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Blood, Vol. 95 No. 11 (June 1), 2000:
pp. 3589-3593
Acquired DNA mutations associated with in vivo hydroxyurea
exposure
Valerie N. Hanft,
Steven R. Fruchtman,
Chrisley V. Pickens,
Wendell F. Rosse,
Thad A. Howard, and
Russell E. Ware
From the Division of Hematology/Oncology, Department of Pediatrics,
and the Division of Hematology, Department of Medicine, Duke University
Medical Center, Durham, NC, and the Bone Marrow Transplantation
Program, Mt Sinai Medical Center, New York, NY.
Hydroxyurea (HU) is an effective therapeutic agent for patients with
myeloproliferative disorders (MPDs) or sickle cell disease (SCD).
Short-term HU toxicities primarily include transient myelosuppression, but long-term HU risks have not been defined. The mutagenic and carcinogenic potential of HU is not established, although HU has been
associated with an increased risk of leukemia in some patients with
MPD. In this study, 2 assays were used to quantitate acquired somatic
DNA mutations in peripheral blood mononuclear cells (PBMCs) after in
vivo HU exposure. The HPRT assay measures hypoxanthine phosphoribosyl
transferase (hprt) mutations, while the VDJ
assay identifies "illegitimate" T-cell receptor V -J
interlocus recombination events. PBMCs were analyzed from patients with
MPD, adults and children with SCD, and normal controls. MPD patients
with prolonged HU exposure had numbers of DNA mutations equivalent to
patients with low HU exposure or controls. Similarly, adults with SCD
had equivalent numbers of DNA mutations regardless of HU exposure. Children with SCD and 30-month HU exposure had equivalent
hprt mutations but significantly more VDJ
mutations (1.82 ± 1.20 events per µg DNA) than children with
7-month HU exposure (1.58 ± 0.87 events) or no HU exposure
(1.06 ± 0.45 events), P = .04 by analysis of variance.
Taken together, these data suggest that the mutagenic and carcinogenic
potential of in vivo HU therapy is low. Although increased numbers of
illegitimate VDJ recombination events do not directly portend leukemia,
young patients with SCD and HU exposure should be monitored serially
for increases in DNA mutations.
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