Selig R A, White L, Gramacho C, Sterling-Levis K, Fraser I W, Naidoo D
Childrens Cancer Research Institute, Sydney Children's Hospital, Randwick, NSW, Australia.
Cancer Res. 1998 Feb 1;58(3):473-8.
Neuroblastoma (NB) is a high risk tumor of childhood, and raised serum ferritin is an adverse prognostic factor. The hypothesis that iron chelation therapy impacts tumor status and patient prognosis through changes in iron metabolism has been systematically evaluated here in a xenograft model of human NB. One of two iron chelators was given in seven different regimens to nude mice xenografted s.c. with either IMR-32, an established cell line, or JBN-1, heterotransplanted directly from a patient. Nude mice (a total of 160 in 24 cohorts) were given: desferrioxamine (DFO) by s.c. bolus or reservoir; 1,2-dimethyl-3-hydroxypyridin-4-one (L1), i.p. or orally; or saline. Measurements of mean Hb and liver iron levels were compared with corresponding saline cohorts per regimen as well as for pooled cohorts per agent for both cell lines. For IMR-32 xenografts, significant differences in Hb were achieved with L1 (10.9 g/dl pooled versus 13.7 g/dl controls) and in liver iron with DFO and L1 (235 microg/g and 306 microg/g, respectively, versus 520 microg/g). For JBN-1, the pattern was similar. With L1, H6 was 10.2 g/dl and controls were 11.7 g/dl (individual DFO cohorts were also significant); liver iron with DFO was 303 microg/g, liver iron with L1 was 270 microg/g, and controls were 387 microg/g. Additional therapy prior to tumor injection (67 mice and 10 cohorts) did not increase the depletion. Despite documentation of iron depletion, no reductions in tumor engraftment, latency, or tumor size at end point were achieved in the chelator-treated mice, compared with controls populations. Accordingly, inclusion of these iron chelators in clinical trials for NB appears unwarranted.
神经母细胞瘤（NB）是一种儿童期高危肿瘤，血清铁蛋白升高是不良预后因素。铁螯合疗法通过铁代谢变化影响肿瘤状态和患者预后这一假说，在人NB异种移植模型中得到了系统评估。将两种铁螯合剂之一以七种不同方案给予皮下接种了已建立的细胞系IMR - 32或直接从患者异种移植的JBN - 1的裸鼠。共24个队列，160只裸鼠被给予：皮下推注或通过储库给予去铁胺（DFO）；腹腔注射或口服1,2 - 二甲基 - 3 - 羟基吡啶 - 4 - 酮（L1）；或生理盐水。将每种方案的平均血红蛋白（Hb）和肝脏铁水平测量值与相应的生理盐水队列进行比较，同时也对两种细胞系每种药物的合并队列进行比较。对于IMR - 32异种移植瘤，L1组的Hb有显著差异（合并组为(10.9 g/dl)，对照组为(13.7 g/dl)），DFO和L1组的肝脏铁有显著差异（分别为(235 μg/g)和(306 μg/g)，对照组为(520 μg/g)）。对于JBN - 1，情况类似。L1组的Hb为(10.2 g/dl)，对照组为(11.7 g/dl)（个别DFO队列也有显著差异）；DFO组的肝脏铁为(303 μg/g)，L1组的肝脏铁为(270 μg/g)，对照组为(387 μg/g)。肿瘤注射前的额外治疗（67只小鼠和10个队列）并未增加铁耗竭。尽管有铁耗竭的记录，但与对照组相比，螯合剂治疗的小鼠在终点时肿瘤植入、潜伏期或肿瘤大小均未降低。因此，在NB临床试验中纳入这些铁螯合剂似乎没有必要。
