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

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Abstract

Objective

Data on the transplacental transfer of chemotherapeutic agents are lacking. We aimed to measure the maternofetal transfer of cytotoxic drugs in a mouse model.

Study design

The transplacental transfer of doxorubicin (9 mg/kg), epirubicin (11 mg/kg), vinblastine (6 mg/kg), carboplatin (50 mg/kg), paclitaxel (10 mg/kg), and cytarabine (100 mg/kg) was tested in a C57/Bl6J mouse model. Ninety minutes after intravenous (IV) drug injection on gestational day 18.5, maternal and fetal blood were collected simultaneously. Plasma drug levels were determined using high performance liquid chromatography or atomic absorption spectrometry.

Results

Fetal plasma concentrations of doxorubicin, epirubicin, vinblastine, and cytarabine were 5.1% ± 0.6% (n = 8), 4.8% ± 3.8% (n = 8), 13.8% ± 5.8% (n = 6), and 56.7% ± 22.6% (n = 6) of the maternal concentrations, respectively. Total platinum passed the mouse placenta easily (117.0% ± 38.9%, n = 6). Paclitaxel could not be detected in fetal plasma samples (n = 6).

Conclusions

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

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References

  1. Stensheim H, Moller B, van Dijk T, Fossa SD. Cause-specific survival for women diagnosed with cancer during pregnancy or lactation: a registry-based cohort study. J Clin Oncol. 2009;27(1):45–51.

    Article  PubMed  Google Scholar 

  2. Cardonick E, Dougherty R, Grana G, Gilmandyar D, Ghaffar S, Usmani A. Breast cancer during pregnancy: maternal and fetal outcomes. Cancer J. 2010;16(1):76–82.

    Article  PubMed  Google Scholar 

  3. Cardonick E, Iacobucci A. Use of chemotherapy during human pregnancy. Lancet Oncol. 2004;5(5):283–291.

    Article  CAS  PubMed  Google Scholar 

  4. Wiebe VJ, Sipila PE. Pharmacology of antineoplastic agents in pregnancy. Crit Rev Oncol Hematol. 1994;16(2):75–112.

    Article  CAS  PubMed  Google Scholar 

  5. Van Calsteren K, Heyns L, De Smet F, et al. Cancer during pregnancy: an analysis of 215 patients emphasizing the obstetrical and the neonatal outcomes. J Clin Oncol. 2010;28(4):683–689.

    Article  PubMed  Google Scholar 

  6. Amant F, Van Calsteren K, Halaska MJ, et al. Gynecologic cancers in pregnancy: guidelines of an international consensus meeting. Int J Gynecol Cancer. 2009;19(suppl 1):S1–S12.

    Article  PubMed  Google Scholar 

  7. Liao C, Wei J, Li Q, Li L, Li J, Li D. Efficacy and safety of cordocentesis for prenatal diagnosis. Int J Gynaecol Obstet. 2006;93(1):13–17.

    Article  PubMed  Google Scholar 

  8. Von Tungeln LS, Williams LD, Doerge DR, et al. Transplacental drug transfer and frequency of Tk and Hprt lymphocyte mutants and peripheral blood micronuclei in mice treated transplacentally with zidovudine and lamivudine. Environ Mol Mutagen. 2007;48(3–4):258–269.

    Article  CAS  Google Scholar 

  9. Theiler K. The House Mouse: Atlas of Embryonic Development. New York: Springer-Verlag; 1989.

    Book  Google Scholar 

  10. Sparreboom A, van Tellingen O, Nooijen WJ, Beijnen JH. Tissue distribution, metabolism and excretion of paclitaxel in mice. Anticancer Drugs. 1996;7(1):78–86.

    Article  CAS  PubMed  Google Scholar 

  11. van Asperen J, Schinkel AH, Beijnen JH, Nooijen WJ, Borst P, van Tellingen O. Altered pharmacokinetics of vinblastine in Mdr1a P-glycoprotein-deficient Mice. J Natl Cancer Inst. 1996;88(14):994–999.

    Article  PubMed  Google Scholar 

  12. Dawrant MJ, Giles S, Bannigan J, Puri P. Adriamycin produces a reproducible teratogenic model of vertebral, anal, cardiovascular, tracheal, esophageal, renal, and limb anomalies in the mouse. J Pediatr Surg. 2007;42(10):1652–1658.

    Article  PubMed  Google Scholar 

  13. Scheving LE, Scheving LA, Feuers RJ, Tsai TH, Cope FO. Chronobiology as it relates to toxicology, pharmacology, and chemotherapy. Regul Toxicol Pharmacol. 1993;17(2 pt 1):209–218.

    Article  CAS  PubMed  Google Scholar 

  14. Boughattas NA, Levi F, Fournier C, et al. Stable circadian mechanisms of toxicity of two platinum analogs (cisplatin and carboplatin) despite repeated dosages in mice. J Pharmacol Exp Ther. 1990;255(2):672–679.

    CAS  PubMed  Google Scholar 

  15. Collins JM. Inter-species differences in drug properties. Chem Biol Interact. 2001;134(3):237–242.

    Article  CAS  PubMed  Google Scholar 

  16. Goldsmith MA, Slavik M, Carter SK. Quantitative prediction of drug toxicity in humans from toxicology in small and large animals. Cancer Res. 1975;35(5):1354–1364.

    CAS  PubMed  Google Scholar 

  17. De Vita VJ, Hellman S, Rosenberg S. Cancer Principles and Practice of Oncology. 6th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2001.

    Google Scholar 

  18. Gaillard B, Leng JJ, Grellet J, Ducint D, Saux MC. [Transplacental passage of epirubicin]. J Gynecol Obstet Biol Reprod (Paris). 1995;24(1):63–68.

    CAS  Google Scholar 

  19. Grohard P, Akbaraly JP, Saux MC, et al. [Transplacental passage of doxorubicin]. J Gynecol Obstet Biol Reprod (Paris). 1989;18(5):595–600.

    CAS  Google Scholar 

  20. Roboz J, Gleicher N, Wu K, Chanihian P, Kerenyi T, Holland J. Does doxorubicin cross the placenta? Lancet. 1979;2(8156–8157):1382–1383.

    Article  CAS  PubMed  Google Scholar 

  21. D’Incalci M, Broggini M, Buscaglia M, Pardi G. Transplacental passage of doxorubicin. Lancet. 1983;1(8314–8315):75.

    Article  PubMed  Google Scholar 

  22. Karp GI, von Oeyen P, Valone F, et al. Doxorubicin in pregnancy: possible transplacental passage. Cancer Treat Rep. 1983;67(9):773–777.

    CAS  PubMed  Google Scholar 

  23. Murray CL, Reichert JA, Anderson J, Twiggs LB. Multimodal cancer therapy for breast cancer in the first trimester of pregnancy. A case report. JAMA. 1984;252(18):2607–2608.

    Article  CAS  PubMed  Google Scholar 

  24. Barni S, Ardizzoia A, Zanetta G, Strocchi E, Lissoni P, Tancini G. Weekly doxorubicin chemotherapy for breast cancer in pregnancy. A case report. Tumori. 1992;78(5):349–350.

    Article  CAS  PubMed  Google Scholar 

  25. Al-Saleh E, Nandakumaran M, Al-Rashdan I, Al-Harmi J, Al-Shammari M. Maternal-fetal transport kinetics of carboplatin in the perfused human placental lobule: in vitro study. J Matern Fetal Neonatal Med. 2007;20(9):695–701.

    Article  CAS  PubMed  Google Scholar 

  26. Al-Saleh E, Al-Harmi J, Nandakumaran M, Al-Shammari M. Transport kinetics of cisplatin in the perfused human placental lobule in vitro. J Matern Fetal Neonatal Med. 2008;21(10):726–731.

    Article  CAS  PubMed  Google Scholar 

  27. Henderson CE, Elia G, Garfinkel D, Poirier MC, Shamkhani H, Runowicz CD. Platinum chemotherapy during pregnancy for serous cystadenocarcinoma of the ovary. Gynecol Oncol. 1993;49(1):92–94.

    Article  CAS  PubMed  Google Scholar 

  28. Koc ON, McFee M, Reed E, Gerson SL. Detection of platinum-DNA adducts in cord blood lymphocytes following in utero platinum exposure. Eur J Cancer. 1994;30A(5):716–717.

    CAS  PubMed  Google Scholar 

  29. Elit L, Bocking A, Kenyon C, Natale R. An endodermal sinus tumor diagnosed in pregnancy: case report and review of the literature. Gynecol Oncol. 1999;72(1):123–127.

    Article  CAS  PubMed  Google Scholar 

  30. Arango HA, Kalter CS, Decesare SL, Fiorica JV, Lyman GH, Spellacy WN. Management of chemotherapy in a pregnancy complicated by a large neuroblastoma. Obstet Gynecol. 1994;84(4 pt 2):665–668.

    CAS  PubMed  Google Scholar 

  31. Germann N, Goffinet F, Goldwasser F. Anthracyclines during pregnancy: embryo-fetal outcome in 160 patients. Ann Oncol. 2004;15(1):146–150.

    Article  CAS  PubMed  Google Scholar 

  32. Syme MR, Paxton JW, Keelan JA. Drug transfer and metabolism by the human placenta. Clin Pharmacokinet. 2004;43(8):487–514.

    Article  CAS  PubMed  Google Scholar 

  33. Gligorov J, Lotz JP. Preclinical pharmacology of the taxanes: implications of the differences. Oncologist. 2004;9(suppl 2):3–8.

    Article  CAS  PubMed  Google Scholar 

  34. Gianni L, Vigano L, Locatelli A, et al. Human pharmacokinetic characterization and in vitro study of the interaction between doxorubicin and paclitaxel in patients with breast cancer. J Clin Oncol. 1997;15(5):1906–1915.

    Article  CAS  PubMed  Google Scholar 

  35. Smit JW, Huisman MT, van Tellingen O, Wiltshire HR, Schinkel AH. Absence or pharmacological blocking of placental P-glycoprotein profoundly increases fetal drug exposure. J Clin Invest. 1999;104(10):1441–1447.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Mir O, Berveiller P, Goffinet F, et al. Taxanes for breast cancer during pregnancy: a systematic review. Ann Oncol. 2010;21(2):425–426.

    Article  CAS  PubMed  Google Scholar 

  37. Chun KC, Kim DY, Kim JH, Kim YM, Kim YT, Nam JH. Neoadjuvant chemotherapy with paclitaxel plus platinum followed by radical surgery in early cervical cancer during pregnancy: three case reports. Jpn J Clin Oncol. 2010;40(7):694–698.

    Article  PubMed  Google Scholar 

  38. Pereg D, Koren G, Lishner M. Cancer in pregnancy: gaps, challenges and solutions. Cancer Treat Rev. 2008;34(4):302–312.

    Article  PubMed  Google Scholar 

  39. Peccatori FA, Azim HA Jr. Scarfone G, et al. Weekly epirubicin in the treatment of gestational breast cancer (GBC). Breast Cancer Res Treat. 2009;115(3):591–594.

    Article  CAS  PubMed  Google Scholar 

  40. Kopf-Maier P. Stage of pregnancy-dependent transplacental passage of 195mPt after cis-platinum treatment. Eur J Cancer Clin Oncol. 1983;19(4):533–536.

    Article  CAS  PubMed  Google Scholar 

  41. Mir O, Berveiller P, Ropert S, Goffinet F, Goldwasser F. Use of platinum derivatives during pregnancy. Cancer. 2008;113(11):3069–3074.

    Article  CAS  PubMed  Google Scholar 

  42. Mihaly GW, Morgan DJ. Placental drug transfer: effects of gestational age and species. Pharmacol Ther. 1983;23(2):253–266.

    Article  CAS  PubMed  Google Scholar 

  43. Sastry BV. Techniques to study human placental transport. Adv Drug Deliv Rev. 1999;38(1):17–39.

    Article  CAS  PubMed  Google Scholar 

  44. Ala-Kokko TI, Myllynen P, Vähäkangas K. Ex vivo perfusion of the human placental cotyledon: implications for anesthetic pharmacology. Int J Obstet Anesth. 2000;9:26–38.

    Article  Google Scholar 

  45. Myllynen P, Vahakangas K. An examination of whether human placental perfusion allows accurate prediction of placental drug transport: studies with diazepam. J Pharmacol Toxicol Methods. 2002;48(3):131–138.

    Article  CAS  PubMed  Google Scholar 

  46. Van Calsteren K, Devlieger R, De Catte L, et al. Feasibility of ultrasound-guided percutaneous samplings in the pregnant baboon: a model for studies on transplacental transport. Reprod Sci. 2009;16(3):280–285.

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Obstetrics and Gynecology, Division Gynecologic Oncology and Experimental Laboratory of Gynecology, University Hospital Gasthuisberg, Katholieke Universiteit Leuven, Leuven, Belgium

    Kristel Van Calsteren MD, PhD & Liesbeth Heyns MSc

  2. Center for Clinical Pharmacology, University Hospital Gasthuisberg, Katholieke Universiteit Leuven, Leuven, Belgium

    Rene Verbesselt PhD & Jan de Hoon MD, PhD

  3. Department of Obstetrics and Gynecology, Experimental Laboratory of Gynecology, University Hospital Gasthuisberg, Katholieke Universiteit Leuven, Leuven, Belgium

    Rieta Van Bree LT

  4. Laboratory of Medical Oncology, University Hospital Gasthuisberg, Katholieke Universiteit Leuven, Leuven, Belgium

    Ernst de Bruijn PhD

  5. Leuven Cancer Institute (LKI), Division of Gynecological Oncology, Department of Obstetrics and Gynecology, University Hospital Gasthuisberg, Katholieke Universiteit Leuven, Herestraat 49, 3000, Leuven, Belgium

    Frédéric Amant MD, PhD

Authors
  1. Kristel Van Calsteren MD, PhD
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  2. Rene Verbesselt PhD
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  3. Rieta Van Bree LT
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  4. Liesbeth Heyns MSc
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  6. Jan de Hoon MD, PhD
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  7. Frédéric Amant MD, PhD
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Correspondence to Frédéric Amant MD, PhD.

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Van Calsteren, K., Verbesselt, R., Van Bree, R. et al. Substantial Variation in Transplacental Transfer of Chemotherapeutic Agents in a Mouse Model. Reprod. Sci. 18, 57–63 (2011). https://doi.org/10.1177/1933719110379650

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