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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

Inhibition of mycoplasma-associated [5-3H]dFdU formation by natural nucleosides. Formation of [5-3H]dFdU from [5-3H]dFdC in the tumor cell-free supernatant of mycoplasma-infected and control MDA.MB.231 (A) and MCF-7 (B) breast cancer cell cultures in the presence/absence of different concentrations of pyrimidine (dThd and Urd) and purine (Ado and Ino) nucleosides. The data are the mean of at least two independent experiments (±S.E.M.).
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f0015: Inhibition of mycoplasma-associated [5-3H]dFdU formation by natural nucleosides. Formation of [5-3H]dFdU from [5-3H]dFdC in the tumor cell-free supernatant of mycoplasma-infected and control MDA.MB.231 (A) and MCF-7 (B) breast cancer cell cultures in the presence/absence of different concentrations of pyrimidine (dThd and Urd) and purine (Ado and Ino) nucleosides. The data are the mean of at least two independent experiments (±S.E.M.).

Mentions: Since THU could efficiently restore the cytostatic activity of dFdC in the presence of M. hyorhinis in the tumor cell culture medium, the stability of radiolabeled dFdC ([5-3H]dFdC) was studied in the tumor cell-free (but mycoplasma-containing) culture medium of M. hyorhinis-infected MDA-MB-231 (Fig. 3A) and MCF-7 (Fig. 3B) breast cancer cells. A pronounced inhibition of [5-3H]-dFdC deamination (i.e. decreased formation of the inactive metabolite [5-3H]-dFdU) by 1 mM THU could be observed [10], but also, a dose-dependent inhibition of [5-3H]dFdC deamination by the exogenous supply of natural pyrimidine (i.e. dThd and Urd) or purine (i.e. Ado and Ino) nucleosides was observed in the spent tumor cell culture medium (Fig. 3). Also, [5-3H]-dFdU formation could be inhibited by exogenous administration of other natural nucleosides such as Guo, dAdo, dIno or dGuo (data not shown).


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

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

Inhibition of mycoplasma-associated [5-3H]dFdU formation by natural nucleosides. Formation of [5-3H]dFdU from [5-3H]dFdC in the tumor cell-free supernatant of mycoplasma-infected and control MDA.MB.231 (A) and MCF-7 (B) breast cancer cell cultures in the presence/absence of different concentrations of pyrimidine (dThd and Urd) and purine (Ado and Ino) nucleosides. The data are the mean of at least two independent experiments (±S.E.M.).
© Copyright Policy - CC BY
Related In: Results  -  Collection

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

f0015: Inhibition of mycoplasma-associated [5-3H]dFdU formation by natural nucleosides. Formation of [5-3H]dFdU from [5-3H]dFdC in the tumor cell-free supernatant of mycoplasma-infected and control MDA.MB.231 (A) and MCF-7 (B) breast cancer cell cultures in the presence/absence of different concentrations of pyrimidine (dThd and Urd) and purine (Ado and Ino) nucleosides. The data are the mean of at least two independent experiments (±S.E.M.).
Mentions: Since THU could efficiently restore the cytostatic activity of dFdC in the presence of M. hyorhinis in the tumor cell culture medium, the stability of radiolabeled dFdC ([5-3H]dFdC) was studied in the tumor cell-free (but mycoplasma-containing) culture medium of M. hyorhinis-infected MDA-MB-231 (Fig. 3A) and MCF-7 (Fig. 3B) breast cancer cells. A pronounced inhibition of [5-3H]-dFdC deamination (i.e. decreased formation of the inactive metabolite [5-3H]-dFdU) by 1 mM THU could be observed [10], but also, a dose-dependent inhibition of [5-3H]dFdC deamination by the exogenous supply of natural pyrimidine (i.e. dThd and Urd) or purine (i.e. Ado and Ino) nucleosides was observed in the spent tumor cell culture medium (Fig. 3). Also, [5-3H]-dFdU formation could be inhibited by exogenous administration of other natural nucleosides such as Guo, dAdo, dIno or dGuo (data not shown).

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