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 [3H]TdR and [14C]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 (Kd) = 0.69 +/- 0.38 nM, compared to a mean receptor concentration of 28.1 +/- 5.2 pmole/g wet weight of tissue and Kd = 0.38 +/- 0.09 nM in receptor-rich dog caudate nucleus, the normal control. A/J mice injected with 1 X 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 less than 0.001) as well as a significant increase in overall survival (35 versus 25 days, P less than 0.001). These data suggest that dopamine antagonists inhibit macromolecular synthesis in the C-1300 MNB . The inhibition of MNB tumor growth in vivo by dopamine antagonists suggests a specific chemotherapeutic approach to neuroblastoma, possibly mediated by dopamine receptors.