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PubMed1995

Four-week oral toxicity study of 1,2-dimethyl-3-hydroxypyrid-4-one (L1) in uremic rats.

A short-term oral toxicity study of 1,2-dimethyl-3-hydroxypyrid-4-one (L1), a promising oral chelating agent for the treatment of iron and aluminum overload, was carried out in uremic rats. L1 was administered to male uremic rats by gastric intubation at 0, 20, 40, 80 or 160 mg/kg/d for 4 w. Body weight and food and fluid intake were monitored daily. Complete hematologic examinations, serum biochemical parameter determinations and histological examinations were carried out. Although body weight gain was significantly reduced at 80 and 160 mg/kg/d, there were no effects of L1 on food and fluid consumption. There were no significant differences between controls and L1-treated groups in most of the hematological and biochemical parameters analyzed. No significant dose-dependent changes in relative organ weights were noted. The non-observed-adverse-effect level (NOAEL) for L1 in uremic rats was 40 mg/kg/d. According to the results of this study, uremia did not increase the toxic effects of L1.

Administration, Oral↗
PubMed1995

Oral iron chelators.

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Administration, Oral↗
PubMed1996

Oral iron chelation.

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Administration, Oral↗
PubMed1998

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 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.

Administration, Oral↗
PubMed1998

The iron chelator L1 potentiates oxidative DNA damage in iron-loaded liver cells.

Iron-mediated carcinogenesis is thought to occur through the generation of oxygen radicals. Iron chelators are used in attempts to prevent the long term consequences of iron overload. In particular, 1,2-dimethyl-3-hydroxypyrid-4-one (L1), has shown promise as an effective chelator. Using an established hepatocellular model of iron overload, we studied the generation of iron-catalyzed oxidative DNA damage and the influence of iron chelators, including L1, on such damage. Iron loading of HepG2 cells was found to greatly exacerbate hydrogen peroxide-mediated DNA damage. Desferrithiocin was protective against iron/hydrogen peroxide-induced DNA damage; deferoxamine had no effect. In contrast, L1 exposure markedly potentiated hydrogen peroxide-mediated oxidative DNA damage in iron-loaded liver cells. However, when exposure to L1 was maintained during incubation with hydrogen peroxide, L1 exerted a protective effect. We interpret this as indicating that L1's potential toxicity is highly dependent on the L1:iron ratio. In vitro studies examining iron-mediated ascorbate oxidation in the presence of L1 showed that an L1:iron ratio must be at least 3 to 1 for L1 to inhibit the generation of free radicals; at lower concentrations of L1 increased oxygen radical generation occurs. In the clinical setting, such potentiation of iron-catalyzed oxidative DNA damage at low L1:iron ratios may lead to long-term toxicities that might preclude administration of L1 as an iron chelator. Whether this implication in fact extends to the in vivo situation will have to be verified in animal studies.

Cell Line↗
PubMed1998

Legal issues surrounding privately funded research cause furore in Toronto.

Toronto physician Miriam Shuchman has spent the last 4 months tracking the research issues surrounding a controversial clinical trial conducted in Toronto. Much of the information appearing in this article was gathered while she was preparing a segment for the CBC Radio program Quirks and Quarks. Earlier, she had reported on similar issues in the US for the Annals of Internal Medicine.

Biomedical Research↗