title: Basic evidence of molecular targeted therapy for oral cancer and salivary gland cancer.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Oral and Maxillofacial Surgery, Ehime University Graduate School of Medicine, Ehime, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Hamakawa
authors.forename: Koh-Ichi
authors.initials: K
authors.lastname: Nakashiro
authors.forename: Tomoki
authors.initials: T
authors.lastname: Sumida
authors.forename: Satoru
authors.initials: S
authors.lastname: Shintani
authors.forename: Jeffrey N
authors.initials: JN
authors.lastname: Myers
authors.forename: Robert P
authors.initials: RP
authors.lastname: Takes
authors.forename: Alessandra
authors.initials: A
authors.lastname: Rinaldo
authors.forename: Alfio
authors.initials: A
authors.lastname: Ferlito
mesh_terms: D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000473:pathology; D052246:Cyclooxygenase 2 Inhibitors / Q000627:therapeutic use; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D006801:Humans; D009062:Mouth Neoplasms / Q000188:drug therapy* / Q000473:pathology; D047495:PPAR gamma / Q000037:antagonists & inhibitors; D011980:Receptors, Progesterone / Q000037:antagonists & inhibitors; D012468:Salivary Gland Neoplasms / Q000188:drug therapy* / Q000473:pathology
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D047495:PPAR gamma; D011980:Receptors, Progesterone; D066246:ErbB Receptors