[Interest of studying the in vitro genotoxicity of an antineoplastic drug on healthy human cells: paclitaxel example].
Paclitaxel is often used as an adjuvant antineoplastic agent. However, very little data is available in literature on its potential genotoxicity on healthy human cells. Our objective is to study the potential in vitro genotoxicity of paclitaxel, by using the cytokinesis-blocked micronucleus assay in combination with fluorescent in situ hybridization of nonspecific centromeric probes on human T-lymphocytes. Paclitaxel was found to significantly increase the micronucleated lymphocyte rates with a concentration-dependant manner. This increase is observed as early as with the weakest concentration tested (2,5 nM). Over 85% of those micronuclei contained one or more whole chromosomes, indicating that paclitaxel is a strong aneugenic drug. Paclitaxel induces the formation of aneuploid daughter cells, as a consequence of abnormalities in the distribution of chromosomes during the cell division. However, aneuploidy is probably one of the first events in the oncogenesis process, and it often seems to be linked to a dysfunction of the centrosome. An interaction between paclitaxel and centrosome could explain a considerable amount of the centromere-positive micronuclei due to multipolar mitosis. Paclitaxel, whose influence is being questioned in clinical practice in the occurrence of secondary acute myeloid leukemia, is therefore an in vitro aneugenic drug, which could be carcinogenic.
Digue
Laurence
L
Laboratoire de biogénotoxicologie (EA 1784, IFR PMSE 112), Faculté de Médecine, Université de la Méditerranée, 27, bd Jean-Moulin, 13385 Marseille Cedex 5, France.
Orsière
Thierry
T
Baciuchka-Palmaro
Marjorie
M
Duffaud
Florence
F
Pompili
Jocelyne
J
Favre
Roger
R
Botta
Alain
A
D000782:Aneuploidy; D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects*; D018385:Centrosome / Q000187:drug effects; D005819:Genetic Markers; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D015162:Micronucleus Tests; D017239:Paclitaxel / Q000009:adverse effects*; D013601:T-Lymphocytes / Q000187:drug effects*
D000972:Antineoplastic Agents, Phytogenic; D005819:Genetic Markers; D017239:Paclitaxel