Although the HPV-negative oral cancer cell lines are more susceptible to cisplatin, which is the mainstay of previously established chemotherapy regimens of head and neck cancer, the inhibition of TS by 5-FU or pemetrexed and the inhibition of Topo II by etoposide exerted greater cytotoxicity in HPV-positive oral and oropharyngeal cancer cell lines in a dose-dependent manner. The gene discussed is TYMS; the disease is lip and oral cavity carcinoma.