title: The role of MTHFR and RFC1 polymorphisms on toxicity and outcome of adult patients with hematological malignancies treated with high-dose methotrexate followed by leucovorin rescue.
abstract: OBJECTIVE
  In the last years, the influence of different genes involved in metabolism of chemotherapeutic agents has been studied. Methotrexate (MTX) is a key compound of chemotherapeutic regimens used in the treatment of acute lymphoblastic leukemia (ALL), primary central nervous system lymphoma (PCNSL) and Burkitt's lymphomas (BL). This study aims to evaluate the role of MTHFR C677T and A1298C polymorphisms and G80A reduced folate carrier gene (RFC1) in a cohort of adult patients with lymphoproliferative malignancies submitted to high-dose MTX followed by leucovorin rescue.
  
  
  METHODS
  We performed the analysis of these polymorphisms on genomic DNA with RFLP-PCR.
  
  
  RESULTS
  Patients carrying MTHFR A1298C variant showed decreased hepatic and hematological toxicity (P = 0.03). Overall survival (OS) and progression-free survival (PFS) between homozygous wild-type and variant patients for the RFC1 G(80)A were significantly different (P = 0.035 and P = 0.02, respectively). A significant correlation between hematological toxicity and age (P = 0.003) was observed. There was no significant influence of MTHFR C677T genotype on toxicity, OS and PFS.
  
  
  CONCLUSIONS
  Leucovorin rescue given after high-dose MTX probably accounts for the lack of influence of C677T polymorphism. To better define a role of RFC1 polymorphism on patients outcome, it would be worthwhile to perform a study on intracellular MTX level and RFC1 substrate binding affinities in different genotypes.
authors: Department of Hematology, Università Cattolica del Sacro Cuore, Largo A. Gemelli 8, 00168, Rome, Italy. p.chiusolo@rm.unicatt.it
authors: Patrizia
authors: P
authors: Chiusolo
authors: Sabrina
authors: S
authors: Giammarco
authors: Silvia
authors: S
authors: Bellesi
authors: Elisabetta
authors: E
authors: Metafuni
authors: Nicola
authors: N
authors: Piccirillo
authors: Daniela
authors: D
authors: De Ritis
authors: Sara
authors: S
authors: Marietti
authors: Sorà
authors: S
authors: Federica
authors: Luca
authors: L
authors: Laurenti
authors: Luana
authors: L
authors: Fianchi
authors: Stefan
authors: S
authors: Hohaus
authors: Leone
authors: L
authors: Giuseppe
authors: Simona
authors: S
authors: Sica
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D015331:Cohort Studies; D018572:Disease-Free Survival; D019337:Hematologic Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D006801:Humans; D053208:Kaplan-Meier Estimate; D002955:Leucovorin / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics*; D008875:Middle Aged; D011110:Polymorphism, Genetic; D058978:Reduced Folate Carrier Protein / Q000235:genetics*; D055815:Young Adult
chemical_list: D058978:Reduced Folate Carrier Protein; C548699:SLC19A1 protein, human; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D002955:Leucovorin; D008727:Methotrexate