Mofarotene (Ro 40-8757) inhibits hematopoiesis in vitro by preventing maturation from primitive progenitor cells.
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.
Department of Oncology, Nippon Roche Research Center, Kanagawa, Japan.
J F
JF
Eliason
M
M
Baumgartner
T
T
Yoshikubo
Y
Y
Hirabayashi
H
H
Mitsui
T
T
Inoue
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001565:Benzoates / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D002839:Chromans / Q000494:pharmacology; D017077:Culture Media, Conditioned / Q000494:pharmacology; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D003864:Depression, Chemical; D004305:Dose-Response Relationship, Drug; D005260:Female; D006410:Hematopoiesis / Q000187:drug effects*; D006412:Hematopoietic Stem Cells / Q000187:drug effects*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009025:Morpholines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis; D012176:Retinoids / Q000494:pharmacology*
D001565:Benzoates; D002839:Chromans; D017077:Culture Media, Conditioned; D016207:Cytokines; D009025:Morpholines; D012333:RNA, Messenger; D012176:Retinoids; C084904:Ro 41-5253; C038864:4-(2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-propenyl)benzoic acid; C081137:mofarotene