Human megakaryocytes cultured in vitro accumulate serotonin but not meta-iodobenzylguanidine whereas platelets concentrate both.
OBJECTIVE
Thrombocytopenia is the major toxicity of radio-iodinated meta-iodobenzylguanidine (MIBG) therapy in patients with recurrent neuroblastoma. MIBG is taken up in platelets via the serotonin transporter. Given the delayed appearance and long duration of the thrombocytopenia, it seems likely that the precursor megakaryocytes are the primary targets of [131I]MIBG radiotoxicity.


METHODS
We investigated MIBG and serotonin uptake in cultured human megakaryocytes grown in vitro from CD34(+) cells obtained from bone marrow.


RESULTS
With radio-iodinated MIBG, cell-associated radioactivity was negligible, even after prolonged incubations for up to 16 hours. In contrast, after 4 or 16 hours with 10(-8) M [3H]serotonin, 6% or 14% of the added substrate was accumulated in the megakaryocytes. This uptake approached saturation above 10(-7) M and was reduced greater than 90% by coincubation by imipramine. This indicates specific uptake, which was confirmed by fluvoxamine and citalopram. The serotonin reuptake inhibitors fluvoxamine (0.3 nM) and citalopram (1 nM) effectively reduced serotonin uptake to 44% +/- 3% and 30% +/- 9% of the controls, respectively.


CONCLUSIONS
Megakaryocytes efficiently retain serotonin in storage granules, as concluded from the consistent reductive effect of tetrabenazine on uptake, retention, and localization (micro-autoradiographic) of serotonin. Thus, serotonin, but not MIBG, is taken up by cultured megakaryocytes.
Tytgat
Godelieve A M
GA
Center of Microscopic Research, Academical Medical Center, Amsterdam, The Netherlands. g.a.tytgat@amc.uva.nl
van den Brug
Marieke Dekker
MD
Voûte
P A
PA
Smets
Lou A
LA
Rutgers
Marja
M
D019797:3-Iodobenzylguanidine / Q000097:blood*; D018952:Antigens, CD34 / Q000032:analysis; D001692:Biological Transport; D001792:Blood Platelets / Q000378:metabolism*; D001854:Bone Marrow Cells / Q000166:cytology; D002478:Cells, Cultured; D006801:Humans; D007700:Kinetics; D008533:Megakaryocytes / Q000378:metabolism*; D012701:Serotonin / Q000097:blood*
D018952:Antigens, CD34; D012701:Serotonin; D019797:3-Iodobenzylguanidine