Weekly administration of paclitaxel induces long-term aneugenicity in nude mice.
We investigated the potential in vivo aneugenic effects associated with paclitaxel treatment. For this purpose, we treated female nude mice with paclitaxel using doses equivalent to those used in weekly schedules at the clinical level (three cycles of 30 mg/kg/week for three consecutive weeks followed by one resting week). We then evaluated the frequencies of micronucleated erythrocytes (MNE) in peripheral blood using the acridine orange micronucleus assay. The frequency of MNE was evaluated after 24 h and 168 h of administration of the last dose of each paclitaxel cycle (STA mice group) as well as after one year of the first dose of treatment (LTA mice group). We also analyzed the cytology of peripheral blood and bone marrows obtained from these mice at each time period. In the STA mice group, three cycles of paclitaxel induced a 2.4-fold increase in MNE frequencies compared to the control group (p < 0.01). This effect was observed after 24 h of the last dose of each chemotherapy cycle and persisted at least for 168 h. In the LTA mice group, paclitaxel-treated mice presented a 1.8-fold increase in the MNE frequency (p = 0.01) indicating that paclitaxel-induced MNE increase lasted for at least one year. Although the appearance of micronuclei in erythrocytes and granulocytes in peripheral blood and bone marrow cytological smears, there was no evidence of myeloproliferative disease. The present data therefore indicate an aneugenic potential of paclitaxel for humans, which should be considered in the risk-benefit analysis of its increasing clinical use.
Galmarini
Carlos M
CM
Université Claude Bernard Lyon 1 CNRS UMR 5239, Lyon, France.
Bouchet
Benjamin P
BP
Falette
Nicole
N
Vila
Liliana
L
Lamblot
Christelle
C
Audoynaud
Carole
C
Bertholon
Jacques
J
Puisieux
Alain
A
D024422:Aneugens / Q000008:administration & dosage / Q000633:toxicity*; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000633:toxicity*; D004912:Erythrocytes / Q000648:ultrastructure*; D005260:Female; D051379:Mice; D008819:Mice, Nude; D015162:Micronucleus Tests; D016296:Mutagenesis; D017239:Paclitaxel / Q000008:administration & dosage / Q000633:toxicity*
D024422:Aneugens; D000970:Antineoplastic Agents; D017239:Paclitaxel