Hamakawa Hiroyuki, Nakashiro Koh-Ichi, Sumida Tomoki, Shintani Satoru, Myers Jeffrey N, Takes Robert P, Rinaldo Alessandra, Ferlito Alfio
Department of Oral and Maxillofacial Surgery, Ehime University Graduate School of Medicine, Ehime, Japan.
Head Neck. 2008 Jun;30(6):800-9. doi: 10.1002/hed.20830.
Recently, attention has been focused on molecular targeted cancer therapy in various tumors. Although there is no single consistent molecular target specific for oral squamous cell carcinoma (OSCC) and salivary gland cancer (SGC), there are a number of promising candidate proteins. The aim of this review is to introduce the basic evidences to support the molecular targeting for OSCC and SGC.
We focused on the 4 molecules, epidermal growth factor receptor (EGFR), cyclooxygenase-2 (COX-2), peroxisome proliferator-activated receptor gamma (PPARgamma), and progesterone receptor, that are, respectively, associated with the proliferation and the differentiation of OSCC and SGC.
Gefitinib ("Iressa," ZD1839), a small molecule EGFR tyrosine kinase inhibitor, can inhibit the proliferation of OSCC cell lines in a dose- and time-dependent manner and lead to cell cycle arrest with accumulation of cells in the G1 phase, and a decrease of cells in S phase. The agent suppressed tumor metastasis in the animal model. Furthermore, a cooperative antiproliferative effect was obtained when cancer cells were treated with radiation followed by gefitinib. While radiation alone did not significantly affect p38 mitogen-activated protein kinase and MAP kinase kinase (MEK)1/2 autophosphorylation, the combination of gefitinib and radiation completely inhibited the downstream signaling of EGFR. Gefitinib enhanced tumor radioresponsiveness by multiple mechanisms, including the growth inhibition and effects on DNA repair after exposure to radiation. Next, the level of COX-2 expression correlated inversely with increased tumor radiation sensitivity. Treatment with celecoxib, a COX-2 selective inhibitor, enhanced the radioresponsiveness of HSC-2 cells, which constitutively expressed COX-2. Another promising molecular target is the PPARgamma, which is a member of the nuclear receptor superfamily of ligand-activated transcription factors. Recent studies have demonstrated that PPARgamma ligands induce cellular differentiation and inhibit cell growth in carcinomas of various types. These data suggest that synthetic PPARgamma ligands may be useful for molecular targeting of oral cancer. Finally, the possibility of using molecular targeted therapy directed at hormone receptors in the treatment of advanced SGCs was described.
The basic data strongly suggested the possibility of tumor suppression by targeting these molecules. Studies of different targeted agents alone or with more conventional treatment modalities are needed to fully determine what role the targeted therapy will play in the management of patients with OSCC and SGC.
近来，分子靶向癌症治疗在各类肿瘤中受到关注。尽管对于口腔鳞状细胞癌（OSCC）和唾液腺癌（SGC）不存在单一一致的特异性分子靶点，但有许多有前景的候选蛋白。本综述的目的是介绍支持OSCC和SGC分子靶向治疗的基础证据。
我们聚焦于4种分子，即表皮生长因子受体（EGFR）、环氧合酶-2（COX-2）、过氧化物酶体增殖物激活受体γ（PPARγ）和孕激素受体，它们分别与OSCC和SGC的增殖及分化相关。
吉非替尼（“易瑞沙”，ZD1839），一种小分子EGFR酪氨酸激酶抑制剂，能以剂量和时间依赖的方式抑制OSCC细胞系的增殖，导致细胞周期停滞，使细胞在G1期积聚，S期细胞减少。该药物在动物模型中抑制肿瘤转移。此外，癌细胞经放射治疗后再用吉非替尼处理可获得协同抗增殖效应。单独放射治疗对p38丝裂原活化蛋白激酶和丝裂原活化蛋白激酶激酶（MEK）1/2的自磷酸化无显著影响，而吉非替尼与放射治疗联合可完全抑制EGFR的下游信号传导。吉非替尼通过多种机制增强肿瘤放射敏感性，包括生长抑制及对放射后DNA修复的影响。其次，COX-2表达水平与肿瘤放射敏感性增加呈负相关。用COX-2选择性抑制剂塞来昔布治疗可增强持续表达COX-2的HSC-2细胞的放射敏感性。另一个有前景的分子靶点是PPARγ，它是配体激活转录因子核受体超家族的成员。近期研究表明，PPARγ配体可诱导多种类型癌症的细胞分化并抑制细胞生长。这些数据提示合成PPARγ配体可能对口腔癌的分子靶向治疗有用。最后，描述了针对激素受体的分子靶向治疗用于晚期SGCs治疗的可能性。
基础数据有力地提示了通过靶向这些分子抑制肿瘤的可能性。需要单独研究不同的靶向药物或与更传统的治疗方式联合，以充分确定靶向治疗在OSCC和SGC患者管理中所起的作用。
