Inhibition of murine neuroblastoma growth by dopamine antagonists

Abstract C-1300 murine neuroblastoma (MNB) contains the catecholamine biosynthetic pathway. This study investigated manipulation of this pathway for effects on cell growth and survival in tumor-bearing mice, and to correlate these findings with specific membrane-bound dopamine-binding activity. The dopamine antagonists domperidone, pimozide, and spiroperidol inhibited macromolecular synthesis in vitro as demonstrated by decreased [ 3 H]TdR and [ 14 C]leu incorporation in a dose-response fashion; 56, 49, and 43% inhibition was noted at 10 −6 M concentration of each drug, respectively, with no loss of cell viability. Dopamine agonists showed no significant inhibition. Scatchard analysis of dopamine binding was consistent with a single class of receptor sites with a mean concentration of 13.2 ± 2.0 pmole/g wet weight of tissue and mean dissociation constant ( K d ) = 0.69 ± 0.38 n M , compared to a mean receptor concentration of 28.1 ± 5.2 pmole/g wet weight of tissue and K d = 0.38 ± 0.09 n M in receptor-rich dog caudate nucleus, the normal control. A/J mice injected with 1 × 10 6 tumor cells and treated with daily pimozide or domperidone had a significant increase in disease-free survival when compared to controls (15 versus 8.5 days, P P in vivo by dopamine antagonists suggests a specific chemotherapeutic approach to neuroblastoma, possibly mediated by dopamine receptors.