This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Selig, R. A. Articles by Naidoo, D. Search for Related Content PubMed PubMed Citation Articles by Selig, R. A. Articles by Naidoo, D.

Failure of Iron Chelators to Reduce Tumor Growth in Human Neuroblastoma Xenografts¹

Childrens Cancer Research Institute, Sydney Children's Hospital [R. A. S., L. W., C. G., K. S-L.], and Department of Clinical Chemistry, Prince of Wales Hospital [I. W. F., D. N.], Randwick, NSW, 2031, Australia

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 µg/g and 306 µg/g, respectively, versus 520 µg/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 µg/g, liver iron with L1 was 270 µg/g, and controls were 387 µg/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.

¹ This work was supported by the Children's Cancer Institute Australia and the Sydney Children's Hospital Foundation.

² To whom requests for reprints should be addressed, at Sydney Childrens Hospital, High Street, Randwick, New South Wales, 2031, Australia.

Received 9/25/97. Accepted 11/26/97.

This article has been cited by other articles:

				V. A. Rao, S. R. Klein, K. K. Agama, E. Toyoda, N. Adachi, Y. Pommier, and E. B. Shacter The Iron Chelator Dp44mT Causes DNA Damage and Selective Inhibition of Topoisomerase II{alpha} in Breast Cancer Cells Cancer Res., February 1, 2009; 69(3): 948 - 957. [Abstract] [Full Text] [PDF]

				Y. Yu, J. Wong, D. B. Lovejoy, D. S. Kalinowski, and D. R. Richardson Chelators at the Cancer Coalface: Desferrioxamine to Triapine and Beyond Clin. Cancer Res., December 1, 2006; 12(23): 6876 - 6883. [Abstract] [Full Text] [PDF]

				J. Yuan, D. B. Lovejoy, and D. R. Richardson Novel di-2-pyridyl-derived iron chelators with marked and selective antitumor activity: in vitro and in vivo assessment Blood, September 1, 2004; 104(5): 1450 - 1458. [Abstract] [Full Text] [PDF]

				D. B. Lovejoy and D. R. Richardson Novel "hybrid" iron chelators derived from aroylhydrazones and thiosemicarbazones demonstrate selective antiproliferative activity against tumor cells Blood, June 28, 2002; 100(2): 666 - 676. [Abstract] [Full Text] [PDF]

				D. A. Green, W. E. Antholine, S. J. Wong, D. R. Richardson, and C. R. Chitambar Inhibition of Malignant Cell Growth by 311, a Novel Iron Chelator of the Pyridoxal Isonicotinoyl Hydrazone Class: Effect on the R2 subunit of Ribonucleotide Reductase Clin. Cancer Res., November 1, 2001; 7(11): 3574 - 3579. [Abstract] [Full Text] [PDF]

				R. D. Abeysinghe, B. T. Greene, R. Haynes, M. C. Willingham, J. Turner, R. P. Planalp, M.W. Brechbiel, F. M. Torti, and S. V. Torti p53-independent apoptosis mediated by tachpyridine, an anti-cancer iron chelator Carcinogenesis, October 1, 2001; 22(10): 1607 - 1614. [Abstract] [Full Text] [PDF]