The Proton-Coupled Folate Transporter: Impact on Pemetrexed Transport and on Antifolates Activities Compared with the Reduced Folate Carrier

• DOI: 10.1124/mol.108.045443
• Publication Date: 2008-06-05T01:19:02Z
• Authors: Rongbao Zhao; Andong Qiu; Eugenia Tsai; Michaela Jansen; Myles H. Akabas; I. David Goldman
• Keywords: Pemetrexed; Antifolate; HeLa

The reduced folate carrier (RFC) and the proton-coupled transporter (PCFT) are ubiquitously expressed in normal malignant mammalian tissues human solid tumor cell lines. This article addresses extent to which PCFT contributes transport of pemetrexed activities this other antifolates relative RFC at physiological pH. Either or cDNA was stably transfected into a transporter-null HeLa variant achieve similar their endogenous function wild-type cells. produced comparable increases activity growth medium with 5-formyltetrahydrofolate. However, had little no effect on methotrexate, <i>N</i>-(5-[<i>N</i>-(3,4-dihydro-2-methyl-4-oxyquinazolin-6-ylmethyl)-<i>N</i>-methyl-amino]-2-thenoyl)-l-glutamic acid (raltitrexed, Tomudex; ZD1694), <i>N</i>^α-(4-amino-4-deoxypteroyl)-<i>N</i>^δ-hemiphthaloyl-l-ornithine (PT523) comparison irrespective source. PCFT, high levels <i>Xenopus laevis</i> oocytes transporter-competent HepG2 cells, exhibited affinity for pemetrexed, an influx <i>K</i>_m value 0.2 0.8 μM pH 5.5. increased inhibitory but not that cells grown 5-formyltetrahydrofolate These findings illustrate unique role plays pharmacological pemetrexed. Because ubiquitous expression tumors, ability sustain even absence RFC, unlikely become resistant as result impaired because redundancy these genetically distinct routes.