Experimental therapeutics with a new 10-deazaaminopterin in human mesothelioma: further improving efficacy through structural design, pharmacologic modulation at the level of MRP ATPases, and combined therapy with platinums.
Studies described here sought to evaluate the therapeutic potential of a new 10-deazaaminopterin analogue, 10-propargyl-10-deazaaminopterin (PDX), alone and in combination with platinum compounds in the treatment of human pleural mesothelioma. In vitro studies documented 25-30-fold and 3-fold, respectively, greater cytotoxic potency of PDX compared with methotrexate and another 10-deazaaminopterin, edatrexate, against VAMT-1 and JMN cell lines derived from human mesothelioma. These tumor cell lines were also inhibited by platinum compounds. Cisplatin (CDDP) was somewhat more inhibitory than oxaloplatin and >1 log order in magnitude more inhibitory than carboplatin (CBCDA). Against the JMN tumor xenografted in nude mice, whereas methotrexate and, more so, edatrexate, were potently growth inhibitory, only PDX brought about substantial regression. By comparison, CDDP and CBCDA, but not oxaloplatin were markedly growth inhibitory to this same tumor in vivo. This high level of therapeutic activity of PDX could be additionally enhanced by coadministration of probenecid, an inhibitor of canicular multispecific organic anion transporter/multidrug resistance-related protein (MRP)-like ATPases, which increased the number of complete regressions by >-3 fold. Canicular multispecific organic anion transporter/MRP genes, primarily 1, 3, 4, 5, and 7, were in fact expressed in these human mesothelioma cell lines as determined by real-time reverse transcription-PCR. These same MRP genes, including, to a lesser extent, MRP-4, were also expressed in pleural mesotheliomas derived from patients as shown by the same methodology. When combined with CDDP or CBCDA, PDX achieved 2-fold greater overall regression of the JMN tumor with a 3-4-fold increase in complete regressions, although some attenuation of dosages of each were required in the combination. These results strongly suggest that PDX has significant potential in the treatment of human pleural mesothelioma, particularly when coadministered with probenecid or combined with platinum compounds.
Khokhar
N Z
NZ
Program in Molecular Pharmacology and Experimental Therapeutics, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
She
Y
Y
Rusch
V W
VW
Sirotnak
F M
FM
D000251:Adenosine Triphosphatases / Q000187:drug effects / Q000378:metabolism; D000630:Aminopterin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D027321:Anion Transport Proteins / Q000187:drug effects / Q000378:metabolism; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D016190:Carboplatin / Q000008:administration & dosage; D018797:Cell Cycle Proteins; D002455:Cell Division / Q000187:drug effects; D002945:Cisplatin / Q000008:administration & dosage; D015195:Drug Design; D005656:Fungal Proteins / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D008654:Mesothelioma / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D008727:Methotrexate / Q000008:administration & dosage; D051379:Mice; D008819:Mice, Nude; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000187:drug effects / Q000378:metabolism; D017671:Platinum Compounds / Q000008:administration & dosage; D020033:Protein Isoforms / Q000235:genetics; D011494:Protein Kinases; D012334:RNA, Neoplasm / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D029702:Schizosaccharomyces pombe Proteins; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D000251:Adenosine Triphosphatases; D000630:Aminopterin; D027321:Anion Transport Proteins; D016190:Carboplatin; D018797:Cell Cycle Proteins; D002945:Cisplatin; D005656:Fungal Proteins; D008727:Methotrexate; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D017671:Platinum Compounds; D020033:Protein Isoforms; D011494:Protein Kinases; D012334:RNA, Neoplasm; D029702:Schizosaccharomyces pombe Proteins; C418863:10-propargyl-10-deazaaminopterin; C413334:Mpr1 protein, S pombe; C040210:edatrexate