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Adjunctive treatment of murine neuroblastoma with 6-hydroxydopamine and Tempol
1Department of Pediatrics, University of Pittsburgh, Pennsylvania 15213, USA.
Abstract:
Currently available therapy for disseminated neuroblastoma affords only a 5-20% 5-year survival rate. We have attempted to design targeted chemotherapy for this disease by exploiting the dopamine uptake system on neuroblastoma cells. 6-Hydroxydopamine (6OHDA) is a neurotransmitter analogue, which generates cytolytic oxygen radicals in neuroblastoma cells that take it up. It is, however, predictably, systemically toxic, because of its spontaneous oxidation. Its toxicity is particularly severe in the sympathetic nervous system, because this tissue selectively concentrates dopamine and its analogues. Lowering the dose of 6OHDA below toxic levels prohibitively compromises its antitumor effect. To avoid both the systemic and sympathetic nervous system toxicity yet retain the antitumor efficacy of 6OHDA, we have used the antioxidant Tempol adjunctively with 6OHDA. Administration of Tempol (250 mg/kg, i.p.) 10 min prior to administration of toxic doses of 6OHDA (350 or 400 mg/kg, i.p.) resulted in a decrease in the mortality rate, sympathetic nervous system impairment, and activity impairment compared with those seen with 6OHDA alone. Tumor weights from mice administered saline or Tempol alone were 3.6 +/- 1.9 and 2.9 +/- 0.7 g, respectively. In contrast, mice administered Tempol followed by 6OHDA had an average tumor weight of 0.7 +/- 0.3 g. Tumor incidence was also reduced from 80-100% to 40%. Studies performed using electron spin resonance spectroscopy suggest that Tempol acts in this system by reacting directly with both the 6OHDA radical and, in the presence of iron, its oxidation product, the hydroxyl radical.
Insights
This study introduces a novel neuroblastoma treatment combining 6-hydroxydopamine (6OHDA) with the antioxidant Tempol. This approach reduces systemic toxicity while effectively targeting neuroblastoma tumors, improving survival rates.
Area of Science:
- Oncology
- Pharmacology
- Toxicology
Background:
- Disseminated neuroblastoma has a poor prognosis with current therapies, offering only a 5-20% 5-year survival rate.
- Targeted chemotherapy strategies are needed to improve treatment efficacy for neuroblastoma.
- 6-Hydroxydopamine (6OHDA) shows promise as a targeted agent due to its uptake by neuroblastoma cells, but its systemic and sympathetic nervous system toxicity limits its use.
Purpose of the Study:
- To design a targeted chemotherapy for neuroblastoma by mitigating the toxicity of 6-hydroxydopamine (6OHDA).
- To evaluate the efficacy and safety of using the antioxidant Tempol in conjunction with 6OHDA for neuroblastoma treatment.
Main Methods:
- Mice were administered Tempol (250 mg/kg, i.p.) 10 minutes prior to toxic doses of 6OHDA (350 or 400 mg/kg, i.p.).
- Mortality rates, sympathetic nervous system impairment, activity impairment, tumor weights, and tumor incidence were assessed.
- Electron spin resonance spectroscopy was used to investigate the mechanism of action.
Main Results:
- Adjunctive administration of Tempol significantly reduced mortality, sympathetic nervous system impairment, and activity impairment compared to 6OHDA alone.
- Average tumor weight was significantly reduced from 3.6 +/- 1.9 g (saline control) and 2.9 +/- 0.7 g (Tempol alone) to 0.7 +/- 0.3 g in mice treated with Tempol followed by 6OHDA.
- Tumor incidence decreased from 80-100% to 40% with the combined treatment.
- Tempol was shown to react with 6OHDA radicals and hydroxyl radicals, suggesting a protective mechanism.
Conclusions:
- Tempol effectively reduces the systemic and neurological toxicity associated with 6OHDA in a preclinical model.
- The combination of Tempol and 6OHDA demonstrates significant antitumor efficacy in neuroblastoma, reducing tumor weight and incidence.
- This strategy offers a promising approach to enhance the therapeutic window of 6OHDA for disseminated neuroblastoma treatment.