Background: Preclinical studies have demonstrated that low-dose hydroxyurea enhances the cytotoxic effects of gemcitabine on human cancer cells, however, the combination has not been well studied on patients with recurrent, locally persistent head and neck squamous cell carcinomas (HNSCC). Additionally, the potential biomarkers to predict the response of HNSCC to the regimen remain largely unknown. Methods: Twenty-two HNSCC patients underwent two-day hydroxyurea (500 mg/m2, day 1 and 8) and gemcitabine (500 mg/m 2, day 2 and 9) infusions every 21 days for a median of 2 (1-12) cycles until disease progression or adverse effects prohibited further therapy. RNA from pre-therapy tissues was subjected to cDNA microarray analysis to identify differentially expressed genes between the stable and progressive diseases. Validation of selected genes was performed by quantitative RT-PCR and immunohistochemistry. To further investigate impact of GADD45α on cellular sensitivity to the combination, GADD45α was overexpressed in human oropharyngeal carcinoma KB cells Results: The trial turned out that 10 patients displayed partial remission and/or stable diseases, while 9 patients displayed progressive diseases. The progressive free survival (PFS) for stable diseases was 5.88 months and the median survival was 12.4 months, while the PFS and the median survival for all patients was 1.71 and 7.23 months, respectively. A set of 112 genes was differentially expressed between stable and progressive diseases. The mRNA expression of Fos, BNIP3, PITX1 and PGK-1 were more highly expressed in the progressive diseases, while the mRNA and protein of GADD45α and GADD45γ were significantly decreased in the progressive diseases compared to the stable diseases. Moreover, overexpression of GADD45α sensitized KB cells to the combination. Conclusions: The combination of hydroxyurea with gemcitabine may be useful in HNSCC control with reasonable tolerance and toxicity. Based on gene expression profiles, a subset of patients may potentially be identified to get increased treatment benefits.
|期刊||Head and Neck Oncology|
|出版狀態||已發佈 - 二月 27 2013|
ASJC Scopus subject areas
Zhang, K., Kim, C., Wu, X., Loera, S., Wang, Y., Chu, P., Lim, D., Shibata, S., & Yen, Y. (2013). A phase II study of hydroxyurea combined with gemcitabine in patients with head and neck squamous carcinoma and gene expression profiles correlated to poor response. Head and Neck Oncology, 5(3), .