Mofarotene (Ro 40-8757) inhibits hematopoiesis in vitro by preventing
maturation from primitive progenitor cells
JF Eliason, M Baumgartner, T Yoshikubo, Y Hirabayashi, H Mitsui and T Inoue
Department of Oncology, Nippon Roche Research Center, Kanagawa, Japan.
The effect of the arotinoid mofarotene (Ro 40-8757; 4-[2-[p-[(E)-
2(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-
propenyl]phenoxy]ethyl]morpholine) on stromal cell-mediated hematopoiesis
was examined in murine long-term bone marrow cultures. Whether added at
week 2 to regenerating cultures or at week 4 to plateau-phase cultures,
mofarotene strongly inhibited total cell production in a dose-dependent
manner. Progenitor cell production was also inhibited, but to a lesser
extent. When added at the initiation of culture, 1 mumol/L mofarotene did
not affect formation of the adherent layer, but production of total
nucleated cells and progenitors was inhibited over the next 10 weeks by 95%
and 96%, respectively. However, after mofarotene treatment ceased,
progenitor cell levels began increasing immediately, and cell production
reached plateau levels comparable with those of control cultures within 4
weeks. Hematopoiesis was maintained for 14 more weeks, indicating that
long-term culture- initiating cells survived the treatment. Assays of
spleen colony- forming units (CFU-S) in the adherent layers showed an
enrichment of day-13 CFU-S relative to the more mature day-9 CFU-S.
Mofarotene did not inhibit colony formation by bone marrow cells stimulated
by exogenous growth factors and did not decrease production of growth
factors by stromal cells in the cultures, as determined by functional
assays and by mRNA levels. These results suggest that mofarotene blocks
differentiation of very primitive progenitors, inhibiting production of
more mature hematopoietic elements.
Volume 86,
Issue 12,
pp. 4516-4526,
12/15/1995
Copyright © 1995 by The American Society of Hematology
