Co-administration of probenecid, an inhibitor of a cMOAT/MRP-like plasma membrane ATPase, greatly enhanced the efficacy of a new 10-deazaaminopterin against human solid tumors in vivo

Earlier studies from this laboratory have shown that the uricosuric agent p robenecid (PBCD) will inhibit the extrusion of folate analogues from tumor cells mediated by a plasma membrane ATPase resembling the canicular multisp ecific organic anion transporter/multidrug resistance-related protein (MRP) family of ATP binding cassette transporters. This inhibition of this outwa rdly directed membrane ATPase has been shown to have a favorable impact upo n the cellular pharmacokinetics, cytotoxicity, and efficacy of methotrexate in vivo, In an extension of these earlier studies, which had focused only on murine ascites tumors, we now report that parental co-administration of PBCD will also enhance net intracellular accumulation in vitro and intracel lular persistence in vivo of a new folate analogue, 10-propargyl-10-deazaam inopterin (PDX) in tumor cells. This resulted in marked enhancement of the efficacy of PDX against murine and human lung neoplasms and human prostate and mammary neoplasms growing as solid tumors in mice, As possible ATPases targeted by PBCD, all of these tumors expressed MRP-1, -4, and -7 genes, wi th expression of MRP-4 being greatest in each case. Four other MRP genes we re expressed to a variable extent in some tumors but not others. The therap eutic enhancement of PDX by PBCD was manifested as tumor regression, where PDX alone was only growth inhibitory (A549 NSCL tumor), or as a substantial increase (3-4-fold) in overall regression and/or number of complete regres sions (Lewis and LX-1 lung, PC3 and TSU-PR1 prostate, and MX-1 mammary tumo rs) compared to PDX alone. Also, only in the case of PDX with PBCD, a signi ficant number of mice transplanted with LX-1 or MX-1 tumors that experience d complete regression did not have regrowth of their tumor. In view of thes e results, clinical trials of this therapeutic modality appear to be warran ted, especially in the case of new more efficacious folate analogues that a re also permeants for this canicular multispecific organic anion transporte r/MRP-like plasma membrane ATPase.