The Therapeutic Potential of 2′-Deoxycytidine

Abstract

2'-Deoxycytidine is a pyrimidine 2'-deoxyribonucleoside composed of cytosine and 2'-deoxyribose, serving as a key DNA component. It is similar to cytidine but lacks a 2'-hydroxyl group. Additionally it is widely distributed in living organisms and participates in essential reactions of human nucleotide metabolism.

Introduction

Pyrimidine 2′-deoxyribonucleosides are compounds consisting of a pyrimidine base linked to a ribose sugar that lacks a hydroxyl group at the 2’position. Deoxycytidine is one such deoxyribonucleoside and a fundamental component of deoxyribonucleic acid (DNA). Structurally, it resembles the ribonucleoside cytidine, except that the hydroxyl group at the 2′ position is replaced by a hydrogen atom. Deoxycytidine is ubiquitous across living organisms, from bacteria and plants to humans. It can be generated through the degradation of DNA during apoptosis or other forms of cell death. In humans, deoxycytidine participates in multiple enzymatic reactions within nucleotide metabolism.[1]

Application in treatment

Treatment for Thymidine Kinase 2 Deficiency

Thymidine kinase 2 (TK2), a critical enzyme in the mitochondrial pyrimidine salvage pathway, is essential for mitochondrial DNA (mtDNA) maintenance. Mutations in the nuclear gene TK2 cause TK2 deficiency, which manifests predominantly in children as myopathy with mtDNA depletion. Molecular bypass therapy with the TK2 products, dCMP and dTMP, prolongs the lifespan of Tk2-deficient (Tk2-/-) mice by 2-3 fold. dC+dT delayed disease onset, prolonged lifespan of Tk2-deficient mice, and restored mtDNA copy number as well as respiratory chain enzyme activities and levels. In contrast, dCMP+dTMP+THU therapy decreased lifespan of Tk2-/- animals compared to dCMP+dTMP. The observation shows rapid catabolism of the deoxynucleoside monophosphates to deoxythymidine (dT) and deoxycytidine (dC), and deoxynucleosides might be the major active agents and inhibition of deoxycytidine deamination might enhance dTMP+dCMP therapy.[2]

Possible application in AIDS treatment

After phosphorylation to the corresponding diphosphates, 2'-azido-2'-deoxycytidine and 2'-difluorocyti-dine act as powerful inhibitors of ribonudeotide reductase. Phosphorylation requires deoxycytidine kinase, an enzyme with particularly high activity in lymphoid cells. Therefore, the deoxycytidine analogs can be expected to inhibit the reductase with some specificity for the lymphoid system. Pretreatment of human CEM lymphoblasts with the analogs considerably in-creased the phosphoryation of 3'-deoxy-3'-azidothymidine (AzT). The increased phosphorylation of AzT is caused by a prolongation of the S phase of the cell cycle. The result suggests the possibility of a combination of 2'-substituted deoxycytidine analogs with AzT in the treatment of AIDS. Gao et al. [Gao,W.-Y., Cara, A., Gallo, R. C. & Lori, F. (1993) Proc. Nai.Acad. Sci. USA 90, 8925-8928] have suggested the use of the ribonucleotide reductase inhibitor hydroxyurea for this purpose, since the resulting decrease in the size of deoxyribonucleotide pools decreases the processivity of the HIV reverse transcriptase. From the results it would appear that the 2'-substituted deoxycytidine analogs might be preferable to hydroxyurea.[3]

Human cancer xenograft

2'-Deoxy-2'-methylidenecytidine (DMDC) is a new 2'-deoxycytidine (dCyd) antimetabolite. DMDC was highly resistant to cytidine (Cyd) deaminase, which deaminates the dCyd analogues to inactive molecules, whereas gemcitabine was susceptible to the enzyme. Given p.o., high antitumor activity with therapeutic index of more than 10 was found with DMDC in 7 of 15 xenograft lines. In contrast, gemcitabine given i.v. or p.o. was highly effective in 4 of 15 human cancer xenograft lines. The antitumor spectrum of these compounds was quite different, although their molecular targets are reported to be similar. DMDC was highly effective in tumors with higher levels of Cyd deaminase activity, whereas it showed only slight activity in those with lower levels of Cyd deaminase. In contrast, gemcitabine appeared to be less effective in tumors with high levels of Cyd deaminase. We also investigated the correlation with the susceptibility to the two dCyd antimetabolites and dCyd kinase activity in tumors, but none was observed. Cyd deaminase activity was found to be high in tumor tissues from various types of human cancers thus far tested, such as colorectal cancer and non-small cell lung cancer. Such cancer types or individual patients who have tumors with high activity of the enzyme may be targets for DMDC therapy.[4]

References

[1] Wishart, D. S., Guo, A. C., Oler, E., Wang, F., Anjum, A., Peters, H., … Gautam, N. (2024). 2′-Deoxycytidine. In Human Metabolome Database. The Metabolomics Innovation Centre.

[2] Lopez‐Gomez, C., Levy, R. J., Sanchez‐Quintero, M. J., Juanola‐Falgarona, M., Barca, E., Garcia‐Diaz, B., ... & Hirano, M. (2017). Deoxycytidine and deoxythymidine treatment for thymidine kinase 2 deficiency. Annals of neurology, 81(5), 641-652.

[3] Bianchi, V., Borella, S., Calderazzo, F., Ferraro, P., Chieco Bianchi, L., & Reichard, P. (1994). Inhibition of ribonucleotide reductase by 2'-substituted deoxycytidine analogs: possible application in AIDS treatment. Proceedings of the National Academy of Sciences, 91(18), 8403-8407.

[4] Miwa, M., Eda, H., Ura, M., Ouchi, K. F., Keith, D. D., Foley, L. H., & Ishitsuka, H. (1998). High susceptibility of human cancer xenografts with higher levels of cytidine deaminase to a 2'-deoxycytidine antimetabolite, 2'-deoxy-2'-methylidenecytidine. Clinical cancer research: an official journal of the American Association for Cancer Research, 4(2), 493-497.

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