Differential methotrexate toxicity between two human oral squamous carcinoma cell lines.
Methotrexate is often used for induction or palliative therapy of advanced head and neck squamous cell carcinoma (HNSCC). However, resistance 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) increase 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 of the cells. This suggested that the difference in drug sensitivity was not due to differential uptake. This was confirmed by the finding of a 22-fold difference in sensitivity to piritrexin, a lipophilic antifolate which enters cells by simple diffusion, and, unlike methotrexate, is not polyglutamated. These results suggest that a quantitative difference in DHFR between the two cell lines probably accounts for the differential sensitivity to antifolates. Screening of patient tumors for DHFR content and drug uptake may provide a basis upon which to recommend whether methotrexate treatment is indicated.
Hanson
W G
WG
Department of Otolaryngology, University of Western Ontario, Canada.
Ferguson
P J
PJ
D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D004351:Drug Resistance; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008339:Mandibular Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D008727:Methotrexate / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D011743:Pyrimidines / Q000493:pharmacokinetics / Q000494:pharmacology; D013762:Tetrahydrofolate Dehydrogenase / Q000187:drug effects; D014062:Tongue Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D014407:Tumor Cells, Cultured / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism
D000970:Antineoplastic Agents; D011743:Pyrimidines; D013762:Tetrahydrofolate Dehydrogenase; C024530:piritrexim; D008727:Methotrexate