Similar specificity of membrane transport for folate analogues and their metabolites by murine and human tumor cells: a clinically directed laboratory study.
Mediated transport of folate compounds exhibited similar kinetic characteristics and structural specificity in a series of cultured murine and human tumor cells examined in a parallel fashion. In each case, influx was characterized by a single saturable component with an approach to steady-state conforming to a single exponential, while efflux was first order (poorly saturable). Both mediated fluxes exhibited high temperature dependence (Q10 27-37 degrees = 6 to 8). During competition studies with various analogues, it was found that positions 4, 5, 7, and 10 and the gamma-carboxyl position of the folate molecule were specified for influx in tumor cells from each species. Also, short-chain alkyl substitution at position 10 was specified in the case of N10, but not in the case of C10. None of the modifications at position 10 affected mediated efflux in either cell type. The linkage of additional glutamyl residues at the gamma-carboxyl-position resulted in reduced saturability (increased value for Ki) of influx in both murine and human tumor cells in a manner proportional to the number of glutamyl residues. Mediated influx in human ovarian carcinoma cells obtained from malignant effusions in several patients and in an established cell line derived from one of these patients showed similar kinetics for folate analogue transport and specificity for modification at position 10 of the 4-amino-folate molecule. Mediated entry of 10-deazaaminopterin and its 10-ethyl derivative compared to entry of methotrexate was 4- to 11-fold greater in murine tumor cells and 4- to 9-fold greater in human tumor cells in culture or when clinically derived. Mediated efflux was not specified for position 10 on the 4-amino folate structure in any tumor cell type. These findings appear to provide some basis for concluding that the results of studies of this type in model murine systems or with tumor cell lines established in culture have relevance to clinical cancer.
D000818:Animals; D001692:Biological Transport; D001943:Breast Neoplasms / Q000378:metabolism; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D005260:Female; D005492:Folic Acid / Q000031:analogs & derivatives* / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D007938:Leukemia / Q000378:metabolism; D007939:Leukemia L1210 / Q000378:metabolism; D009369:Neoplasms / Q000378:metabolism*; D012510:Sarcoma 180 / Q000378:metabolism; D013329:Structure-Activity Relationship; D013762:Tetrahydrofolate Dehydrogenase / Q000378:metabolism
D005492:Folic Acid; D013762:Tetrahydrofolate Dehydrogenase