Studies on the uptake of synthetic conjugated folates by human marrow cells.

Pteroyltriglutamate shows little abiility Streptococcus focal/s rather than Lacto(between 1#{176}/o and 5#{176}/o), compared to bacillus case!) are unable to take up pteroylmonoglutamate (folio acid), to enter efficiently polyglutamyl forms of folate. human marrow cells and to act as a coenThe suggestion that polyglutamyl anazyme In intracellular DNA synthesis. This logues of the antifolates might be more was shown by comparing the effectiveness effective chemotherapeutic agents than of these two forms of the vitamin at corresponding monoglutamates, while biostimulating folate-dependent pyrimidine inchemically possible, would appear to be corporation into DNA in vitro in the bone precluded because of failure of transport marrow cells and lymphocytes of patients of these compounds into human hemowith megaloblastic anemia. It, therefore, poietic cells. appears that human hemopoietic cells (like I T HAS BEEN APPRECIATED for some time that folate occurs in natural materials largely with three or more glutamic acid residues attached to the pteroyl portion of the molecule. During absorption of food folates, these folate polyglutamates are enzymatically hydrolyzed to the equivalent monoglutamate derivatives.’ It is still uncertain where this hydrolysis occurs, but the finding that the enzyme involved, y-glutamyl carboxypeptidase (folate conjugase, pteroylpolyglutamate hydrolase), is found within the lysosomes of the small intestinal cells2 raises the possibility that conjugated folates may enter the intestinal cell as such before hydrolysis to the monoglutamate form.3 Some bacterial cells (e.g., L. casei) are capable of transporting triglutamate forms of folate, while others (e.g., S. fecalis) cannot transport compounds with more than two glutamate moieties.4 No equivalent information is available, however, about transport of conjugated folates into animal or human cells. The demonstration that polyglutamyl analogues of at least some antifolates are more effective in vitro than the corresponding monoglutamate forms5 and the suggestion that antifolate polyglutamates might be used in chemotherapy#{176} make the question of the cellular transport of conjugated folates more urgent. Previous work has shown that dU (deoxyuridine) does not inhibit the uptake