Weekly administration of paclitaxel induces long-term aneugenicity in nude mice

Abstract

ABBreViAtioNs MNE ACKNowLedGeMeNtsBenjamin Bouchet is a recipient of a "Foundation pour la Recherche Medicale" grant. ABstrACtWe 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.

Positive electrostatic therapy of metastatic tumors: selective induction of apoptosis in cancer cells by pure charges

“…Daily abdominal swelling, abdominal distension, regular activity, weight loss, muscle wasting, and any other signs or symptoms of toxicity were assessed. 23 , 24 , 25 The other two groups received RT in two fractions of 1 and 2 Gy each at 48‐h intervals. The animals were then anesthetized intravenously with xylazine/ketamine (10 mg/kg xylazine and 90 mg/kg ketamine).…”

GDF-15 Neutralization Alleviates Platinum-Based Chemotherapy-Induced Emesis, Anorexia, and Weight Loss in Mice and Nonhuman Primates

“…Feather et al (2018) andSorensen et al (2017); carboplatin:Das et al (2008) and Rauh-Hain et al (2017); cyclophosphamide: Drumond et al (2011) and Khan et al (2017); dacarbazine: Cruz-Munoz et al (2009) and Malvi et al (2016); doxorubicin: Desai et al (2013) and Olson et al (2003); gemcitabine: Pfizer internal data; melphalan: de Lima et al (2013) andLu et al (2015); methotrexate:Lobo and Balthasar (2003) andPesce et al (1985); paclitaxel:Galmarini et al (2007) andHuehnchen et al (2017); irinotecan:Spilker et al (2017); pemetrexed:Izbicka et al (2009).…”

Paclitaxel resistance in untransformed human mammary epithelial cells is associated with an aneuploidy-prone phenotype

“…Several previous works have addressed the aneugenic potential of this agent in various in vitro and in vivo models (Tinwell and Ashby, 1994;Jagetia and Adiga, 1995;Jagetia and Nayak, 1996;Digue et al, 1999;Galmarini et al, 2007). However, despite its increasing use, almost no data are currently available concerning its effects in normal human mammary epithelial cells.…”