Synergistic effects of gemcitabine and gefitinib in the treatment of head and neck carcinoma.

Department of Radiation Oncology, University of Michigan Medical School, 1331 East Ann Street, Ann Arbor, MI 48109, USA.
Cancer Research (Impact Factor: 8.65). 02/2006; 66(2):981-8. DOI: 10.1158/0008-5472.CAN-05-2665
Source: PubMed

ABSTRACT Although the combination of gemcitabine and radiation produces a high frequency of complete responses in the treatment of locally advanced head and neck cancer, substantial toxicity suggests that an improvement in the therapeutic index is required. The purpose of this study was to determine if gefitinib could improve the efficacy of gemcitabine and if drug schedule is important. We hypothesized that gemcitabine followed by gefitinib would be superior to the opposite order because of both cell cycle and growth factor signaling interactions. Using UMSCC-1 cells in vitro, we confirmed that gefitinib arrested cells in G(1) and suppressed phospho-epidermal growth factor receptor (p(Y845)EGFR) and that gemcitabine arrested cells in S phase and stimulated p(Y845)EGFR. The schedule of gemcitabine followed by gefitinib caused arrest of cells in S phase. Gefitinib suppressed gemcitabine-mediated p(Y845)EGFR stimulation. This schedule caused decreased p(S473)AKT, increased poly(ADP-ribose) polymerase cleavage, and increased apoptosis compared with gemcitabine alone. The schedule of gefitinib followed by gemcitabine also caused suppression of p(Y845)EGFR but arrested cells in G(1). This schedule in which gefitinib was used first was associated with stable levels of p(S473)AKT and minimal poly(ADP-ribose) polymerase cleavage and apoptosis. These results were reflected in experiments in nude mice bearing UMSCC-1 xenografts, in which there was greater tumor regression and apoptosis when animals received gemcitabine followed by gefitinib during the first week of therapy. These findings suggest that the schedule of gemcitabine followed by gefitinib may increase the therapeutic index over gemcitabine alone and, combined with clinical data, encourage exploration of combination of gemcitabine, EGFR inhibitors, and radiation.

  • [Show abstract] [Hide abstract]
    ABSTRACT: Radiosensitization with antimetabolites has improved clinical outcome for patients with solid malignancies, especially cancers of the GI tract, cervix, and head and neck. Fluorouracil (FU) and hydroxyurea have been widely used clinically during the last four decades, and promising results have been observed more recently with gemcitabine. Although the antimetabolites all target DNA replication, they differ with respect to the mechanisms by which they produce radiosensitization. The antimetabolite radiosensitizers may inhibit thymidylate synthase (TS) or ribonucleotide reductase, and the nucleoside/nucleobase analogs can be incorporated into DNA. Radiosensitization can result from chemotherapy-induced increase in DNA double-strand breaks or inhibition of their repair. Studies of repair pathways involved in radiosensitization with antimetabolites implicate base excision repair with the TS inhibitors, homologous recombination with gemcitabine, and mismatch repair with FU and gemcitabine. Gemcitabine can also stimulate epidermal growth factor receptor (EGFR) phosphorylation; inhibiting this effect with EGFR inhibitors can potentiate cytotoxicity and radiosensitization. Additional work is necessary to determine more precisely the processes by which antimetabolites act as radiation sensitizers and to define the optimal sequencing of these agents with EGFR inhibitors to provide better guidance for clinical protocols combining these drugs with radiotherapy.
    Journal of Clinical Oncology 10/2007; 25(26):4043-50. · 18.04 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Development of noninvasive, real-time molecular imaging tools to assess responsiveness of a given therapy may be a critical component of the success of individualized therapy approach for patients. Toward this, we have previously developed and validated molecular sensors for Akt and caspase-3 activity, and in this report, we have explored the utility of these reporters in assessing the responsiveness of tumors to a combination of gemcitabine (Gem) and cetuximab (Cet) delivered in two opposite schedules. We found that human head and neck cancer (UMSCC1) xenografts responded significantly better in a schedule where cetuximab was administered after gemcitabine when compared with the schedule of cetuximab followed by gemcitabine. Wilcoxon two-sample tests suggested that the difference in tumor volumes in two schedules became significant on day 7 (P > .05 on day 4, and P < .05 on days 7 and 10), and the difference in activity of Akt in two schedules became significant on day 4 (P < .05 on days 4, 6, and 10). Using Akt reporter activity and cubic spline interpolation, the distinction between the two schedules could be detected 2 days before using the tumor volume, suggesting that molecular imaging of Akt may allow early prediction of therapy responsiveness. We did not observe a significant difference between the two schedules in the caspase-3 activity. In summary, this proof-of-concept study provides a basis for using molecular imaging of Akt as an early indicator of therapeutic efficacy.
    Translational oncology 06/2011; 4(3):122-5. · 3.40 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The Src gene product (Src) and the epidermal growth factor receptor (EGFR) are prototypes of oncogene products and function primarily as a cytoplasmic non-receptor tyrosine kinase and a transmembrane receptor tyrosine kinase, respectively. The identification of Src and EGFR, and the subsequent extensive investigations of these proteins have long provided cutting edge research in cancer and other molecular and cellular biological studies. In 1995, we reported that the human epidermoid carcinoma cells, A431, contain a small fraction of Src and EGFR in which these two kinase were in physical association with each other, and that Src phosphorylates EGFR on tyrosine 845 (Y845) in the Src-EGFR complex. Y845 of EGFR is located in the activation segment of the kinase domain, where many protein kinases contain kinase-activating autophosphorylation sites (e.g., cAMP-dependent protein kinase, Src family kinases, transmembrane receptor type tyrosine kinases) or trans-phosphorylation sites (e.g., cyclin-dependent protein kinase, mitogen-activated protein kinase, Akt protein kinase). A number of studies have demonstrated that Y845 phosphorylation serves an important role in cancer as well as normal cells. Here we compile the experimental facts involving Src phosphorylation of EGFR on Y845, by which cell proliferation, cell cycle control, mitochondrial regulation of cell metabolism, gamete activation and other cellular functions are regulated. We also discuss the physiological relevance, as well as structural insights of the Y845 phosphorylation.
    International Journal of Molecular Sciences 01/2013; 14(6):10761-10790. · 2.46 Impact Factor


Available from