Abstract
Imatinib is an oral chemotherapeutic used primarily to treat chronic myeloid leukemia (CML) and gastrointestinal stromal tumors (GIST). The potential effects of cancer treatments on a patient’s future fertility are a major concern affecting the quality of life for cancer survivors. The effects of imatinib on future fertility are unknown. It is teratogenic. Therefore, patients are advised to stop treatment before pregnancy. Unfortunately, CML and GIST have high rates of recurrence in the absence of the drug, therefore halting imatinib during pregnancy endangers the mother. Possible long-term (post-treatment) effects of imatinib on reproduction have not been studied. We have used a mouse model to examine the effects of imatinib on the placenta and implantation after long-term imatinib exposure. We found significant changes in epigenetic markers of key imprinted genes in the placenta. There was a significant decrease in the labyrinth zone and vasculature of the placenta, which could impact fetal growth later in pregnancy. These effects on placental growth occurred even when imatinib was stopped prior to pregnancy. These results indicate potential long-term effects of imatinib on pregnancy and implantation. A prolonged wash-out period prior to pregnancy or extra monitoring for possible placental insufficiency may be advisable.
Highlights
significant growth abnormalities leading to a reduction in the size
when imatinib was continued during pregnancy
Problems with placental development and implantation may be due to long-term effects of imatinib
Summary
Mouse model.Mice were purchased from Envigo, USA (formerly Harlan), housed in a temperature and light cycle controlled animal facility. Young adult female mice (CF1 strain), aged 7 weeks old were assigned to each of three treatment groups (Table 1). Treatment Group 1 (4wk): daily dose of 400 mg/kg of intraperitoneal (100 μl, IP) imatinib plus imatinib ad lib in drinking water (1 mg/ml) for four weeks. Group 2 (4wk + p): The same treatment as in Group 1, plus imatinib was continued ad lib in their drinking water throughout pregnancy. Controls: injected IP with 100 μl of sterile water (diluent) daily for four weeks. Imatinib was purchased from Tocris Biotechne and prepared daily, by mixing in sterile water followed by 0.22um filtration. There were total of 30 female mice assigned to this study. There were n = 8 (controls), n = 9 (4wk), and n = 12 (4wk + p) female mice in this study
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