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. [Footnotes omitted]
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