title: Leucovorin rescue allows effective high-dose pralatrexate treatment and an increase in therapeutic index in mesothelioma xenografts.
abstract: OBJECTIVE
  To investigate the ability of leucovorin (LV) to abrogate dose-limiting toxicities of pralatrexate (PDX) while maintaining efficacy, in vivo.
  
  
  METHODS
  H2052 mesothelioma cells were treated with the antifolates methotrexate (MTX), PDX and pemetrexed, with and without LV rescue 24 h later. Cell killing was evaluated 48 h later. Female nude mice bearing H2052 xenografts were treated with varying doses and schedules of the antifolate PDX and LV.
  
  
  RESULTS
  In vitro, H2052 cells were more sensitive to PDX as compared to MTX and pemetrexed. Administration of LV 24 h after antifolate treatment reduced efficacy of antifolates MTX and pemetrexed, but not PDX. In vivo, LV was found to reduce toxicity of PDX at the maximum tolerated dose without sacrificing efficacy. Lethal doses of PDX were rescued by LV, and mice bearing the H2052 tumor demonstrated prolonged and enhanced tumor regression.
  
  
  CONCLUSIONS
  High-dose PDX with subsequent LV rescue may be a viable treatment strategy in mesothelioma and other cancers. The inclusion of LV rescue into new and existing PDX treatment protocols should be explored as a way to expand the tolerability and effectiveness of PDX in the clinic.
authors.affiliation: Departments of Pharmacology and Medicine, Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, 195 Little Albany Street, New Brunswick, NJ, USA.
authors.forename: Philip M
authors.initials: PM
authors.lastname: Tedeschi
authors.forename: Yamini K
authors.initials: YK
authors.lastname: Kathari
authors.forename: Iqra N
authors.initials: IN
authors.lastname: Farooqi
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Bertino
mesh_terms: D000630:Aminopterin / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001835:Body Weight / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005260:Female; D005493:Folic Acid Antagonists / Q000008:administration & dosage / Q000494:pharmacology; D005971:Glutamates / Q000494:pharmacology; D006147:Guanine / Q000031:analogs & derivatives / Q000494:pharmacology; D006801:Humans; D002955:Leucovorin / Q000008:administration & dosage / Q000494:pharmacology; D008654:Mesothelioma / Q000188:drug therapy* / Q000473:pathology; D008727:Methotrexate / Q000494:pharmacology; D008819:Mice, Nude; D000068437:Pemetrexed; D013997:Time Factors; D047368:Tumor Burden / Q000187:drug effects; D014803:Vitamin B Complex / Q000008:administration & dosage / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: C418863:10-propargyl-10-deazaaminopterin; D005493:Folic Acid Antagonists; D005971:Glutamates; D000068437:Pemetrexed; D014803:Vitamin B Complex; D006147:Guanine; D000630:Aminopterin; D002955:Leucovorin; D008727:Methotrexate