Molecular Pharmacology, Vol 14, 299-305, Copyright © 1978 by the American Society for Pharmacology and Experimental Therapeutics

Transport and Inhibitory Activity of New Folate Analogues in HeLa Cells

¹ Departments of Microbiology/Immunology and Biochemistry, University of South Alabama College of Medicine, Mobile, Alabama 36688

Evidence supporting the existence of distinct transport systems for folate and methotrexate (MTX) in HeLa cells has been presented. Folate and MTX were observed not to compete with each other in competitive transport experiments in HeLa cells. The selective inhibition of folate and/or MTX transport by folate analogues further substantiated the existence of separate transport systems. 10-Oxaaminopterin inhibited the uptake of both MTX and folate, whereas 10-thioaminopterin selectively inhibited MTX uptake. The thio and oxa analogues of folic acid effectively inhibited folate transport and had a negligible effect on MTX transport. In comparison with the inhibitory activity of MTX, the oxa and thio analogues of aminopterin had a high level of antifolate activity as determined by inhibition of the incorporation of [2-¹⁴C]deoxyuridine into acid-precipitable DNA and cell growth. The potential use of 10-oxaaminopterin in the treatment of MTX-resistant forms of cancer is discussed in relation to its unique transport characteristics and its high antifolate activity.