Variable Pharmacodynamics of Antifolates in Squamous Cell Carcinoma of the Head and Neck

Abstract

The effectiveness of surgery or radiotherapy to control locoregional head and neck squamous cell carcinoma (HNSCC) is well established, but patients with advanced disease still have a bad prognosis. Over the last two decades chemotherapy has been integrated into combined modality treatment for patients with progressive cancer. Despite good initial responses to chemotherapeutic treatment, the survival of patients is not enhanced.¹ Methotrexate (MTX) and 10-Ethyl-l0-deazaaminopterin (10-EdAM), both antifolate drugs, can be considered as two of the most active drugs against HNSCC. Responses, mostly partial remissions, are observed in 15–40% of the patients.^2,3 Mechanisms of resistance to antifolate drugs include defective membrane transport, increased levels of intracellular dihydrofolate reductase (DHFR) and a failure to form polyglutamates.^4–6 In this report we aimed to characterize intrinsic resistance of three HNSCC cell lines to MTX and 10-EdAM. Sensitivity was related to 1) the time of exposure, 2) the capacity to regrow after a drug free period, and 3) the ability to synthesize polyglutamate forms.