In vitro effect of fludarabine, cyclophosphamide, and cytosine arabinoside on chromosome breakage in Fanconi anemia patients: relevance to stem cell transplantation.
Designing stem cell transplantation (SCT) conditioning regimens for Fanconi anemia (FA) has proved difficult because of hypersensitivity to the DNA cross-linking agents. We performed chromosome fragility tests with 56 FA patients and with 50 non-FA patients with severe aplastic anemia or myelodysplastic syndrome. We evaluated peripheral blood lymphocyte specimens cultured for 72 hours and treated with mitomycin C, diepoxybutane (DEB), cyclophosphamide (CY) metabolites, cytosine arabinoside (Ara-C), and fludarabine (Flu) metabolite (9-beta-D-arabinofuranosyl-2-fluoroadenine [2-F-Ara-A]). The DEB and CY metabolite tests were highly sensitive and specific for FA (P<10(-4)) for both tests), and the number of aberrations per cell for DEB correlated with that for the CY metabolite test (P < 10(-4)) but did not correlate with the number of aberrations per cell for the Ara-C and 2-F-Ara-A tests. The difference in breakage frequencies between FA and non-FA patients for cultures treated with 2-F-Ara-A was not statistically significant. Most of the breakages observed in cells treated with 2-F-Ara-A-and Ara-C were chromatid breaks. It may be possible to determine the appropriate CY dose in the preconditioning regimen for SCT in FA patients on the basis of the in vitro effects on fragility, and Flu or Ara-C may be a safer drug than high-dose CY for conditioning in FA patients.
Yabe
Miharu
M
Department of Laboratory Medicine, Tokai University School of Medicine, Isehara, Japan. miharu@is.icc.u-tokai.ac.jp
Yabe
Hiromasa
H
Hamanoue
Satoshi
S
Inoue
Hiroyasu
H
Matsumoto
Masae
M
Koike
Takashi
T
Ishiguro
Hiroyuki
H
Morimoto
Tsuyoshi
T
Arakawa
Satoshi
S
Ohshima
Toshio
T
Masukawa
Atsuko
A
Miyachi
Hayato
H
Yamashita
Takayuki
T
Katob
Shunichi
S
D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D002478:Cells, Cultured; D019457:Chromosome Breakage / Q000187:drug effects*; D002873:Chromosome Fragility / Q000187:drug effects; D003520:Cyclophosphamide / Q000494:pharmacology*; D003561:Cytarabine / Q000494:pharmacology*; D005199:Fanconi Anemia / Q000235:genetics* / Q000378:metabolism / Q000628:therapy; D005260:Female; D006801:Humans; D008297:Male; D019653:Myeloablative Agonists / Q000494:pharmacology*; D033581:Stem Cell Transplantation; D019172:Transplantation Conditioning; D014740:Vidarabine / Q000031:analogs & derivatives* / Q000494:pharmacology
D000964:Antimetabolites, Antineoplastic; D019653:Myeloablative Agonists; D003561:Cytarabine; D003520:Cyclophosphamide; D014740:Vidarabine; C024352:fludarabine