Bai L, Kon K, Tatsumi M, Ito H, Hayashi S, Brautigam M
Preclinical Development Department, R&D, Nihon Schering K.K., Yodogawa-ku, Osaka 532-0004, Japan.
Oncol Rep. 2000 Jan-Feb;7(1):33-8. doi: 10.3892/or.7.1.33.
The present study was carried out to establish a human chronic lymphocytic leukemia (CLL) mouse model by transplantation of a JOK-1 human CLL cell line into SCID (severe combined immunodeficient) mice and to examine anti-leukemic effects of fludarabine phosphate, a prodrug of 9-beta-D-arabinofuranosyl-2-fluoroadenine (2F-ara-A). In vitro cytotoxic screening pattern of 2F-ara-A differed from those of other anticancer agents. Intraperitoneal inoculation with JOK-1 cells in SCID mice allowed the cells to infiltrate into a variety of organs including the liver and thymus, and resulted in the death of the mice with a median survival time of 29.5 days, associated with hepatomegaly, splenomegaly and enlarged lymph nodes. The ascitic cells expressing the human B-lymphocytic cell surface antigen CD19 actually grew after a latent period of 15 days. In this model, twice daily administration of fludarabine phosphate at a dose of 135 mg/kg for 5 days prolonged the survival time of the mice for considerably longer period than once-a-day treatment. Fludarabine phosphate in the doubled course of twice daily increased life span of 32.9%, which was in a similar range to that of doxorubicin. Thus, intraperitoneal inoculation of the human JOK-1 CLL cells into SCID mice seems to serve as an animal model potentially for human leukemia, suggesting that transplantation and subsequent infiltration processes of human CLL cells is useful measures to explore mechanistic aspects for drug-induced modulation of the tumor progression.
本研究旨在通过将JOK-1人慢性淋巴细胞白血病（CLL）细胞系移植到SCID（严重联合免疫缺陷）小鼠中建立人慢性淋巴细胞白血病小鼠模型，并研究9-β-D-阿拉伯呋喃糖基-2-氟腺嘌呤（2F-ara-A）的前体药物磷酸氟达拉滨的抗白血病作用。2F-ara-A的体外细胞毒性筛选模式与其他抗癌药物不同。在SCID小鼠腹腔内接种JOK-1细胞可使细胞浸润到包括肝脏和胸腺在内的各种器官，并导致小鼠死亡，中位生存时间为29.5天，伴有肝肿大、脾肿大和淋巴结肿大。表达人B淋巴细胞细胞表面抗原CD19的腹水细胞在15天的潜伏期后实际生长。在该模型中，以135mg/kg的剂量每日两次给予磷酸氟达拉滨，连续5天，与每日一次治疗相比，可将小鼠的生存时间延长相当长的时间。每日两次加倍疗程的磷酸氟达拉滨使寿命延长32.9%，与阿霉素的延长幅度相似。因此，将人JOK-1 CLL细胞腹腔内接种到SCID小鼠中似乎可作为一种潜在的人类白血病动物模型，这表明人CLL细胞的移植及随后的浸润过程是探索药物诱导肿瘤进展调节机制方面的有用措施。
