Inhibition of murine neuroblastoma growth by dopamine antagonists.
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.
D000818:Animals; D002460:Cell Line; D004247:DNA / Q000096:biosynthesis; D004294:Domperidone / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism; D018492:Dopamine Antagonists; D007930:Leucine / Q000378:metabolism; D008297:Male; D051379:Mice; D008805:Mice, Inbred A; D009368:Neoplasm Transplantation; D009447:Neuroblastoma / Q000378:metabolism / Q000473:pathology*; D010868:Pimozide / Q000494:pharmacology; D011954:Receptors, Dopamine / Q000378:metabolism; D013134:Spiperone / Q000494:pharmacology; D013936:Thymidine / Q000378:metabolism
D018492:Dopamine Antagonists; D011954:Receptors, Dopamine; D010868:Pimozide; D013134:Spiperone; D004294:Domperidone; D004247:DNA; D007930:Leucine; D013936:Thymidine; D004298:Dopamine