Abstract
Chemotherapy, as an important clinical treatment, has greatly enhanced survival in cancer patients, but the side effects and long-term sequelae bother both patients and clinicians. 5-Fluorouracil (5-FU) has been widely used as a chemotherapeutic agent in the clinical treatment of various cancers, but several studies showed its adverse effects on reproduction. Reproductive toxicity of 5-FU often associates with developmental block, malformation and ovarian damage in the females. In males, 5-FU administration alters the morphology of sexual organs, the levels of reproductive endocrine hormones and the progression of spermatogenesis, ultimately reducing sperm numbers. Mechanistically, 5-FU exerts its effect through incorporating the active metabolites into nucleic acids directly, or inhibiting thymidylate synthase to disrupt the function of DNA and RNA, leading to profound effects on cellular metabolism and viability. However, some studies suggested that the toxicity of 5-FU on reproduction is reversible and certain drugs used in combination with 5-FU during chemotherapy could protect reproductive systems from 5-FU damage both in females and males. Herein, we summarise the recent findings and discuss underlying mechanisms of the 5-FU-induced reproductive toxicity, providing a reference for future research and clinical treatments.
Highlights
Chemotherapy is a form of drug therapy meant to kill fast-growing tumour cells by powerful chemicals in the body. 5-Fluorouracil (5-FU) is one of the most commonly used chemotherapy drugs during clinical treatment of cancers in gastrointestinal tract, pancreas, ovary, oesophageal, colorectal and breast since 1957 (Refs 1–7)
Varied among different strains, the incorporation amount of 5-FU is positively correlated with the weight of the embryos (Ref. 42). These findings collectively indicates that negative effects of 5-FU on embryonic development is closely related to its dosage, which in turn suggests that it is crucial to apply an optimal dosage that has expected anticancer activity but does not induce significant developmental defects (Refs 43, 44)
In addition to self-recovery, combined administration of triptorelin, a GnRH agonist often used as a hormone responsive anti-cancer drug, alleviates 5-FU-induced follicle number reduction, probably via decreasing the levels of E2, follicle-stimulating hormone (FSH), Bax and nuclear factor (NF)-κB, and increasing the levels of anti-Müllerian hormone (AMH) and Bcl-2 in the serum (Ref. 26)
Summary
Chemotherapy is a form of drug therapy meant to kill fast-growing tumour cells by powerful chemicals in the body. 5-Fluorouracil (5-FU) is one of the most commonly used chemotherapy drugs during clinical treatment of cancers in gastrointestinal tract, pancreas, ovary, oesophageal, colorectal and breast since 1957 (Refs [1,2,3,4,5,6,7]). Adverse effects of 5-FU on female reproduction In Caenorhabditis elegans, 5-FU induces germ cell death and inhibits embryonic and larval development (Ref. 33), which presumably because of cell-cycle arrest and apoptosis of germline cells (Ref. 25).
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