Abstract | PURPOSE: EXPERIMENTAL DESIGN AND 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:
|
Authors | F Christopher Holsinger, Dao D Doan, Samar A Jasser, Eric A Swan, Jayson S Greenberg, Bradley A Schiff, B Nebiyou Bekele, Maher N Younes, Corazon D Bucana, Isaiah J Fidler, Jeffrey N Myers |
Journal | Clinical cancer research : an official journal of the American Association for Cancer Research
(Clin Cancer Res)
Vol. 9
Issue 8
Pg. 3183-9
(Aug 01 2003)
ISSN: 1078-0432 [Print] United States |
PMID | 12912971
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
|
Chemical References |
- Antineoplastic Agents, Phytogenic
- Ligands
- Pyrimidines
- Pyrroles
- Propidium
- Tyrosine
- PKI 166
- ErbB Receptors
- Paclitaxel
|
Topics |
- Animals
- Antineoplastic Agents, Phytogenic
(therapeutic use)
- Apoptosis
- Blotting, Western
- Cell Death
- Cell Line, Tumor
- Dose-Response Relationship, Drug
- ErbB Receptors
(antagonists & inhibitors)
- Head and Neck Neoplasms
(pathology)
- Humans
- In Situ Nick-End Labeling
- Ligands
- Male
- Mice
- Mice, Nude
- Microscopy, Fluorescence
- Mouth Neoplasms
(drug therapy, metabolism, mortality)
- Neoplasms
(pathology)
- Paclitaxel
(therapeutic use)
- Phosphorylation
- Propidium
(therapeutic use)
- Pyrimidines
(therapeutic use)
- Pyrroles
(therapeutic use)
- Tongue
(pathology)
- Tongue Neoplasms
(drug therapy)
- Tyrosine
(metabolism)
|