective therapies, targeting the signaling pathways in melanoma progression. Gleevec, a novel class of anti-tumor drugs, may have a potential therapeutic benefit in melanoma, which involves abnormal activation of abl, c-kit, and platelet-derived growth factor (PDGF) tyrosine kinases.
Tumor biopsies from 13 patients with metastatic melanoma were screened by immunohistochemistry for PTK [c-kit, C-abl, Abl-related gene (ARG), PDGF receptor-alpha (PDGFR-alpha) and PDGFR-beta] expression before and after being treated with Gleevec @ 400 mg bid for 2 weeks. Both, percentage of positive cells and staining intensity were evaluated.
We found a statistically significant (p < 0.01) selective loss of PTK expression in the follow-up biopsy, both in intensity and number of positive cells. PDGFR-alpha and -beta had the highest level of expression reduction. One patient had a durable clinical response, and the follow-up biopsy showed negative expression for four of the PTKs, namely c-abl, ARG, PDGFR-alpha, and beta.
Our study reports for the first time the in vivo effect of Gleevec in the induction of apparently selective reduction of PTKs expression under anti-tyrosine kinases treatment, suggesting its potential role in melanoma treatment.
蛋白质酪氨酸激酶（PTK）抑制已被确定为开发新的选择性疗法的一种有前景的策略，该疗法针对黑色素瘤进展中的信号通路。格列卫是一类新型抗肿瘤药物，可能对黑色素瘤具有潜在治疗益处，黑色素瘤涉及abl、c-kit和血小板衍生生长因子（PDGF）酪氨酸激酶的异常激活。
对13例转移性黑色素瘤患者的肿瘤活检组织在接受400mg格列卫每日两次治疗2周前后，通过免疫组织化学法筛查PTK[c-kit、C-abl、Abl相关基因（ARG）、血小板衍生生长因子受体-α（PDGFR-α）和PDGFR-β]的表达。对阳性细胞百分比和染色强度进行评估。
我们发现在后续活检中，PTK表达在强度和阳性细胞数量上均有统计学意义的（p<0.01）选择性降低。PDGFR-α和-β的表达降低水平最高。1例患者有持久的临床反应，后续活检显示4种PTK，即c-abl、ARG、PDGFR-α和-β呈阴性表达。
我们的研究首次报道了格列卫在抗酪氨酸激酶治疗下诱导PTK表达明显选择性降低的体内效应，提示其在黑色素瘤治疗中的潜在作用。
