Expression of the human concentrative nucleotide transporter 1 (hCNT1) gene correlates with clinical response in patients affected by Waldenström's Macroglobulinemia (WM) and small lymphocytic lymphoma (SLL) undergoing a combination treatment with 2-chloro-2'-deoxyadenosine (2-CdA) and Rituximab.
OBJECTIVE
Resistance to nucleoside analogues agents is likely to be multifactorial and could involve a number of mechanisms affecting drug penetration, metabolism and targeting. In vitro studies of resistant human cell lines have confirmed that human concentrative nucleoside transporter 1 (hCNT1)-deficient cells display resistance.


METHODS
We applied real-time PCR method to assess the mRNA expression of equilibrative and concentrative nucleoside transporter (hENT1, hCNT1), deoxycytidine and deoxyguanosine kinase (dCK, dGK), 5'-nucleotidase (5'-NT), ribonucleotide reductase catalytic and regulatory (RR1, RR2) subunits in bone marrow cells from 32 patients with Waldenström's Macroglobulinemia (WM) and small lymphocytic lymphoma (SLL) who received 2CdA-based chemotherapy. Responses to chemotherapy, were then correlated to the expression of these markers.


RESULTS
All 32 patients enrolled expressed lower levels of hCNT1 as compared to healthy donors. In univariate analysis, lower expression level of hCNT1 (p=0.0021) and RR2 (p=0.02) correlated with response to chemotherapy. In particular, patients with low levels of hCNT1 achieved inferior clinical response. No significant correlation between these genes expression and age, stage of disease was found. This study suggests that nucleotidase expression levels can be used to identify subgroups of WM and SLL patients who will likely respond differently to a 2CdA-based therapy.
Rabascio
C
C
Dept of Haematology, European Institute of Oncology, via Ripamonti 435, 20141 Milano, Italy. cristina.rabascio@ieo.it
Laszlo
D
D
Andreola
G
G
Saronni
L
L
Radice
D
D
Rigacci
L
L
Fabbri
A
A
Frigeri
F
F
Calabrese
L
L
Billio
A
A
Bertolini
F
F
Martinelli
G
G
D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D058846:Antibodies, Monoclonal, Murine-Derived; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000235:genetics; D017338:Cladribine / Q000008:administration & dosage*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics*; D008875:Middle Aged; D008954:Models, Biological; D011379:Prognosis; D000069283:Rituximab; D016896:Treatment Outcome; D008258:Waldenstrom Macroglobulinemia / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics
D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D014408:Biomarkers, Tumor; D026901:Membrane Transport Proteins; C065171:cif nucleoside transporter; D017338:Cladribine; D000069283:Rituximab