title: Comparative activity of doxorubicin and its major metabolite, doxorubicinol, on V79/AP4 fibroblasts: a morphofunctional study.
abstract: Doxorubicin (DXR), an anthracycline antineoplastic drug, is mainly metabolized to the C-13 dihydroderivative doxorubicinol (DXR-ol), which displays cytotoxic activity on various cell lines. To better characterize the cytotoxic activity of this metabolite, we have studied the effect of DXR (0.1-10 micrograms/ml) or DXR-ol (1-100 micrograms/ml) on the transformed fibroblast cell line V79/AP4 by means of the clonogenic assay, cytofluorescence, and light and electron microscopy. Both DXR and DXR-ol displayed a dose-dependent inhibition of colony formation with an IC50 factor DXR-ol/DXR of 19.5. A striking nuclear fluorescence was observed after DXR but not after DXR-ol. A low number of mitoses and a decrease in nucleoli staining affinity were the most evident alterations induced by DXR. Electron microscopy showed both nuclear and cytoplasmic changes in DXR treated cells: nucleolar segregation, cytoplasmic vacuoles, and mitochondrial swelling with dense needle-shaped material were observed. Exposure to formic acid confirmed the calcific nature of the mitochondrial bodies. Only the highest dose of DXR-ol brought about nuclear and cytoplasmic ultrastructural changes similar to those induced by DXR. Our data describe new in vitro findings on the cytotoxicity and morphological alterations induced by both DXR and DXR-ol, with a lower activity of DXR-ol against V79/AP4 fibroblasts.
authors.affiliation: Istituto di Anatomia Umana Normale, Università degli Studi di Pisa, Italy.
authors.forename: N
authors.initials: N
authors.lastname: Bernardini
authors.forename: F
authors.initials: F
authors.lastname: Giannessi
authors.forename: F
authors.initials: F
authors.lastname: Bianchi
authors.forename: A
authors.initials: A
authors.lastname: Dolfi
authors.forename: M
authors.initials: M
authors.lastname: Lupetti
authors.forename: L
authors.initials: L
authors.lastname: Zaccaro
authors.forename: G
authors.initials: G
authors.lastname: Malvaldi
authors.forename: M
authors.initials: M
authors.lastname: Del Tacca
mesh_terms: D000818:Animals; D002455:Cell Division / Q000187:drug effects*; D002461:Cell Line, Transformed; D002470:Cell Survival / Q000187:drug effects*; D003114:Colony-Forming Units Assay; D006224:Cricetinae; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000633:toxicity*; D005347:Fibroblasts / Q000187:drug effects* / Q000648:ultrastructure; D008854:Microscopy, Electron; D008856:Microscopy, Fluorescence; D008940:Mitotic Index
chemical_list: D004317:Doxorubicin; C010013:adriamycinol