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Mycoplasma hyorhinis-encoded cytidine deaminase efficiently inactivates cytosine-based anticancer drugs.

Vande Voorde J, Vervaeke P, Liekens S, Balzarini J - FEBS Open Bio (2015)

Bottom Line: This mycoplasma-driven drug deamination could be prevented by exogenous administration of the cytidine deaminase (CDA) inhibitor tetrahydrouridine, but also by the natural nucleosides or by a purine nucleoside phosphorylase inhibitor.The M. hyorhinis-encoded CDAHyor gene was cloned, expressed as a recombinant protein and purified.CDAHyor was found to be more catalytically active than its human equivalent and efficiently deaminates (inactivates) cytosine-based anticancer drugs.

View Article: PubMed Central - PubMed

Affiliation: Rega Institute for Medical Research, KU Leuven, Minderbroedersstraat 10, blok x - bus 1030, B-3000 Leuven, Belgium.

ABSTRACT
Mycoplasmas may colonize tumor tissue in patients. The cytostatic activity of gemcitabine was dramatically decreased in Mycoplasma hyorhinis-infected tumor cell cultures compared with non-infected tumor cell cultures. This mycoplasma-driven drug deamination could be prevented by exogenous administration of the cytidine deaminase (CDA) inhibitor tetrahydrouridine, but also by the natural nucleosides or by a purine nucleoside phosphorylase inhibitor. The M. hyorhinis-encoded CDAHyor gene was cloned, expressed as a recombinant protein and purified. CDAHyor was found to be more catalytically active than its human equivalent and efficiently deaminates (inactivates) cytosine-based anticancer drugs. CDAHyor expression at the tumor site may result in selective drug inactivation and suboptimal therapeutic efficiency.

No MeSH data available.


Related in: MedlinePlus

Molecular structure of the (2′-deoxy)cytidine analogues gemcitabine (A) and cytarabine (B).
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f0005: Molecular structure of the (2′-deoxy)cytidine analogues gemcitabine (A) and cytarabine (B).

Mentions: Recently, we reported efficient CDA-catalyzed deamination of gemcitabine (2′,2′-difluoro-2′-deoxycytidine; dFdC) resulting in a dramatically decreased cytostatic activity (up to 60-fold) of this drug in different Mycoplasma hyorhinis-infected tumor cell cultures [10]. Similarly, the response of M. hyorhinis-infected tumor xenografts in mice to gemcitabine treatment was significantly lower compared with uninfected control tumors [10]. The biological function of CDA is to catalyze the irreversible deamination of the natural pyrimidine nucleosides cytidine (Cyd) and 2′-deoxycytidine (dCyd) to uridine (Urd) and 2′-deoxyuridine (dUrd), respectively [24]. However, several clinical anticancer (d)Cyd analogues, including gemcitabine and cytarabine (cytosine arabinoside; ara-Cyd) (Fig. 1), can be catabolized by (cellular) drug deamination producing the corresponding, less active, (2′-deoxy)uridine metabolites. These molecules therefore show a decreased cytostatic activity in CDA-overexpressing tumor cells [25,26]. In the present study we biochemically and kinetically characterized M. hyorhinis-encoded CDA and report on a surprising interaction between mycoplasma CDA and purine nucleoside phosphorylase (PNP) activity in mycoplasma-infected tumor cells.


Mycoplasma hyorhinis-encoded cytidine deaminase efficiently inactivates cytosine-based anticancer drugs.

Vande Voorde J, Vervaeke P, Liekens S, Balzarini J - FEBS Open Bio (2015)

Molecular structure of the (2′-deoxy)cytidine analogues gemcitabine (A) and cytarabine (B).
© Copyright Policy - CC BY
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4541722&req=5

f0005: Molecular structure of the (2′-deoxy)cytidine analogues gemcitabine (A) and cytarabine (B).
Mentions: Recently, we reported efficient CDA-catalyzed deamination of gemcitabine (2′,2′-difluoro-2′-deoxycytidine; dFdC) resulting in a dramatically decreased cytostatic activity (up to 60-fold) of this drug in different Mycoplasma hyorhinis-infected tumor cell cultures [10]. Similarly, the response of M. hyorhinis-infected tumor xenografts in mice to gemcitabine treatment was significantly lower compared with uninfected control tumors [10]. The biological function of CDA is to catalyze the irreversible deamination of the natural pyrimidine nucleosides cytidine (Cyd) and 2′-deoxycytidine (dCyd) to uridine (Urd) and 2′-deoxyuridine (dUrd), respectively [24]. However, several clinical anticancer (d)Cyd analogues, including gemcitabine and cytarabine (cytosine arabinoside; ara-Cyd) (Fig. 1), can be catabolized by (cellular) drug deamination producing the corresponding, less active, (2′-deoxy)uridine metabolites. These molecules therefore show a decreased cytostatic activity in CDA-overexpressing tumor cells [25,26]. In the present study we biochemically and kinetically characterized M. hyorhinis-encoded CDA and report on a surprising interaction between mycoplasma CDA and purine nucleoside phosphorylase (PNP) activity in mycoplasma-infected tumor cells.

Bottom Line: This mycoplasma-driven drug deamination could be prevented by exogenous administration of the cytidine deaminase (CDA) inhibitor tetrahydrouridine, but also by the natural nucleosides or by a purine nucleoside phosphorylase inhibitor.The M. hyorhinis-encoded CDAHyor gene was cloned, expressed as a recombinant protein and purified.CDAHyor was found to be more catalytically active than its human equivalent and efficiently deaminates (inactivates) cytosine-based anticancer drugs.

View Article: PubMed Central - PubMed

Affiliation: Rega Institute for Medical Research, KU Leuven, Minderbroedersstraat 10, blok x - bus 1030, B-3000 Leuven, Belgium.

ABSTRACT
Mycoplasmas may colonize tumor tissue in patients. The cytostatic activity of gemcitabine was dramatically decreased in Mycoplasma hyorhinis-infected tumor cell cultures compared with non-infected tumor cell cultures. This mycoplasma-driven drug deamination could be prevented by exogenous administration of the cytidine deaminase (CDA) inhibitor tetrahydrouridine, but also by the natural nucleosides or by a purine nucleoside phosphorylase inhibitor. The M. hyorhinis-encoded CDAHyor gene was cloned, expressed as a recombinant protein and purified. CDAHyor was found to be more catalytically active than its human equivalent and efficiently deaminates (inactivates) cytosine-based anticancer drugs. CDAHyor expression at the tumor site may result in selective drug inactivation and suboptimal therapeutic efficiency.

No MeSH data available.


Related in: MedlinePlus