FAILURE OF IRON CHELATORS TO REDUCE TUMOR-GROWTH IN HUMAN NEUROBLASTOMA XENOGRAFTS

Neuroblastoma (NB) is a high risk tumor of childhood, and raised serum ferritin is an adverse prognostic factor, The hypothesis that iron ch elation therapy impacts tumor status and patient prognosis through cha nges in iron metabolism has been systematically evaluated here in a xe nograft model of human NB. One of two iron chelators was given in seve n 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: desfer rioxamine (DFO) by s.c. bolus or reservoir; 1,2-dimethyl-3-hydroxypyri din-4-one (L1), i.p. or orally; or saline. Measurements of mean Db 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 wit h L1 (10.9 g/dl pooled versus 13.7 g/dl controls) and in liver iron wi th DFO and L1 (235 mu g/g and 306 mu g/g, respectively, versus 520 mu g/g). For JBN-1, the pattern was similar. With L1, H6 was 10.2 g/dl an d controls were 11.7 g/dl (individual DFO cohorts were also significan t); liver iron with DFO was 303 mu g/g, liver iron with L1 was 270 mu g/g, and controls were 387 mu g/g. Additional therapy prior to tumor i njection (67 mice and 10 cohorts) did not increase the depletion. Desp ite documentation of iron depletion, no reductions in tumor engraftmen t, latency, or tumor size at end point were achieved in the chelator-t reated mice, compared with controls populations. Accordingly, inclusio n of these iron chelators in clinical trials for NB appears unwarrante d.