Adjunctive treatment of murine neuroblastoma with 6-hydroxydopamine and Tempol.

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.