Neuroblastoma is the most common solid tumor of childhood. Survival rates of patients with disseminated neuroblastoma are as low as 5%. The proposed research will pave the way for investigations of new chemotherapeutic strategies for neuroblastoma and related neural crest tumors. The presence of receptors for catecholamines on the surface of the neuroblastoma cell has led to the use of cytotoxic neurotransmitter analogues, such as 6-hydroxydopamine, to retard the growth of C1300 mouse neuroblastoma. The efficacy of 6-hydroxydopamine is mediated by its generation of toxic oxygen free radicals. Unfortunately, systemic toxicity has limited the usefulness of this approach. Our proposed approach to this problem is two-fold: (1) to design less toxic agents to selectively attack neural crest cells; and (2) to design ways to selectively protect normal neuronal elements from the toxic free radicals generated by 6- hydroxydopamine, thereby facilitating its safe use. We will approach the first objective by using neocarzinostatin, a chemotherapeutic agent whose therapeutic efficacy is contingent upon a high cellular sulfhydryl content, adjunctively with 6- mercaptodopamine, a sulfhydryl-containing dopamine analogue which has been shown to selectively enter neural crest cells, in the C1300-A/J mouse neuroblastoma model. In this way, we hope to render neocarzinostatin selectively toxic to neural crest cells, like neuroblastoma. Because it is more toxic for rapidly dividing cells, neocarzinostatin might not be prohibitively toxic to normal neurons. In line with the second objective, we have begun studies on the adjunctive use of WR2721, a free radical scavenger which has been reported to obviate the toxic effects of several free radical-generating chemotherapeutic agents. We have obtained preliminary evidence that WR2721 is taken up by normal cells, but not by C1300 neuroblastoma cells, making it a possible protective agent for normal cells in animals treated with 6- hydroxydopamine. However, we have also obtained evidence that, in some strains of mice, WR2721 can exacerbate the toxicity of 6- hydroxydopamine by depleting cellular glutathione. We are therefore directing our efforts to determine the mechanisms of glutathione depletion by WR2721, of uptake and exclusion of WR2721, and of resistances to glutathione depletion by oxygen free radicals seen in some mouse strains, preliminary to the design of new free radical-scavenging agents which might maintain selectivity for entry into normal cells, without depleting cellular glutathione.
