Reduced folate carrier and dihydrofolate reductase expression in acute lymphocytic leukemia may predict outcome: a Children's Cancer Group Study.
OBJECTIVE
Methotrexate is a major component of current treatment regimens for children with acute lymphocytic leukemia (ALL). Potential mechanisms of methotrexate resistance include impaired drug uptake, decreased drug retention, and dihydrofolate reductase (DHFR) amplification. The purpose of this study was to assess whether reduced folate carrier (RFC) and DHFR expression in untreated leukemic blasts correlated with outcome.


METHODS
Quantitative real-time RT-PCR was used to measure RFC and DHFR mRNA expression in leukemic blasts from 40 newly diagnosed patients with ALL obtained in a blinded fashion from Children's Cancer Group studies.


RESULTS
Low RFC expression at diagnosis correlated significantly with an unfavorable event free survival. Surprisingly, low, not high, DHFR expression correlated significantly with an unfavorable event-free survival. Proliferative cell nuclear antigen (PCNA) expression demonstrated a weak inverse relationship between sample PCNA and DHFR or RFC expression, suggesting that DHFR and RFC expression may be markers for factors other than drug resistance.


CONCLUSIONS
These results suggest that impaired transport may be an important mechanism of intrinsic methotrexate resistance in ALL, and DHFR expression also may be an important prognostic factor in ALL. Additional studies are necessary to clarify the mechanism for the correlation of low DHFR expression with poor outcome.
Levy
Adam S
AS
Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
Sather
Harland N
HN
Steinherz
Peter G
PG
Sowers
Rebecca
R
La
Mei
M
Moscow
Jeffrey A
JA
Gaynon
Paul S
PS
Uckun
Fatih M
FM
Bertino
Joseph R
JR
Gorlick
Richard
R
D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001692:Biological Transport; D002352:Carrier Proteins / Q000096:biosynthesis* / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D005260:Female; D058973:Folate Receptors, GPI-Anchored; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D007223:Infant; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D014411:Neoplastic Stem Cells / Q000737:chemistry; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000401:mortality; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D011956:Receptors, Cell Surface; D013762:Tetrahydrofolate Dehydrogenase / Q000096:biosynthesis* / Q000235:genetics
D000964:Antimetabolites, Antineoplastic; D002352:Carrier Proteins; D004791:Enzyme Inhibitors; D058973:Folate Receptors, GPI-Anchored; D018809:Proliferating Cell Nuclear Antigen; D011956:Receptors, Cell Surface; D013762:Tetrahydrofolate Dehydrogenase; D008727:Methotrexate