Substantial Variation in Transplacental Transfer of Chemotherapeutic Agents in a Mouse Model

Calsteren, Kristel Van; Verbesselt, René; Bree, Rieta Van; Heyns, Liesbeth; Bruijn, Ernst de; Hoon, Jan de; Amant, Frédéric

doi:10.1177/1933719110379650

Cited by 47 publications

(24 citation statements)

References 42 publications

(77 reference statements)

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“…Fetal safety during the administration of anthracycline-based chemotherapy in pregnancy is of theoretical concern because anthracyclines can cross the placenta, even if their fetal plasma concentrations are lower than those found in the mother, and have cumulative toxicity [ 31 ]. Available data provide only limited experimental and clinical data on the transplacental transfer of these chemotherapeutics in pregnant women; in a baboon model, fetal plasma concentrations of doxorubicin, epirubicin and paclitaxel were about 7.5 %, 4.0 %, and 1.4 %, of the respective maternal concentrations [ 32 ].…”

Section: Discussionmentioning

confidence: 99%

Epirubicin: a new entry in the list of fetal cardiotoxic drugs? Intrauterine death of one fetus in a twin pregnancy. Case report and review of literature

Framarino-dei-Malatesta

Perrone

Giancotti

et al. 2015

BMC Cancer

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BackgroundCurrent knowledge indicate that epirubicin administration in late pregnancy is almost devoid of any fetal cardiotoxicity. We report a twin pregnancy complicated by breast cancer in which epirubicin administration was causatively linked to the death of one twin who was small for gestational age (SGA) and in a condition of oligohydramnios and determined the onset of a transient cardiotoxicity of the surviving fetus/newborn.Case presentationA 38-year-old caucasic woman with a dichorionic twin pregnancy was referred to our center at 20 and 1/7 weeks for a suspected breast cancer, later confirmed by the histopathology report. At 31 and 3/7 weeks, after the second chemotherapy cycle, ultrasound examination evidenced the demise of one twin while cardiac examination revealed a monophasic diastolic ventricular filling, i.e. a diastolic dysfunction of the surviving fetus who was delivered the following day due to the occurrence of grade II placental abruption. The role of epirubicin cardiotoxicity in the death of the first twin was supported by post-mortem cardiac and placental examination and by the absence of structural or genomic abnormalities that may indicate an alternative etiology of fetal demise. The occurrence of epirubicin cardiotoxicity in the surviving newborn was confirmed by the report of high levels of troponin and transient left ventricular septal hypokinesia.ConclusionBased on our findings we suggest that epirubicin administration in pregnancy should be preceded by the screening of some fetal conditions like SGA and oligohydramnios that may increase its cardiotoxicity and that, during treatment, the diastolic function of the fetal right ventricle should be specifically monitored by a pediatric cardiologist; also, epirubicin and desamethasone for lung maturation should not be closely administered since placental effects of glucocorticoids may increase epirubicin toxicity.

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Section: Discussionmentioning

confidence: 99%

Epirubicin: a new entry in the list of fetal cardiotoxic drugs? Intrauterine death of one fetus in a twin pregnancy. Case report and review of literature

Framarino-dei-Malatesta

Perrone

Giancotti

et al. 2015

BMC Cancer

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“…In baboons, the transplacental transfer is 7.5 6 3.2%, and doxorubicin is not detectable after 24 hours (Van Calsteren et al, 2010b). In mice, transplacental transfer is 5.1 6 0.6% (Van Calsteren et al, 2011). In our pregnant rat model, we used established chromatographic techniques to quantify doxorubicin levels in maternal and fetal plasma 24 and 48 hours after administration and estimated transplacental passage of 6.2 6 3.2%.…”

Section: Discussionmentioning

confidence: 99%

Fetal Rat Hearts Do Not Display Acute Cardiotoxicity in Response to Maternal Doxorubicin Treatment

Gzirí

Pokreisz

Vos

et al. 2013

J Pharmacol Exp Ther

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Anthracyclines are used to treat cancers during the second and third trimester of pregnancy. The chemotherapeutic effect of anthracyclines is associated with a dose-and time-dependent cardiotoxicity that is well described for infants and adults. However, data regarding fetal anthracycline-related cardiotoxicity after administration of chemotherapeutics during pregnancy are limited. In this study, we analyzed the acute effect of doxorubicin, an anthracycline derivative, on fetal and maternal rat myocardium. We injected 10 or 20 mg/kg i.v. doxorubicin to pregnant Wistar rats at day 18 of pregnancy; age-matched pregnant rats injected with physiologic saline served as controls. Maternal echocardiography and fetal Doppler scanning were performed before the injection and before sacrifice. Cesarean operation was performed at day 19 or 20, and maternal and fetal blood samples and heart biopsies were collected to measure apoptosis, the impact on cell proliferation, and structural cardiac damage. Acute maternal cardiotoxicity is associated with loss of body weight, moderately deteriorated left ventricular function, induction of apoptosis, and a decrease in cell turnover. Despite a 30% lower fetal body weight and elevated plasma B-type natriuretic peptide concentrations after doxorubicin administration, the fetal hearts had intact microstructure, an unaltered number of apoptotic cells, and preserved cell proliferation compared with controls. Our study suggests that acute treatment using anthracyclines during pregnancy impairs maternal cardiac function, whereas fetal hearts are protected.

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“…Indeed, it has been reported that intravenous administration of paclitaxel to pregnant dams revealed a 16-fold higher trans-placental transfer rate in mdr1a/1b (-/-) knockout mice than in wild-type mice (Smit et al ., 1999). In a recent report, paclitaxel could not be detected in fetal plasma at ninety minutes after IV injection in pregnant mice (Van Calsteren et al ., 2011). Therefore, we hypothesize that the placental P-gp reduces the trans-placental transfer of paclitaxel, making their clinical use possible during the 2nd and 3rd trimesters of pregnancy.…”

Section: Discussionmentioning

confidence: 94%

Identification of P-Glycoprotein and Transport Mechanism of Paclitaxel in Syncytiotrophoblast Cells

Lee

Kang

2014

Biomolecules & Therapeutics

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When chemotherapy is administered during pregnancy, it is important to consider the fetus chemotherapy exposure, because it may lead to fetal consequences. Paclitaxel has become widely used in the metastatic and adjuvant settings for woman with cancer including breast and ovarian cancer. Therefore, we attempted to clarify the transport mechanisms of paclitaxel through blood-placenta barrier using rat conditionally immortalized syncytiotrophoblast cell lines (TR-TBTs). The uptake of paclitaxel was time- and temperature-dependent. Paclitaxel was eliminated about 50% from the cells within 30 min. The uptake of paclitaxel was saturable with Km of 168 μM and 371 μM in TR-TBT 18d-1 and TR-TBT 18d-2, respectively. [3H]Paclitaxel uptake was markedly inhibited by cyclosporine and verapamil, well-known substrates of P-glycoprotein (P-gp) transporter. However, several MRP substrates and organic anions had no effect on [3H]paclitaxel uptake in TR-TBT cells. These results suggest that P-gp may be involved in paclitaxel transport at the placenta. TR-TBT cells expressed mRNA of P-gp. These findings are important for therapy of breast and ovarian cancer of pregnant women, and should be useful data in elucidating teratogenicity of paclitaxel during pregnancy.

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Substantial Variation in Transplacental Transfer of Chemotherapeutic Agents in a Mouse Model

Abstract: Substantial variations in transplacental transfer were noted among the tested drugs. Current findings contribute to the understanding of reported pregnancy outcomes in humans.

Cited by 47 publications

References 42 publications

Epirubicin: a new entry in the list of fetal cardiotoxic drugs? Intrauterine death of one fetus in a twin pregnancy. Case report and review of literature

Epirubicin: a new entry in the list of fetal cardiotoxic drugs? Intrauterine death of one fetus in a twin pregnancy. Case report and review of literature

Fetal Rat Hearts Do Not Display Acute Cardiotoxicity in Response to Maternal Doxorubicin Treatment

Identification of P-Glycoprotein and Transport Mechanism of Paclitaxel in Syncytiotrophoblast Cells

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