Abstract: The combination of cisplatin and pemetrexed remains the gold standard chemotherapy for malignant pleural mesothelioma (MPM), although resistance and poor response pose a significant challenge. Cytidine deaminase (CDA) is a key enzyme in the nucleotide salvage pathway and is involved in the adaptive stress response to chemotherapy. The cytidine analog capecitabine and its metabolite 5′-deoxy-5-fluorocytidine (5’-DFCR) are converted via CDA to 5-fluorouracil, which affects DNA and RNA metabolism. This study investigated a schedule-dependent treatment strategy, proposing that initial chemotherapy induces CDA expression, sensitizing cells to subsequent capecitabine treatment. Basal CDA protein expression was low in different mesothelioma cell lines but increased in the corresponding xenografts. Standard chemotherapy increased CDA protein levels in MPM cells in vitro and in vivo in a schedule-dependent manner. This was associated with epithelial-to-mesenchymal transition and with HIF-1alpha expression at the transcriptional level. In addition, pretreatment with cisplatin and pemetrexed in combination sensitized MPM xenografts to capecitabine. Analysis of a tissue microarray (TMA) consisting of samples from 98 human MPM patients revealed that most human MPM samples had negative CDA expression. While survival curves based on CDA expression in matched samples clearly separated, significance was not reached due to the limited sample size. In non-matched samples, CDA expression before but not after neoadjuvant therapy was significantly associated with worse overall survival. In conclusion, chemotherapy increases CDA expression in xenografts, which is consistent with our in vitro results in MPM and lung cancer. A subset of matched patient samples showed increased CDA expression after therapy, suggesting that a schedule-dependent treatment strategy based on chemotherapy and capecitabine may benefit a selected MPM patient population.
Introduction: Malignant pleural mesothelioma (MPM) is a rare and deadly cancer originating from mesothelial cells of the pleura. Currently, there are several treatment options for malignant mesothelioma, e.g., surgery, radiotherapy, chemo- and immunotherapy, and combinations thereof. In 2020, the FDA approved immunotherapy for treating treatment-naive unresectable MPM patients as a first-line therapy. However, due to contraindications or side effects, not all patients with mesothelioma are eligible for immunotherapy. Since 2004, the standard first-line therapy for MPM has been combination therapy with cisplatin and pemetrexed (MTA). It has already been shown that schedule-dependent administration of various treatment regimens can increase the efficacy of standard therapy. In this context, in comparison to concurrent treatment, pretreatment with pemetrexed followed by chemotherapy results in reduced cancer cell growth due to persistent DNA damage and the induction of senescence not only in MPM but also in non-small cell lung cancer (NSCLC), which was also sensitized to subsequent radiotherapy by pretreatment with pemetrexed.
DNA replication is a prerequisite for uncontrolled cell proliferation and is a hallmark of cancer. DNA replication is dependent on sufficiently high nucleotide levels. Cancer cells can switch to the energy-efficient nucleotide salvage pathway to maintain DNA replication. In detail, pyrimidine de novo synthesis is critically dependent on thymidylate synthase (TS), which is the principal target of MTA. It has been shown that MTA treatment allows cancer cells to adapt their metabolism and increase their thymidine salvage pathway activity. Pyrimidine salvage is fueled by recycling intracellular nucleic acids derived from DNA and RNA degradation or by the uptake of extracellular nucleosides and nucleobases. Cytidine deaminase (CDA) and thymidine phosphorylase (TYMP) perform the first and second steps of the salvage pathway, e.g., the conversion of cytidine to uridine and uracil, respectively. Capecitabine (sold under the brand name Xeloda among others) is a prodrug processed in the liver to the cytidine analog 5′-deoxy-5-fluorocytidine (5’-DFCR). CDA and TYMP convert 5’-DFCR to 5-fluorouracil (5-FU), which inhibits TS. Previously, our group reported that a chemotherapy-resistant subpopulation of the NSCLC cell line A549 exhibited high CDA and TYMP expression. Moreover, the expression of CDA and TYMP in NSCLC cells was associated with the induction of an epithelial-to-mesenchymal transition (EMT) and increased expression in response to standard chemotherapy, which further augmented the efficacy of subsequent treatment with 5’-DFCR in vitro.
In this study, we aimed to demonstrate that standard chemotherapy also increases CDA expression in MPM in a schedule-dependent manner, thereby increasing sensitivity to treatment with 5’-DFCR and capecitabine in vitro and in vivo, respectively. Importantly, minimal toxicity of the schedule-dependent triplet regimen was observed in vivo. In addition, in a subset of MPM patient samples, CDA expression was increased after therapy, suggesting that a schedule-dependent treatment strategy based on chemotherapy and capecitabine may be a potentially beneficial treatment strategy for a selected MPM patient population. [Footnotes omitted]
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