An ex vivo organ culture screening model revealed that low temperature conditions prevent side effects of anticancer drugs

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  • Tian, Tian
    Section of Orthodontics and Dentofacial Orthopedics, Division of Oral Health, Growth and Development, Faculty of Dental Science, Kyushu University
  • Miyazaki, Kanako
    Section of Orthodontics and Dentofacial Orthopedics, Division of Oral Health, Growth and Development, Faculty of Dental Science, Kyushu University
  • Chiba, Yuta
    Section of Pediatric Dentistry, Division of Oral Health, Growth and Development, Faculty of Dental Science, Kyushu University
  • Funada, Keita
    Section of Orthodontics and Dentofacial Orthopedics, Division of Oral Health, Growth and Development, Faculty of Dental Science, Kyushu University
  • Yuta, Tomomi
    Section of Orthodontics and Dentofacial Orthopedics, Division of Oral Health, Growth and Development, Faculty of Dental Science, Kyushu University
  • Mizuta, Kanji
    Section of Orthodontics and Dentofacial Orthopedics, Division of Oral Health, Growth and Development, Faculty of Dental Science, Kyushu University
  • Fu, Yao
    Section of Orthodontics and Dentofacial Orthopedics, Division of Oral Health, Growth and Development, Faculty of Dental Science, Kyushu University
  • Kawahara, Jumpei
    Section of Orthodontics and Dentofacial Orthopedics, Division of Oral Health, Growth and Development, Faculty of Dental Science, Kyushu University
  • Han, Xue
    Department of Pediatric Dentistry, School and Hospital of Stomatology, Tongji University Shanghai Engineering Research Centre of Tooth Restoration and Regeneration
  • Ando, Yuna
    Department of Medicine, School of Medicine, Kyushu University
  • Funada, Ami
    Section of Oral and Maxillofacial Oncology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University
  • Yamada, Aya
    Division of Pediatric Dentistry, Department of Community Social Dentistry, Tohoku University Graduate School of Dentistry
  • Iwamoto, Tsutomu
    Department of Pediatric Dentistry/Special Needs Dentistry, Division of Oral Health Sciences, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University
  • Nakamura, Seiji
    Section of Oral and Maxillofacial Oncology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University
  • Takahashi, Ichiro
    Section of Orthodontics and Dentofacial Orthopedics, Division of Oral Health, Growth and Development, Faculty of Dental Science, Kyushu University
  • Fukumoto, Satoshi
    Section of Pediatric Dentistry, Division of Oral Health, Growth and Development, Faculty of Dental Science, Kyushu University Division of Pediatric Dentistry, Department of Community Social Dentistry, Tohoku University Graduate School of Dentistry
  • Yoshizaki, Keigo
    Section of Orthodontics and Dentofacial Orthopedics, Division of Oral Health, Growth and Development, Faculty of Dental Science, Kyushu University

Abstract

Development of chemotherapy has led to a high survival rate of cancer patients; however, the severe side effects of anticancer drugs, including organ hypoplasia, persist. To assume the side effect of anticancer drugs, we established a new ex vivo screening model and described a method for suppressing side effects. Cyclophosphamide (CPA) is a commonly used anticancer drug and causes severe side effects in developing organs with intensive proliferation, including the teeth and hair. Using the organ culture model, we found that treatment with CPA disturbed the growth of tooth germs by inducing DNA damage, apoptosis and suppressing cellular proliferation and differentiation. Furthermore, low temperature suppressed CPA-mediated inhibition of organ development. Our ex vivo and in vitro analysis revealed that low temperature impeded Rb phosphorylation and caused cell cycle arrest at the G1 phase during CPA treatment. This can prevent the CPA-mediated cell damage of DNA replication caused by the cross-linking reaction of CPA. Our findings suggest that the side effects of anticancer drugs on organ development can be avoided by maintaining the internal environment under low temperature.

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