In situ analysis of doxorubicin uptake and cytotoxicity in a 3D culture model of human HT-1080 fibrosarcoma cells.
In solid tumors, chemotherapeutics must adequately diffuse through the extracellular compartment to achieve their cytotoxic effect. Using quantitative microspectrofluorometry, both Doxorubicin penetration through three-dimensional (3D) collagen I matrices and its subsequent intranuclear accumulation into HT-1080 cells cultured in this microenvironment were directly assessed. Evidence that collagen delayed the Doxorubicin penetration for 1 h is presented. During that period, drug concentrations were lower in the nuclei in 3D compared to 2D matrices. Anthracyclines were also found to exhibit similar cytotoxicity in 2D and 3D after long term incubation. In conclusion, in this 3D culture model, collagen type I matrices delayed the early distribution of low molecular weight therapeutics and failed to affect their long-term cytotoxic effects, as previously reported. This model may provide a rationale for avoiding the emergence of intrinsic chemoresistance in tissue.
Fourré
Nicolas
N
Unité MéDIAN, CNRS UMR 6142, UFR de Pharmacie, IFR 53-Biomolécules, 51 Rue Cognacq-Jay, 51096 Reims, France.
Millot
Jean-Marc
JM
Garnotel
Roselyne
R
Jeannesson
Pierre
P
D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000633:toxicity*; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000493:pharmacokinetics / Q000633:toxicity*; D005354:Fibrosarcoma / Q000378:metabolism* / Q000473:pathology; D006801:Humans
D000970:Antineoplastic Agents; D004317:Doxorubicin