Yabe Miharu, Yabe Hiromasa, Hamanoue Satoshi, Inoue Hiroyasu, Matsumoto Masae, Koike Takashi, Ishiguro Hiroyuki, Morimoto Tsuyoshi, Arakawa Satoshi, Ohshima Toshio, Masukawa Atsuko, Miyachi Hayato, Yamashita Takayuki, Katob Shunichi
Department of Laboratory Medicine, Tokai University School of Medicine, Isehara, Japan.
Int J Hematol. 2007 May;85(4):354-61. doi: 10.1532/IJH97.06191.
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.
由于对DNA交联剂高度敏感，为范可尼贫血（FA）设计干细胞移植（SCT）预处理方案已被证明具有难度。我们对56例FA患者以及50例患有严重再生障碍性贫血或骨髓增生异常综合征的非FA患者进行了染色体脆性试验。我们评估了经丝裂霉素C、二环氧丁烷（DEB）、环磷酰胺（CY）代谢产物、阿糖胞苷（Ara-C）和氟达拉滨（Flu）代谢产物（9-β-D-阿拉伯呋喃糖基-2-氟腺嘌呤[2-F-Ara-A]）处理72小时后的外周血淋巴细胞标本。DEB和CY代谢产物试验对FA具有高度敏感性和特异性（两种试验的P<10⁻⁴），并且DEB处理后每个细胞的畸变数量与CY代谢产物试验的结果相关（P < 10⁻⁴），但与Ara-C和2-F-Ara-A试验中每个细胞的畸变数量无关。对于用2-F-Ara-A处理的培养物，FA患者和非FA患者之间的断裂频率差异无统计学意义。在用2-F-Ara-A和Ara-C处理的细胞中观察到的大多数断裂为染色单体断裂。基于体外对脆性的影响，有可能在FA患者SCT的预处理方案中确定合适的CY剂量，并且对于FA患者的预处理，Flu或Ara-C可能是比高剂量CY更安全的药物。
