DIFFERENTIAL METHOTREXATE TOXICITY BETWEEN 2 HUMAN ORAL SQUAMOUS CARCINOMA CELL-LINES

Methotrexate is often used for induction or palliative therapy of adva nced head and neck squamous cell carcinoma (HNSCC). However, resistanc e to this drug is a common clinical problem, which may be conferred by several mechanisms, including: i) decreased level of folate transport proteins, required for entry of methotrexate into cells, and ii) incr ease in amount of dihydrofolate reductase (DHFR), the target enzyme of this drug. Two established, clonal cell lines of HNSCC, having equal growth rates, differed 9-fold in sensitivity to methotrexate. Cellular accumulation of radiolabelled methotrexate was measured, and did not differ between the two lines when corrected for the different volume o f the cells. This suggested that the difference in drug sensitivity wa s not due to differential uptake. This was confirmed by the finding of a 22-fold difference in sensitivity to piritrexim, a lipophilic antif olate which enters cells by simple diffusion, and, unlike methotrexate , is not polyglutamated. These results suggest that a quantitative dif ference in DHFR between the two cell lines probably accounts for the d ifferential sensitivity to antifolates. Screening of patient tumors fo r DHFR content and drug uptake may provide a basis upon which to recom mend whether methotrexate treatment is indicated.