Pemetrexed: biochemical and cellular pharmacology, mechanisms, and clinical applications

Abstract

Pemetrexed is a new-generation antifolate, approved for the treatment of mesothelioma and non -small cell lung cancer, currently being evaluated for the treatment of a variety of other solid tumors. This review traces the history of antifolates that led to the development of pemetrexed and describes the unique properties of this agent that distinguish it from other antifolates. These include (a) its very rapid conversion to active polyglutamate derivatives in cells that build to high levels and are retained for long intervals to achieve prolonged and potent inhibition of its major target enzyme thymidylate synthase, (b) its high affinity for three folate transporters, and (c) its marked sensitivity to the level of physiologic folates in cells. The latter results in the unique and paradoxical finding that when transport mediated by the major folate transporter (the reduced folate carrier) is impaired, pemetrexed activity is preserved. This is due to concurrent contraction of competing cellular physiologic folates and utilization of a novel second transport carrier for which pemetrexed has high affinity, recently identified as the proton-coupled folate transporter (PCFT). Laboratory studies are reviewed that raise the possibility of new approaches to the use of folic acid supplementation in clinical regimens with pemetrexed. [Mol Cancer Ther 2007;6(2):404 -17]

Structures of human folate receptors reveal biological trafficking states and diversity in folate and antifolate recognition

“…More recently, the emphasis in folatemediated drug therapy has shifted to obtain a better understanding of transport mechanisms of antifolates because dose-limiting toxicities arise from their transport via RFC, and possibly PCFT, into normal cells (6,11,(15)(16)(17). To date, antifolates approved for clinical use are transported primarily via RFC, although one of the most recently developed antifolates, pemetrexed (PMX), may also transit through PCFT (6,11,(18)(19)(20)(21). Given the toxicities associated with transport via facilitative transporters, the development of therapeutic molecules specifically transported via the FRs has been explored over the last two decades (22)(23)(24).…”

Interstitial nephritis and nephrogenic diabetes insipidus in a patient treated with pemetrexed

“…12 Folates and antifolates are reabsorbed at kidney proximal tubules via folate receptors and transported into cells. [13][14][15] We hypothesize that the accumulation of the drug intracellularly and the subsequent inhibition of purine and protein synthesis, result in tubular cytotoxicity and possibly secondary tubulointerstitial inflammation leading to AKI. Our patient did not respond to corticosteroid treatment.…”

Conserved molecular mechanisms underlying the effects of small molecule xenobiotic chemotherapeutics on cells

“…This cumulates in increased sub-cellular vesiculization-mediated generation of pro-oxidant reactive oxygen species (109,110), and in case of the mitochondria, vesiculization-mediated loss of MM electromotive potential (109,(111)(112)(113). Therefore, the mechanism for anti-folate chemoxenobiotic-mediated cellular cytotoxicity is FAR endocytosis-driven sub-cellular pro-oxidant oxidative stress (114)(115)(116)(117), particularly mitochondrial, whereby there is only limited potential for CM receptor endocytosis-mediated (Pseudo) 3ary indirect pressuromodulation (110,118) (Table VIII and Fig. 8).…”