Can 5-Fluorocytosine be used to treat cancer?

Yes. The therapeutic fluoropyrimidines 5-fluorouracil (5-FU) and 5-fluorocytosine (5-FC) have long been used to treat human cancer and severe invasive fungal infections, respectively. 5-FC is a well-known antifungal drug that can be used to treat cryptococcosis, candidiasis, and chromobl astomycosis. 5-FC is also the treatment of choice for cryptococcal meningitis. Structurally, 5-FC is a fluorinated analog of cytosine and a prodrug of 5-fluorouracil that must first be metabolized through the pyrimidine salvage pathway to produce toxic nucleotides that disrupt DNA, RNA, and protein synthesis.

Pyrimidine analogs, including 5-FU, cytosine arabinoside, 5-azacytidine, and gemcitabine, are effective drugs that can be used as part of a variety of anticancer regimens. However, they lack cell specificity and can cause severe side effects. Although 5-FC itself has no chemotherapeutic effects, it is incorporated into ribonucleosides and, more importantly, RNA oligonucleotides, which exert cytotoxic effects on cancer cells in vitro. Interestingly, these effects were rescued by uridine and thymidine. Similarly, 2'-deoxy-5-fluorocytidine inhibited tumor cell growth in vitro, but was less toxic to human primary cells compared to 5-fluorocytidine, suggesting that deoxyribonucleosides may exhibit fewer side effects in vivo. In particular, oligonucleotides containing 5-FC may be novel chemotherapeutic agents that can be formulated into cancer-specific particles for safe and effective cancer treatment.

5-Fluorouridine triphosphate is a bioactive metabolite of 5-FU and 5-FC drugs and is incorporated into the RNA of target cells. It has been previously demonstrated that tRNA methylation defects caused by Trm4 and Trm8 deletions trigger RNA quality control mechanisms, resulting in the destabilization of the low-modified tRNAValAAC fraction. We demonstrate that fluoropyrimidine incorporation into tRNAs strongly enhances the degradation of tRNAValAAC in yeast lacking Trm4- and Trm8-dependent methylation. This effect occurs even in the absence of Trm8 at elevated temperatures. Genetic approaches and quantification of tRNA modification levels indicate that enhanced fluoropyrimidine cytotoxicity results from drug-induced loss of uridine modifications and activation of tRNAValAAC decay involving the exonuclease Xrn1. These results suggest that inhibition of tRNA methylation could be used to enhance the therapeutic efficacy of 5-FU and 5-FC.

In addition, a promising de novo approach for the treatment of castration-resistant prostate cancer (CRPC) has been reported that utilizes a cell-mediated enzyme prodrug therapy consisting of cytosine deaminase (CD) and fluorouracil (5-FC). In vitro hTERT-ADSC.CD cytotoxicity and suicide effects were significantly enhanced after administration of 5 μM 5-FC. hTERT-ADSC.CD combined with 5-FC increased the number of apoptotic PC3 cells. hTERT-ADSC.CD combined with 5-FC resulted in better tumor suppression compared to the control group administered with hTERT-ADSC.CD monotherapy. In mice with CPRC, CD-overexpressing ADSCs combined with the prodrug 5-FC enhanced tumor suppression.

References:

[1] KATHARINA GÖRLITZ. Fluoropyrimidines trigger decay of hypomodified tRNA in yeast.[J]. Nucleic Acids Research, 2024: 5841-5851. DOI:10.1093/nar/gkae341.

[2] KIM J H, YANG H J, LEE S H, et al. Cytosine Deaminase-Overexpressing hTERT-Immortalized Human Adipose Stem Cells Enhance the Inhibitory Effects of Fluorocytosine on Tumor Growth in Castration Resistant Prostate Cancer[J]. International Journal of Molecular Sciences, 2024. DOI:10.3390/ijms25105519.

[3] TIM HOLZINGER. Differential functionality of fluoropyrimidine nucleosides for safe cancer therapy.[J]. Anti-Cancer Drugs, 2024. DOI:10.1097/CAD.0000000000001644.

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