In vitro sensitivity and cross-resistance to deoxynucleoside analogs in childhood acute leukemia.
OBJECTIVE
Cytarabine (ara-C) is a key drug in the treatment of acute leukemia. Resistance to ara-C might be circumvented by the use of other deoxynucleoside analogs.


METHODS
Using the MTT assay, we determined in vitro sensitivity and cross-resistance to deoxynucleoside analogs in 362 acute leukemia samples from untreated children and 32 normal bone marrow mononuclear cell samples.


RESULTS
Normal bone marrow samples were significantly more resistant to ara-C, cladribine and fludarabine than were acute myeloid leukemia (AML) samples and significantly more resistant to ara-C and fludarabine than were acute lymphoblastic leukemia (ALL) samples. The only drug to which AML samples were more sensitive in vitro than ALL was cladribine. AML FAB M5 was significantly more sensitive in vitro to ara-C and cladribine than FAB M1/2 or FAB M4. T-ALL was significantly more resistant to cladribine than B-cell precursor ALL. A paired analysis of 60 AML and 99 ALL samples demonstrated significant cross-resistance between all four deoxynucleoside analogs. Cross-resistance was also observed between ara-C and etoposide (Rp=0.54, p<0.0001), and ara-C and daunorubicin (Rp=0.48, p<0.0001) in AML. In ALL blasts, cross-resistance was observed between ara-C and vincristine (Rp=0.50; p<0.0001), and between ara-C and daunorubicin and L-asparaginase (Rp=0.25; p=0.01; Rp=0.28; p=0.005).


CONCLUSIONS
Cladribine appears to be a useful drug in AML, particularly in FAB M5. We observed cross-resistance between ara-C and other deoxynucleoside analogs, as well as between ara-C and drugs with different modes of action in childhood acute leukemia.
Hubeek
Isabelle
I
Dept. of Pediatric Hematology/Oncology, VU University Medical Center, Amsterdam, The Netherlands. isabelle.hubeek@vumc.nl
Peters
Godefridus J
GJ
Broekhuizen
Richard
R
Zwaan
Christian M
CM
Kaaijk
Patricia
P
van Wering
Elisabeth S
ES
Gibson
Brenda E S
BE
Creutzig
Ursula
U
Janka-Schaub
Gritta E
GE
den Boer
Monique L
ML
Pieters
Rob
R
Kaspers
Gertjan J L
GJ
D000208:Acute Disease; D002648:Child; D003561:Cytarabine / Q000627:therapeutic use; D018432:Drug Resistance, Multiple; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007938:Leukemia / Q000188:drug therapy* / Q000473:pathology; D009705:Nucleosides / Q000627:therapeutic use*
D009705:Nucleosides; D003561:Cytarabine