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.
Highlights
Mycoplasmas are considered to be the smallest self-replicating organisms, both in dimension and genome size [1]
Deamination of gemcitabine by mycoplasma cytidine deaminase (CDA) can be prevented in the presence of exogenous natural purine and pyrimidine nucleosides
The substrate specificity of recombinant M. hyorhinis CDA (CDAHyor) was studied and compared with CDAHuman. Both enzymes catalyzed the deamination of the natural pyrimidine nucleosides Cyd and dCyd, and the well-known anticancer drugs dFdC and cytosine arabinoside (ara-Cyd)
Summary
Mycoplasmas are considered to be the smallest self-replicating organisms, both in dimension and genome size [1]. We and others showed that certain catabolic mycoplasma enzymes (i.e. pyrimidine nucleoside phosphorylase, purine nucleoside phosphorylase and cytidine deaminase) interfere with the biological (i.e. cytostatic and antiviral) activity of different therapeutic nucleoside analogues (NAs) by producing less active or inactive drug metabolites. This was demonstrated for both pyrimidine- and purine-derived antimetabolites including gemcitabine, floxuridine, trifluridine, cladribine, and others [6,7,8,9,10]. 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, (20-deoxy)uridine metabolites These molecules show a decreased cytostatic activity in CDA-overexpressing tumor cells [25,26]. Gemcitabine stability in the supernatant of mycoplasma-infected and uninfected cell cultures
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