Modulation of Myogenic Differentiation in a Human Rhabdomyosarcoma Cell Line by a New Derivative of 5‐Fluorouracil (QF‐3602)

• Published in: Cancer science Vol. 91; no. 9; pp. 934 - 940
• Main Authors: Marchal, Juan Antonio, Melguizo, Consolación, Prados, Jose, Aránega, Amelia Eva, Gómez, Jose Antonio, Campos, Joaquin, Gallo, Miguel Angel, Espinosa, Antonio, Arena, Nicolo, Aránega, Antonia
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.09.2000; Japanese Cancer Association; John Wiley & Sons, Inc
• Subjects: 5-Fluorouracil; Acyclonucleoside prodrugs; Antineoplastic agents; ATP Binding Cassette Transporter, Subfamily B, Member 1 - genetics; Biological and medical sciences; Cell differentiation; Cell Differentiation - drug effects; Cytotoxicity; Differentiation therapy; Fibronectin; Fibronectins - analysis; Fluorouracil - analogs & derivatives; Fluorouracil - pharmacology; General aspects; Growth inhibition; Humans; Immunohistochemistry; Medical sciences; Microscopy, Electron; Pharmacology. Drug treatments; Polymerase Chain Reaction; Rhabdomyosarcoma; Rhabdomyosarcoma - drug therapy; Rhabdomyosarcoma - pathology; Rhabdomyosarcoma - ultrastructure; Transmission electron microscopy; Tumor Cells, Cultured; Tumors; Vimentin; Vimentin - analysis; Antineoplastic agent; Human; Vimentin; Sarcoma; Fluoropyrimidine derivatives; Rhabdomyosarcoma; Malignant tumor; Prodrug; Cell differentiation; In vitro; Biological activity; Fibronectin; Striated muscle disease; Analog; Established cell line; Pyrimidine derivatives; Fluorine Organic compounds; Fluorouracil
• ISSN: 0910-5050; 1347-9032; 1349-7006; 1876-4673
• DOI: 10.1111/j.1349-7006.2000.tb01037.x

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.