Inhibition of human neuroblastoma by dopamine antagonists.
The effects of dopamine agonists and antagonists were investigated in human neuroblastoma (HNB) tissue culture cell lines and correlated with the presence of specific membrane-bound dopamine-binding activity ("receptor"). In four HNB cell lines the dopamine antagonists domperidone, pimozide, and spiroperidol inhibited macromolecular synthesis in vitro as indicated by decreased 3H-TdR and 14C-leu incorporation in a dose-response fashion with at least 50% inhibition noted at 10(-6)M concentration of each drug. Dopamine agonists showed no significant inhibition. Scatchard analysis of competitive dopamine-binding assays in all four HNB cell lines and in five of eight solid tumors obtained at surgery demonstrated high affinity, limited-capacity binding consistent with a single class of receptor sites with receptor concentrations (Rc) ranging from 8.8 to 26.7 pmol/gm wet weight of tissue with dissociation constants (KD) from 0.40 to 6.6 nmol/L, compared with a mean Rc of 28.1 +/- 5.2 pmol/gm wet weight of tissue and KD = 0.38 +/- 0.09 nmol/L in receptor-rich dog caudate nucleus, the normal dopamine-sensitive control. Survival was prolonged after inoculation of the SK-N-AS cell line into nude mice and subsequent domperidone administration by 50% (24 days after drug initiation versus 16 days in control mice). These data demonstrate inhibition of macromolecular synthesis in HNB by dopamine antagonists and suggest that dopamine receptor is associated with this inhibition. The determination of dopamine receptors may prove useful in the selection of dopamine antagonists as specific chemotherapy for patients with neuroblastoma.
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D004294:Domperidone / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism / Q000494:pharmacology; D018492:Dopamine Antagonists; D005260:Female; D006801:Humans; D007980:Levodopa / Q000494:pharmacology; D051379:Mice; D008819:Mice, Nude; D009447:Neuroblastoma / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality; D010868:Pimozide / Q000494:pharmacology; D011954:Receptors, Dopamine / Q000032:analysis / Q000187:drug effects; D013134:Spiperone / Q000494:pharmacology
D018492:Dopamine Antagonists; D011954:Receptors, Dopamine; D010868:Pimozide; D007980:Levodopa; D013134:Spiperone; D004294:Domperidone; D004298:Dopamine