THE ROLE OF IMPAIRED TRANSPORT IN (PRE)CLINICAL RESISTANCE TO METHOTREXATE - INSIGHTS ON NEW ANTIFOLATES

Impaired transport appears to be a common mechanism of resistance of n eoplastic cells to the antifolate methotrexate. The extensive knowledg e of the molecular, biochemical and functional properties of the membr ane transport systems for folates, in particular the reduced folate ca rrier (RFC) and membrane folate receptors (MFR), has made an important contribution to the rational design of novel antifolates that are eit her more efficiently internalized via these transporters or can simply bypass these transport routes. The current status of exploiting the R FC and MFR for transport of novel antifolates active in preclinical mo del systems and a clinical setting will be reviewed, with a special re ference to childhood acute lymphoblastic leukemia (ALL) and acute nonl ymphoblastic leukemia (ANLL).