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Reproductive and developmental toxicities of 5-fluorouracil in model organisms and humans

Published online by Cambridge University Press:  31 January 2022

Gerile Naren
Affiliation:
State Key Laboratory of Reproductive Regulation and Breeding of Grassland Livestock, School of Life Sciences, Inner Mongolia University, Hohhot, China
Jiaojiao Guo
Affiliation:
State Key Laboratory of Reproductive Regulation and Breeding of Grassland Livestock, School of Life Sciences, Inner Mongolia University, Hohhot, China
Qiujuan Bai
Affiliation:
State Key Laboratory of Reproductive Regulation and Breeding of Grassland Livestock, School of Life Sciences, Inner Mongolia University, Hohhot, China
Na Fan
Affiliation:
State Key Laboratory of Reproductive Regulation and Breeding of Grassland Livestock, School of Life Sciences, Inner Mongolia University, Hohhot, China
Buhe Nashun*
Affiliation:
State Key Laboratory of Reproductive Regulation and Breeding of Grassland Livestock, School of Life Sciences, Inner Mongolia University, Hohhot, China
*
Author for correspondence: Buhe Nashun, E-mail: bnashun@imu.edu.cn
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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.

Type
Review
Creative Commons
Creative Common License - CCCreative Common License - BY
This is an Open Access article, distributed under the terms of the Creative Commons Attribution licence (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted re-use, distribution and reproduction, provided the original article is properly cited.
Copyright
Copyright © The Author(s), 2022. Published by Cambridge University Press

Introduction

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 Reference Ng1Reference Vodenkova7). However, it has various side effects, such as long-term memory impairments, myelosuppression and cardiotoxicity (Refs Reference Muhammad8Reference Ishibashi13). With the continuous development of modern oncology and pharmacology, a series of 5-FU derivatives and analogues, including 1-hexylcarbamoyl-5-fluorouracil, tegafur, uracil tegafur, capecitabine, TAS-102 (trifluridine-tipiracil) and S-1 (tegafur, gimeracil and oteracil potassium) have been developed, which could increase and maintain higher 5-FU concentration in the serum (Refs Reference Wang14Reference Wormann18).

It is currently believed that 5-FU and its derivatives exert their anti-tumour effect mainly through inhibiting thymidylate synthase (TS) and incorporating its metabolites into DNA and RNA (Ref. Reference Baba19). After administration, most of the 5-FU is metabolised into inactive dihydrofluorouracil by the rate-limiting enzyme dihydropyrimidine dehydrogenase (DPD) in the liver (Ref. Reference Lee20). The rest of the administered 5-FU is transformed mainly into active metabolites of fluorodeoxyuridine monophosphate (FdUMP), fluorodeoxyuridine triphosphate (FdUTP) and fluorouridine triphosphate (FUTP). FdUMP binds with TS and the methyl donor, folate 5,10-methylenetetrahydrofolate to inhibit the normal function of TS. This ternary complex blocks deoxyuridine monophosphate binding to TS and inhibits synthesis of deoxythymidine monophosphate (dTMP). Since dTMP is a key substrate for the production of deoxythymidine triphosphate (dTTP), depletion of dTMP results in the subsequent depletion of dTTP, and induces perturbations in the levels of other deoxynucleotides (dATP, dGTP and dCTP), disrupting DNA synthesis and repair. Meanwhile, inhibition of TS also results in an increased level of dUTP, which along with the FdUTP can be misincorporated into DNA, leading to breaking of DNA strands (Ref. Reference Longley21). Additionally, the 5-FU metabolite FUTP is also incorporated extensively into RNA, disrupting normal RNA processing and function (Ref. Reference Machon22). Therefore, 5-FU severely disrupts synthesis, repair and function of nucleic acids through its active metabolites, inhibiting growth of cells and killing tumour cells ultimately. However, 5-FU also impairs cellular metabolism and viability in normal cells, which underlies the developmental and reproductive toxicities (Refs Reference Shuey23Reference Kumar25).

To date, several attempts have been made to alleviate the reproductive side effects of 5-FU. Apart from the combined administration of 5-FU with other drugs such as triptorelin, 6-alkylguanine-DNA alkyltransferase (AGT) and iridoids-rich containing fraction of Pentas lanceolata leaves (IFPL) (Refs Reference Wang26Reference Fahmy28), manipulation of gene expression including down-regulation of the uracil-DNA glycosylase (UNG) or overexpression of DPD and TS homologues also alleviates the reproductive toxicity (Refs Reference Kumar25, Reference Kim29). Moreover, targeted delivery and controlled release of 5-FU by biocompatible and biodegradable particles represents a promising direction to overcome the side effects of 5-FU (Ref. Reference Xu30). 5-FU has a narrow therapeutic window, and for this reason, selection of the appropriate dosage is crucial to reduce its side effects. In this context, the test of single-nucleotide polymorphisms (SNPs) shows great potential in optimising 5-FU dosage. In patients with DPYD variants (DPD coding genes) of c.190511G > A (rs3918290), c.1679T > G (rs55886062), c.2846A > T (rs67376798) and c.1129-5923C > G (rs75017182), lower dosage of 5-FU inhibits cancer cell growth and achieve equal anti-tumour efficacy (Ref. Reference Amstutz31). Similarly, SNPs in 5-FU metabolic genes such as CDA, CES2, TYMS (TS) and MTHFR can also be used to predict the efficacy and toxicity of capecitabine-based therapy (Ref. Reference Lam32). Therefore, genetic SNPs provide pharmacogenomics information for clinical application of 5-FU to adjust dosage, improve efficacy and reduce side effects, ultimately. However, it should be noted that though increasing efforts to alleviate reproductive toxicity of 5-FU, currently, there is no effective way to avoid the damage completely.

Adverse effects of 5-FU on female reproduction

In Caenorhabditis elegans, 5-FU induces germ cell death and inhibits embryonic and larval development (Ref. Reference Kim and Shim33), which presumably because of cell-cycle arrest and apoptosis of germline cells (Ref. Reference Kumar25). Particularly, 5-FU down-regulates expression of several collagen genes, which are important players in extracellular matrix (ECM)–receptor interaction and focal adhesion. Therefore, impairment of the ECM–receptor interaction and focal adhesion during germ cell development may underlie the 5-FU-induced fertility decline in C. elegans (Ref. Reference Si Zhang34). 5-FU also down-regulates LIN-29, which is an important transcription factor that affects vulva development and egg laying system (Ref. Reference Kumar25). Interestingly, down-regulation of UNG could alleviate the 5-FU effects on embryo hatching (Ref. Reference Kumar25), suggesting that UNG-mediated removal of the misincorporated 5-FU is involved in this process. Indeed, it was proposed that UNG-1 excise uracil, but the subsequent repair synthesis results in uracil reincorporation, leading to futile cycling of the base excision repair pathway (Ref. Reference Seiple35). Overexpression of the homologues of DPD (DPYD-1) and TS (Y110A7A.4) in C. elegans prevented the death of germ cells following 5-FU exposure. In contrast, depletion of DPYD-1 increased sensitivity of 5-FU and depletion of the 110A7A.4 resulted in severe embryonic lethality (Ref. Reference Kim29) (Table 1). Therefore, down-regulation or overexpression of certain 5-FU metabolic enzymes could be an alternative way to reduce the reproductive toxicity.

Table 1. Adverse effects of 5-FU on female reproduction

The mammalian fertility cycle is responsible for the coordination of various cellular events, including DNA synthesis in ovarian follicle cells, and of potential importance to the toxicity of 5-FU (Refs Reference Hrushesky36, Reference Meistrich37). Female mice received 5-FU during the oestrous phase were suffered from greater fertility loss compared with those exposed to 5-FU during the metestrus, diestrus and proestrus stages, probably because ovarian follicular DNA synthesis is most active within the oestrous phase and 5-FU leads to pronounced DNA damage accumulation (Refs Reference Hrushesky36, Reference Hirshfield38). Therefore, it is likely that choosing an appropriate oestrus cycle for 5-FU treatment is helpful to reduce reproductive damage.

Teratogenesis is another severe reproductive abnormality induced by 5-FU. The number of externally malformed foetuses increases in a dose-dependent fashion after single administration of 10–30 mg/kg 5-FU during pregnancy in rats (Ref. Reference Kuwagata39). Studies using in vitro whole embryo culture systems also demonstrated that 5-FU dose-dependently induces tail and hindlimb bud defects, and leads to hypoplastic optic vesicles in rat embryos (Refs Reference Kuwagata39, Reference Grafton40). Similarly, 5-FU exposure reduces embryo implantation rate and increases embryo deformity and mortality in a dose- and time-dependent manner in mice (Ref. Reference Dagg41). Of note, when injected into pregnant mice, 5-FU is incorporated into the embryos and accumulates mostly in RNAs. Although varied among different strains, the incorporation amount of 5-FU is positively correlated with the weight of the embryos (Ref. Reference Dagg CP and Offutt42). 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 Reference Arshad43, Reference Beumer44). In this context, the mouse embryonic stem cell test seemed extremely useful to assess the developmental toxicities and determine the optimal dosage of 5-FU (Ref. Reference van Oostrom45).

Cytotoxicity of 5-FU potentially contributes to the ovarian dysfunction and puts the patients at risk of menopause-related complications and infertility (Ref. Reference Marhhom and Cohen46). When young C57BL/6J female mice were injected with 5-FU, secondary follicles were lost totally (Ref. Reference Almeida47). Furthermore, genes involved in apoptosis and Wnt signalling pathways were significantly up-regulated when ovaries from young mice were cultured in vitro with 5-FU (Ref. Reference Almeida47). In adult mice, administration of 5-FU-induced atresia of secondary and antral follicles, and profoundly reduced corpus luteum counts, leading to a decreased ovarian volume (Refs Reference Lambouras48, Reference Stringer49). However, primordial or primary follicles were not affected by the 5-FU treatment (Refs Reference Lambouras48, Reference Stringer49), suggesting that the reproductive toxicity of 5-FU could be recovered with continuous growth of the follicles. In support of this view, we recently reported that multiple intraperitoneal administration of 5-FU in adult female mice resulted in small ovarian size and reduced number of corpus luteum, and led to ovulation failure. However, these defects could be recovered and no obvious abnormality was observed in their offspring, suggesting that the adverse effects could be reversed following withdrawal of 5-FU administration (Ref. Reference Naren50). 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. Reference Wang26). Additionally, when 5-FU was loaded in poly-glucono-δ-lactone particle and delivered precisely to the target sites and released in a controlled manner, the toxic effect on non-cancer cells was effectively avoided (Ref. Reference Xu30).

In human clinical cases, inadvertent exposure to 5-FU (Ref. Reference Kopelman and Miyazawa51) or treatment with FOLFOX, a mixture of 5-FU, leucovorin and oxaliplatin, during the second and third trimesters of pregnancy had no harm to foetal health (Ref. Reference Jeppesen and Osterlind52). However, the developmental and reproductive toxicities of 5-FU cannot be evaluated comprehensively in humans and are assessed instead in human-induced pluripotent stem cells (hiPSCs), which has been suggested to achieve similar findings (Ref. Reference Aikawa53). In hiPSCs, 5-FU inhibited neural differentiation via down-regulating expression of the mitochondrial fusion proteins Mfn1/2 and decreasing intracellular ATP levels (Ref. Reference Yamada54), suggesting that 5-FU-induced mitochondrial dysfunction may underlie the developmental and reproductive toxicities.

Adverse effects of 5-FU on the reproduction and development were also reported in amphibian, arthropods and aquatic species. Exposure to 5-FU at environmentally relevant concentrations during the early developmental stage did not adversely affect the survival or behaviour in larval zebra fish, but larvae growth represented by body length was significantly increased when exposed to higher concentration of 5-FU (Ref. Reference Ng55). In Xenopus laevis embryos, malformations in abdominal oedema, axial flexure, head, eyes, gut and heart were observed after 5-FU treatment (Ref. Reference Anderson56). Moreover, 5-FU treatment resulted in reduction in the number of offspring and DNA damage in Ceriodaphnia dubia (Ref. Reference Russo57).

In general, 5-FU inhibits embryonic or larval development in C. elegans, arthropods, amphibian, mouse and rat, and dose-dependently induces embryonic malformation in mice and rat. Of note, 5-FU impairs ovarian function and leads to ovulation failure, but the negative effects could be reduced by combinatorial drug administration or eliminated naturally after 5-FU withdrawal in mice. However, the underlying mechanisms remain largely unknown and the potential long-term effect could not be ruled out.

Side effects of 5-FU on male reproduction

Usually, chemotherapy is toxic for testicular tissue and increases the risk of infertility in males (Ref. Reference Delessard58). Studies in mice demonstrated that 5-FU induces morphological changes of Sertoli cells and reduces weights of reproductive organs including seminal vesicle and prostate. This effect is probably mediated by hormonal imbalance in the serum, whereby the levels of GnRH and pro-alpha C were remarkably increased, whereas the levels of testosterone, activin A, prolactin and inhibin B were significantly decreased (Table 2) (Ref. Reference Horii59). 6-Mercaptopurine (6-MP) is an antimetabolite drug as the 5-FU, which induces ROS, activates caspase 3 and promotes apoptosome generation, ultimately leading to the loss of Leydig cells in mice (Ref. Reference Lynch60). Therefore, it is tempting to speculate that whether 5-FU also impairs the Leydig cells that produce testosterone through similar mechanism.

Table 2. Adverse effects of 5-FU on male reproduction

In male rats, 5-FU induces sloughing of epithelium and promotes giant cell formation (Ref. Reference Narayana61), accompanied by a significant decrease of the testis weights (Ref. Reference D'Souza and Narayana62). Moreover, tubular shrinkage, atrophy and abnormal sperm cells were also observed following 5-FU administration (Refs Reference D'Souza and Narayana62, Reference Russell and Russell63), eventually leading to a significant reduction of spermatocytes/spermatids cell count in a dose- and time-dependent manner (Ref. Reference D'Souza64). Although direct mechanistic evidence is missing for 5-FU-induced reproductive toxicity in males, 6-MP has been reported to induce DNA damage in rat spermatocytes (Ref. Reference Habas65), suggesting that 5-FU may potentially induce DNA damage in spermatocytes. Moreover, 5-FU-induced swelling and crazing of tubules (Ref. Reference Ghafouri-Fard66) is reminiscent of the alkylating agent cisplatin-induced degenerative changes in seminiferous tubules and germ cell depletion, mediated by aggravated oxidative damage (Refs Reference Ghafouri-Fard66, Reference Yadav67). Therefore, it will be interesting to test whether 5-FU-induced abnormal seminiferous tubules is also because of the free radical-associated oxidative stress.

Importantly, combinatory use of certain agents also relieves the side effects of 5-FU on male reproduction. N-2-Chloroethyl-N-nitrosourea (CNU) is an alkylating agent often used in combination with 5-FU against a range of cancers (Ref. Reference Mitchell and Schein68). The B.4152, composed of 5-FU and CNU, only induces minor damage in spermatogenic tissue in mice when administrated with AGT. AGT is a DNA repair protein that repairs mutagenic lesions in DNA and protects testis from alkylating agent-induced damage (Ref. Reference Thompson27). Another agent IFPL, which is the iridoids-rich fraction of P. lanceolata leaves, also plays protective role during 5-FU-induced sperm defects (Ref. Reference Fahmy28). Furthermore, several extracts from medicinal plants and herbs possess antioxidant, anti-inflammatory or anti-oedematous activities, and potentially protect sperm from inflammation and oxidative stress induced by chemicals such as 5-FU, and reduce the adverse effects (Refs Reference Tahvilzadeh69, Reference Diab70).

The report regarding the effects of 5-FU on human male reproduction is extremely limited, but some other chemotherapy agents have been reported to exert non-negligible adverse effects. Cisplatin treatment resulted in a remarkable reduction of the number of germ cells both in human foetal and prepubertal testis, which involves an initial loss of gonocytes followed by a significant reduction in spermatogonia (Ref. Reference Tharmalingam71). Paclitaxel, a taxane-based chemotherapy drug, reduced serum inhibin B and testicular volume, while elevated serum FSH level in male patients (Ref. Reference Chatzidarellis72). Therefore, it is reasonable to speculate that 5-FU, as a chemotherapeutic agent, also negatively affects male reproduction. Given the current status that lacking mechanistic studies of the 5-FU-induced reproductive toxicities in males, the integrated multi-organoid body-on-a-chip system containing male reproductive organoid would be a desirable model to systematically investigate the potential mechanisms of 5-FU toxicity on male reproduction (Refs Reference Skardal73, Reference Rajan74).

Conclusion and perspectives

Collectively, 5-FU causes reproductive and developmental toxicities mainly via disrupting cellular functions and inducing hormonal imbalance. The adverse effects could be alleviated by combinatory administration of certain agents or eliminated naturally following 5-FU withdrawal, probably because 5-FU has minor gonadal toxicity compared with other chemotherapy agents and induces a lower degree of gonadal damage (Ref. Reference Oktem75). However, long-term reproductive effect of 5-FU treatment is still under debates and further in-depth evaluation including systematic analysis of health condition and life span of the descendants should be performed. Given the superior advantages of nanocarriers in drug delivery and release, it will be crucial to develop novel, efficient nanocarriers to reduce the reproductive and developmental toxicities of 5-FU (Refs Reference Paroha76Reference Patra79). Moreover, metabolic and multiomics analysis combined with organoid studies will be a promising strategy to elucidate mechanistic details of the 5-FU-induced reproductive toxicities.

Acknowledgements

We are grateful to all members of Buhe Nashun lab for stimulating discussions. Apologise to all colleagues whose work could not be cited because of the space constraints. This study is funded by the National Natural Science Foundation of China (31970759), the National Natural Science Foundation of China (32160145), the National Natural Science Foundation of China (31760335), the Fund for Excellent Young Scholars of Inner Mongolia (2021JQ04) and the Science and Technology Major Project of Inner Mongolia Autonomous Region of China to the State Key Laboratory of Reproductive Regulation and Breeding of Grassland Livestock (2019ZD031).

Conflict of interest

The authors declare that they have no conflict of interest.

Footnotes

*

These authors contributed equally to this work.

References

Ng, SY et al. (2019) Induction chemotherapy reduces patient-reported toxicities during neoadjuvant chemoradiation with intensity modulated radiotherapy for rectal cancer. Clinical Colorectal Cancer 18, 167174.CrossRefGoogle ScholarPubMed
Tsujii, K et al. (2018) 5-Fluororacil-induced gastrointestinal damage impairs the absorption and anticoagulant effects of dabigatran etexilate. Journal of Pharmaceutical Sciences 107, 14301433.CrossRefGoogle ScholarPubMed
Glassman, DC et al. (2018) Nanoliposomal irinotecan with fluorouracil for the treatment of advanced pancreatic cancer, a single institution experience. BMC Cancer 18, 693.CrossRefGoogle ScholarPubMed
Klopotowska, D and Matuszyk, J (2020) VDR agonists increase sensitivity of MCF-7 and BT-474 breast cancer cells to 5-FU. Anticancer Research 40, 837840.CrossRefGoogle ScholarPubMed
Chen, Q et al. (2019) miR-145 regulates the sensitivity of esophageal squamous cell carcinoma cells to 5-FU via targeting REV3L. Pathology Research and Practice 215, 152427.CrossRefGoogle ScholarPubMed
Koh, I et al. (2019) Regulation of REG4 expression and prediction of 5-fluorouracil sensitivity by CDX2 in ovarian mucinous carcinoma. Cancer Genomics & Proteomics 16, 481490.CrossRefGoogle ScholarPubMed
Vodenkova, S et al. (2020) 5-Fluorouracil and other fluoropyrimidines in colorectal cancer: past, present and future. Pharmacology & Therapeutics 206, 107447.CrossRefGoogle ScholarPubMed
Muhammad, RN et al. (2020) Activated ROCK/Akt/eNOS and ET-1/ERK pathways in 5-fluorouracil-induced cardiotoxicity: modulation by simvastatin. Scientific Reports 10, 14693.CrossRefGoogle ScholarPubMed
Chong, JH and Ghosh, AK (2019) Coronary artery vasospasm induced by 5-fluorouracil: proposed mechanisms, existing management options and future directions. Interventional Cardiology 14, 8994.Google ScholarPubMed
Anderson, JE et al. (2020) Early effects of cyclophosphamide, methotrexate, and 5-fluorouracil on neuronal morphology and hippocampal-dependent behavior in a murine model. Toxicological Sciences 173, 156170.CrossRefGoogle ScholarPubMed
Saif, MW (2019) Capecitabine-induced cerebellar toxicity and TYMS pharmacogenetics. Anti-Cancer Drugs 30, 431434.CrossRefGoogle ScholarPubMed
Sofis, MJ et al. (2017) KU32 prevents 5-fluorouracil induced cognitive impairment. Behavioural Brain Research 329, 186190.CrossRefGoogle ScholarPubMed
Ishibashi, M et al. (2021) Possible involvement of TRPM2 activation in 5-fluorouracil-induced myelosuppression in mice. European Journal of Pharmacology 891, 173671.CrossRefGoogle ScholarPubMed
Wang, J et al. (2020) Anlotinib combined with SOX regimen (S1 (tegafur, gimeracil and oteracil porassium capsules) + oxaliplatin) in treating stage IV gastric cancer: study protocol for a single-armed and single-centred clinical trial. BMJ Open 10, e034685.CrossRefGoogle ScholarPubMed
Burki, TK (2018) TAS-102 in metastatic colorectal cancer. The Lancet. Oncology 19, e18.CrossRefGoogle ScholarPubMed
Liu, P et al. (2017) HCFU inhibits cervical cancer cells growth and metastasis by inactivating Wnt/beta-catenin pathway. Journal of Cellular Biochemistry 12, 26570.Google Scholar
Cohen, PR (2020) Discoid lupus erythematosus lesions associated with systemic fluorouracil agents: a case report and review. Cureus 12, e7828.Google ScholarPubMed
Wormann, B et al. (2020) Dihydropyrimidine dehydrogenase testing prior to treatment with 5-fluorouracil, capecitabine, and tegafur: a consensus paper. Oncology Research and Treatment 43, 628636.CrossRefGoogle ScholarPubMed
Baba, H et al. (2003) Dihydropyrimidine dehydrogenase and thymidylate synthase activities in hepatocellular carcinomas and in diseased livers. Cancer Chemotherapy and Pharmacology 52, 469476.CrossRefGoogle ScholarPubMed
Lee, JJ et al. (2016) Therapeutic drug monitoring of 5-fluorouracil. Cancer Chemotherapy and Pharmacology 78, 447464.CrossRefGoogle ScholarPubMed
Longley, DB et al. (2003) 5-Fluorouracil: mechanisms of action and clinical strategies. Nature Reviews Cancer 3, 330338.CrossRefGoogle ScholarPubMed
Machon, C et al. (2021) Study of intracellular anabolism of 5-fluorouracil and incorporation in nucleic acids based on an LC-HRMS method. Journal of Pharmaceutical Analysis 11, 7787.CrossRefGoogle Scholar
Shuey, DL et al. (1995) Biological modeling of 5-fluorouracil developmental toxicity. Toxicology 102, 207213.CrossRefGoogle ScholarPubMed
Wang, X et al. (2018) Inhibition of thymidylate synthase affects neural tube development in mice. Reproductive Toxicology 76, 1725.CrossRefGoogle ScholarPubMed
Kumar, S et al. (2010) Anticancer drug 5-fluorouracil induces reproductive and developmental defects in Caenorhabditis elegans. Reproductive Toxicology 29, 415420.CrossRefGoogle ScholarPubMed
Wang, Y et al. (2015) Mechanistic study on triptorelin action in protecting from 5-FU-induced ovarian damage in rats. Oncology Research 22, 283292.CrossRefGoogle Scholar
Thompson, MJ et al. (1996) Potentiation of testicular cytotoxicity by the alkyltransferase inhibitor O6 benzylguanine and the 5-fluorouracil/N-(Z-chloroethel)-N-nithosourea molecular combination. Reproductive Toxicology 10, 122131.CrossRefGoogle Scholar
Fahmy, MA et al. (2020) Genotoxicity and sperm defects induced by 5-FU in male mice and the possible protective role of Pentas lanceolata-iridoids. Mutation Research 850–851, 503145.CrossRefGoogle ScholarPubMed
Kim, S et al. (2008) Thymidylate synthase and dihydropyrimidine dehydrogenase levels are associated with response to 5-fluorouracil in Caenorhabditis elegans. Molecules and Cells 26, 344349.Google ScholarPubMed
Xu, X et al. (2017) Poly(glucono-delta-lactone) based nanocarriers as novel biodegradable drug delivery platforms. International Journal of Pharmaceutics 526, 137144.CrossRefGoogle ScholarPubMed
Amstutz, U et al. (2018) Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for dihydropyrimidine dehydrogenase genotype and fluoropyrimidine dosing: 2017 update. Clinical Pharmacology and Therapeutics 103, 210216.CrossRefGoogle ScholarPubMed
Lam, SW et al. (2016) The role of pharmacogenetics in capecitabine efficacy and toxicity. Cancer Treatment Reviews 50, 922.CrossRefGoogle ScholarPubMed
Kim, S and Shim, J (2008) A forward genetic approach for analyzing the mechanism of resistance to the anti-cancer drug, 5-fluorouracil, using Caenorhabditis elegans. Molecules and Cells 25, 119123.Google Scholar
Si Zhang, ZL et al. (2015) The analysis of gene expression on fertility decline in Caenorhabditis elegans after the treatment with 5-fluorouracil. Iranian Journal of Public Health 44, 10611071.Google Scholar
Seiple, L et al. (2006) Linking uracil base excision repair and 5-fluorouracil toxicity in yeast. Nucleic Acids Research 34, 140151.CrossRefGoogle ScholarPubMed
Hrushesky, WJM et al. (1999) Fertility maintenance and 5-fluorouracil timing within the mammalian fertility cycle. Reproductive Toxicology 13, 413420.CrossRefGoogle ScholarPubMed
Meistrich, ML et al. (1982) Damaging effects of fourteen chemotherapeutic drugs on mouse testis cells. Cancer Research 42, 7177.Google ScholarPubMed
Hirshfield, AN (1984) Stathmokinetic analysis of granulosa cell proliferation in antral follicles of cyclic rats. Biology of Reproduction 31, 5258.CrossRefGoogle ScholarPubMed
Kuwagata, M et al. (1998) A comparison of the in vivo and in vitro response of rat embryos to 5-fluorouracil. Journal of Veterinary Medical Science 60, 9399.CrossRefGoogle ScholarPubMed
Grafton, TF et al. (1987) The in vitro embryotoxicity of 5-fluorouracil in rat embryos. Teratology 36, 371377.CrossRefGoogle ScholarPubMed
Dagg, CP (1960) Sensitive stages for the production of developmental abnormalities in mice with 5-fluorouracil. American Journal of Anatomy 106, 8996.CrossRefGoogle ScholarPubMed
Dagg CP, DA and Offutt, C (1966) Incorporation of 5-fluorouracil-2-C-14 by mouse embryos. Biologia Neonatorum. Neo-natal Studies 10, 3246.CrossRefGoogle ScholarPubMed
Arshad, U et al. (2020) Prediction of exposure-driven myelotoxicity of continuous infusion 5-fluorouracil by a semi-physiological pharmacokinetic-pharmacodynamic model in gastrointestinal cancer patients. Cancer Chemotherapy and Pharmacology 85, 711722.CrossRefGoogle ScholarPubMed
Beumer, JH et al. (2019) Therapeutic drug monitoring in oncology: international association of therapeutic drug monitoring and clinical toxicology recommendations for 5-fluorouracil therapy. Clinical Pharmacology & Therapeutics 105, 598613.CrossRefGoogle ScholarPubMed
van Oostrom, CTM et al. (2020) Defining embryonic developmental effects of chemical mixtures using the embryonic stem cell test. Food and Chemical Toxicology 140, 111284.CrossRefGoogle ScholarPubMed
Marhhom, E and Cohen, I (2007) Fertility preservation options for women with malignancies. Obstetrical & Gynecological Survey 62, 5872.CrossRefGoogle ScholarPubMed
Almeida, JZ et al. (2021) 5-Fluorouracil disrupts ovarian preantral follicles in young C57BL6J mice. Cancer Chemotherapy and Pharmacology 87, 567578.CrossRefGoogle ScholarPubMed
Lambouras, M et al. (2018) Examination of the ovotoxicity of 5-fluorouracil in mice. Journal of Assisted Reproduction and Genetics 35, 10531060.CrossRefGoogle ScholarPubMed
Stringer, JM et al. (2018) Multidose 5-fluorouracil is highly toxic to growing ovarian follicles in mice. Toxicological Sciences 166, 97107.CrossRefGoogle ScholarPubMed
Naren, G et al. (2021) The reversible reproductive toxicity of 5-fluorouracil in mice. Reproductive Toxicology 101, 18.CrossRefGoogle ScholarPubMed
Kopelman, JN and Miyazawa, K (1990) Inadvertent 5-fluorouracil treatment in early pregnancy: a report of three cases. Reproductive Toxicology 4, 233235.CrossRefGoogle ScholarPubMed
Jeppesen, JB and Osterlind, K (2011) Successful twin pregnancy outcome after in utero exposure to FOLFOX for metastatic colon cancer: a case report and review of the literature. Clinical Colorectal Cancer 10, 348352.CrossRefGoogle ScholarPubMed
Aikawa, N (2020) A novel screening test to predict the developmental toxicity of drugs using human induced pluripotent stem cells. Journal of Toxicological Sciences 45, 187199.CrossRefGoogle ScholarPubMed
Yamada, S et al. (2018) 5-Fluorouracil inhibits neural differentiation via Mfn1/2 reduction in human induced pluripotent stem cells. Journal of Toxicological Sciences 43, 727734.CrossRefGoogle ScholarPubMed
Ng, M et al. (2020) Using zebrafish to assess the effect of chronic, early developmental exposure to environmentally relevant concentrations of 5-fluorouracil and leucovorin. Environmental Toxicology and Pharmacology 76, 103356.CrossRefGoogle ScholarPubMed
Anderson, JE et al. (2020) Early effects of cyclophosphamide, methotrexate, and 5-fluorouracil on neuronal morphology and hippocampal-dependent behavior in a murine model. Toxicological Sciences 173, 156170.CrossRefGoogle ScholarPubMed
Russo, C et al. (2018) Benzalkonium chloride and anticancer drugs in binary mixtures: reproductive toxicity and genotoxicity in the freshwater crustacean Ceriodaphnia dubia. Archives of Environmental Contamination and Toxicology 74, 546556.CrossRefGoogle ScholarPubMed
Delessard, M et al. (2020) Exposure to chemotherapy during childhood or adulthood and consequences on spermatogenesis and male fertility. International Journal of Molecular Sciences 21, 14541476.CrossRefGoogle ScholarPubMed
Horii, STAI (2002) Endocrinological assessment of toxic effects on the male reproductive system in rats treated with 5-fluorouracil for 2 or 4 weeks. The Journal of Toxicological Sciences 27, 4956.Google Scholar
Lynch, JA et al. (2016) The ABC transporter MRP4 limits apoptosome activation 6-mercaptopurine, an important molecular instigator in induced Leydig cell death. Drug Metabolism Reviews 48, 153153.Google Scholar
Narayana, K et al. (2000) 5-Fluorouracil (5-FU) induces the formation of giant cells and sloughing of seminiferous epithelium in the rat testis. Indian Journal of Physiology and Pharmacology 44, 317322.Google ScholarPubMed
D'Souza, UJ and Narayana, K (2001) Induction of seminiferous tubular atrophy by single dose of 5-fluorouracil (5-FU) in Wistar rats. Indian Journal of Physiology and Pharmacology 45, 8794.Google Scholar
Russell, LD and Russell, JA (1991) Short-term morphological response of the rat testis to administration of five chemotherapeutic agents. The American Journal of Anatomy 192, 142168.CrossRefGoogle ScholarPubMed
D'Souza, UJ (2003) Toxic effects of 5-fluorouracil on sperm count in Wistar rats. The Malaysian Journal of Medical Sciences 10, 4345.Google ScholarPubMed
Habas, K et al. (2016) Detection of phase specificity of in vivo germ cell mutagens in an in vitro germ cell system. Toxicology 353, 110.CrossRefGoogle Scholar
Ghafouri-Fard, S et al. (2021) Effects of chemotherapeutic agents on male germ cells and possible ameliorating impact of antioxidants. Biomedicine & Pharmacotherapy 142, 112040.CrossRefGoogle ScholarPubMed
Yadav, YC (2019) Effect of cisplatin on pancreas and testis in Wistar rats: biochemical parameters and histology. Heliyon 5, e02247.CrossRefGoogle ScholarPubMed
Mitchell, EP and Schein, PS (1986) Contributions of nitrosoureas to cancer treatment. Cancer Treatment Reports 70, 3141.Google ScholarPubMed
Tahvilzadeh, M et al. (2016) An evidence-based approach to medicinal plants for the treatment of sperm abnormalities in traditional Persian medicine. Andrologia 48, 860879.CrossRefGoogle ScholarPubMed
Diab, KAE et al. (2018) Genotoxicity of carbon tetrachloride and the protective role of essential oil of Salvia officinalis L. in mice using chromosomal aberration, micronuclei formation, and comet assay. Environmental Science and Pollution Research 25, 16211636.CrossRefGoogle ScholarPubMed
Tharmalingam, MD et al. (2020) Cisplatin and carboplatin result in similar gonadotoxicity in immature human testis with implications for fertility preservation in childhood cancer. BMC Medicine 18, 374.CrossRefGoogle ScholarPubMed
Chatzidarellis, E et al. (2010) Effects of taxane-based chemotherapy on inhibin B and gonadotropins as biomarkers of spermatogenesis. Fertility and Sterility 94, 558563.CrossRefGoogle ScholarPubMed
Skardal, A et al. (2020) Drug compound screening in single and integrated multi-organoid body-on-a-chip systems. Biofabrication 12, 025017.CrossRefGoogle ScholarPubMed
Rajan, SAP et al. (2020) Probing prodrug metabolism and reciprocal toxicity with an integrated and humanized multi-tissue organ-on-a-chip platform. Acta Biomaterialia 106, 124135.CrossRefGoogle ScholarPubMed
Oktem, O et al. (2018) Ovarian and uterine functions in female survivors of childhood cancers. The Oncologist 23, 214224.CrossRefGoogle ScholarPubMed
Paroha, S et al. (2021) Recent advances and prospects in gemcitabine drug delivery systems. International Journal of Pharmaceutics 592, 120043.CrossRefGoogle ScholarPubMed
Handali, S et al. (2020) PHBV/PLGA nanoparticles for enhanced delivery of 5-fluorouracil as promising treatment of colon cancer. Pharmaceutical Development and Technology 25, 206218.CrossRefGoogle ScholarPubMed
Shandilya, R et al. (2020) Nanotechnology in reproductive medicine: opportunities for clinical translation. Clinical and Experimental Reproductive Medicine 47, 245262.CrossRefGoogle ScholarPubMed
Patra, JK et al. (2018) Nano based drug delivery systems: recent developments and future prospects. Journal of Nanobiotechnology 16, 71.CrossRefGoogle ScholarPubMed
Kim, S et al. (2008) Thymidylate synthase and dihydropyrimidine dehydrogenase levels Are associated with response to 5-fluorouracil in Caenorhabditis elegans. Molecules and Cells 26, 344349.Google ScholarPubMed
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Table 1. Adverse effects of 5-FU on female reproduction

Figure 1

Table 2. Adverse effects of 5-FU on male reproduction