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

Background Preclinical studies have demonstrated that low-dose hydroxyurea (HU) 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 HU (500 mg/m 2 , day 1 and 8) and gemcitabine (500 mg/m 2 , day 2 and 9) infusions every 21 days for a median of two (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 stable and progressive disease. Validation of selected genes was performed by quantitative RT-PCR and immunohistochemistry. To further investigate the impact of growth arrest and DNA-damageinducible protein alpha (GADD45α) on cellular sensitivity to the combination of HU and gemcitabine, GADD45α was over expressed in human oropharyngeal carcinoma KB cells. Results Ten patients displayed partial remission and/or stable disease, while nine patients displayed progressive disease. The progression free survival for stable disease was 5.88 months and the median overall survival was 12.4 months, while the progression free survival and the median overall survival for all patients were 1.71 and 7.23 months, respectively. A set of 112 genes was differentially expressed between stable and progressive disease. mRNA expression of c-Fos, BCL2/ adenovirus E1B 19 kDa-interacting protein 3, paired-like homeodomain 1 and phosphoglycerate kinase 1 was more highly expressed in progressive disease, while mRNA and protein expression of GADD45α and GADD45γ were significantly decreased in progressive disease in stable disease. Moreover, over expression of GADD45α sensitized KB cells to the combination of HU and gemcitabine. Conclusions The combination of HU and gemcitabine may be useful in HNSCC control with reasonable tolerance and toxicity. Based on gene expression profiles, a subset of patients may be potentially identified to gain increased treatment benefits.