Modulation of myogenic differentiation in a human rhabdomyosarcoma cell line by a new derivative of 5-fluorouracil (QF-3602).
The in vitro study of mechanisms involved in drug-induced maturation has made it possible to use differentiation-based therapy in clinical practice. The goal of this new therapy is the development of specific agents to induce cancer cells to stop proliferating and express characteristics of normal cells. Recently, by structural modifications of 5-fluorouracil (5-FU), we synthesized a new pyrimidine acyclonucleoside-like compound, 1-¿[3-(3-chloro-2-hydroxypropoxy)-1-methoxy]propyl¿-5-fluorouracil (QF-3602), which showed in rhabdomyosarcoma cells a low toxicity and time-dependent growth inhibition. In this work, we compared the degree of myogenic differentiation of RD rhabdomyosarcoma (RMS) cells after treatment with QF-3602 and 5-FU. Scanning and transmission electron microscopy (SEM and TEM) and immunocytochemical analyses showed that QF-3602 induced the appearance of myofilaments along the myotube-like giant RD cells, an increase in fibronectin and a decrease in vimentin expression. In contrast, only minor changes were observed with 5-FU. Moreover, polymerase chain reaction (PCR) analyses showed that QF-3602 did not induce overexpression of the mdr 1 gene, a resistance mechanism that frequently appears in classical cytotoxic therapy in these tumors. Compounds obtained by structural modifications of 5-FU may be useful in differentiation therapy as a new approach to the treatment of RMS.
Marchal
J A
JA
Departamento de Ciencias de la Salud, Facultad de Ciencias Experimentales, Universidad de Jaé, 23071 Jaé, Spain.
Melguizo
C
C
Prados
J
J
Aránega
A E
AE
Gómez
J A
JA
Campos
J
J
Gallo
M A
MA
Espinosa
A
A
Arena
N
N
Aránega
A
A
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D002454:Cell Differentiation / Q000187:drug effects; D005353:Fibronectins / Q000032:analysis; D005472:Fluorouracil / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D007150:Immunohistochemistry; D008854:Microscopy, Electron; D016133:Polymerase Chain Reaction; D012208:Rhabdomyosarcoma / Q000188:drug therapy* / Q000473:pathology / Q000648:ultrastructure; D014407:Tumor Cells, Cultured; D014746:Vimentin / Q000032:analysis
C416766:1-((3-(3-chloro-2-hydroxyproxy)-1-methoxy)propyl)-5-fluorouracil; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D005353:Fibronectins; D014746:Vimentin; D005472:Fluorouracil