Epidermal growth factor receptor blockade potentiates apoptosis mediated by Paclitaxel and leads to prolonged survival in a murine model of oral cancer.
OBJECTIVE
Because survival for patients with oral cancer has not improved over the past 25 years, new approaches for treatment are needed. Targeted molecular therapy against epidermal growth factor receptor (EGFR) has shown promise as an adjuvant therapy in preliminary studies in several solid tumors, including head and neck cancer. The objective of this study was to determine the efficacy of paclitaxel and PKI166, a novel inhibitor of EGFR, against oral cavity cancer.


RESULTS
JMAR human oral cancer cells were pretreated for 1 h with PKI166 and then stimulated with epidermal growth factor. EGFR-specific tyrosine kinase autophosphorylation measured by Western immunoblotting was inhibited by PKI166 in a dose-dependent fashion at all doses tested (0.01-1 micro M). Next, the induction of apoptosis in JMAR cells treated with paclitaxel (0.001 to 0.1 micro M) with or without PKI166 (0, 1, or 2 micro M) was determined using a propidium iodide assay. The addition of 2.0 micro M PKI166 significantly increased tumor cell death, shifting the amount of paclitaxel needed to induce apoptosis in 50% of cells from 0.1 to 0.001 micro M. These in vitro findings were confirmed using an orthotopic model of oral cancer. JMAR oral cancer cells were implanted into the tongues of nude mice. After lingual tumors developed, mice were randomized into four groups (n = 10): (a) oral PKI166 (100 mg/kg); (b) i.p. paclitaxel (200 micro g/wk); (c) PKI166 and paclitaxel; or (d) placebo. Mice treated with PKI166/paclitaxel demonstrated a significant increase in survival (P = 0.028). After necropsy, all tongue tumors were evaluated for apoptosis by the terminal deoxynucleotidyl transferase-mediated nick end labeling assay. A greater apoptotic fraction of tumor cells was found in tumors of mice treated with paclitaxel and PKI166 as compared with the other treatment groups (136.4 versus 37.8; P = 0.016).


CONCLUSIONS
Combination therapy with paclitaxel and PKI166 prolongs survival in an orthotopic preclinical model of tongue cancer by increasing programmed cell death of oral cancer.
Holsinger
F Christopher
FC
Department of Head and Neck Surgery, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030-4009, USA.
Doan
Dao D
DD
Jasser
Samar A
SA
Swan
Eric A
EA
Greenberg
Jayson S
JS
Schiff
Bradley A
BA
Bekele
B Nebiyou
BN
Younes
Maher N
MN
Bucana
Corazon D
CD
Fidler
Isaiah J
IJ
Myers
Jeffrey N
JN
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use*; D017209:Apoptosis; D015153:Blotting, Western; D016923:Cell Death; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D006258:Head and Neck Neoplasms / Q000473:pathology; D006801:Humans; D020287:In Situ Nick-End Labeling; D008024:Ligands; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008856:Microscopy, Fluorescence; D009062:Mouth Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality*; D009369:Neoplasms / Q000473:pathology; D017239:Paclitaxel / Q000627:therapeutic use*; D010766:Phosphorylation; D011419:Propidium / Q000627:therapeutic use; D011743:Pyrimidines / Q000627:therapeutic use*; D011758:Pyrroles / Q000627:therapeutic use*; D014059:Tongue / Q000473:pathology; D014062:Tongue Neoplasms / Q000188:drug therapy; D014443:Tyrosine / Q000378:metabolism
D000972:Antineoplastic Agents, Phytogenic; D008024:Ligands; D011743:Pyrimidines; D011758:Pyrroles; D011419:Propidium; D014443:Tyrosine; C410026:PKI 166; D066246:ErbB Receptors; D017239:Paclitaxel