Photodynamic therapy (PDT) is being investigated as an alternative treatment modality in cancer treatment. It has been shown to induce tumor hypoxia and upregulation of cyclooxygenase-2 (COX-2) and vascular endothelial growth factor (VEGF). The objective of this study was to improve in vivo tumor growth control of nasopharyngeal carcinoma (NPC), treated at a subcurative dosage by using a combination of Hypericin-PDT and COX-2 inhibitor, Celebrex (CX). The effect of an initial CX dose at 6- and 24-h post-PDT was investigated simultaneously. It was observed that hypoxic NPC/CNE2 cells upregulate both COX-2 and VEGF A genes in vitro. In vivo studies, down-regulation of COX-2 and hypoxia inducible factor-1alpha (HIF-1alpha) genes at 24-h post-PDT and bulk tumor ablation at 48-h post-PDT was observed. However, 24-28 days later regrowth was observed. In a combination treatment, 1st CX dose at 6-h post-PDT had the highest tumor control in which tumors were <or=0.52 cm(3) (64.29%, P<0.05). However, the tumors administered with a initial dose of CX at 24-h post-PDT had no tumor control. Co-suppression of COX-2, HIF-1alpha and VEGF A genes were observed in tumors with tumor control. Mice without tumor control that were subjected to therapy had increased human VEGF in serum compared to Hypericin-PDT mice. Thus, suggesting that the time of initial administration of CX post-PDT is an important factor for effective tumor control.