Performance of capecitabine in novel combination therapies in colorectal cancer

Pouya, Fahima Danesh; Rasmi, Yousef; Camci, Irem Yalim; Tutar, Yusuf; Nemati, Mohadeseh

doi:10.1080/1120009x.2021.1920247

Cited by 12 publications

(6 citation statements)

References 123 publications

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“…This point needs to be concerned and elaborated on in the future, so as to provide a more substantial theoretical basis for the treatment of cetuximab-resistant CRC. Additionally, Pouya et al [ 54 ] demonstrated that the effect of combining radiotherapy and cetuximab was better in CRC. Whether the combined therapy has a synergistic effect in cetuximab-resistant CRC remains unclear and could be verified in the future.…”

Section: Discussionmentioning

confidence: 99%

ACY1 Downregulation Enhances the Radiosensitivity of Cetuximab-Resistant Colorectal Cancer by Inactivating the Wnt/β-Catenin Signaling Pathway

Shan

Dai

Zhang

et al. 2022

Cancers

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Treatment of cetuximab-resistant colorectal cancer (CRC) is a global healthcare problem. This study aimed to assess the effects of radiotherapy on cetuximab-resistant CRC and explore the underlying mechanism. We established a cetuximab-resistant HCT116 cell line (HCT116-R) by extracorporeal shock. Differentially expressed mRNAs were screened from cells treated with different radiation doses using second-generation high-throughput sequencing. Sequence data showed that ACY1 was significantly downregulated in HCT116-R cells after irradiation. Analysis of the GEO and TCGA datasets revealed that high ACY1 expression was associated with lymph node metastasis and a poor prognosis in CRC patients. In addition, immunohistochemistry results from CRC patients revealed that ACY1 protein expression was related to cetuximab resistance and lymph node metastasis. These findings suggested that ACY1 may function as an oncogene to promote CRC progression and regulate the radiosensitivity of cetuximab-resistant CRC. As expected, ACY1 silencing weakened the proliferation, migration, and invasion abilities of HCT116-R cells after radiotherapy. Mechanistically, TCGA data demonstrated that ACY1 expression was closely related to the Wnt/β-catenin pathway in CRC. We validated that radiotherapy first reduced β-catenin levels, followed by decreased expression of the metastasis-related protein E-cadherin. Silencing ACY1 dramatically enhanced these changes in β-catenin and E-cadherin after radiotherapy. In conclusion, ACY1 downregulation could enhance the radiosensitivity of cetuximab-resistant CRC by inactivating Wnt/β-catenin signaling, implying that ACY1 may serve as a radiotherapy target for cetuximab-resistant CRC.

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Section: Discussionmentioning

confidence: 99%

ACY1 Downregulation Enhances the Radiosensitivity of Cetuximab-Resistant Colorectal Cancer by Inactivating the Wnt/β-Catenin Signaling Pathway

Shan

Dai

Zhang

et al. 2022

Cancers

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“…To circumvent the unacceptable gastrointestinal toxicity of doxifluridine, researchers at Roche continually developed a series of N 4 -substituted 5′-deoxy-5-fluorocytidine derivatives, which could be hydrolyzed to doxifluridine and 5-FU. As a result, N 4 -pentyloxycarbonyl-5′-deoxy-5-fluorocytidine (capecitabine, CAP, Table 1 ) stood out by such prodrug strategy as an orally chemotherapeutic drug that was FDA-approved for the treatment of colorectal cancer, pancreatic adenocarcinoma, stomach cancer, esophageal cancer, or gastroesophageal junction cancer ( Siddiqui et al, 2019 ; Pouya et al, 2021 ; Ge et al, 2023 ). As mentioned above, the gastrointestinal toxicity of doxifluridine is attributed to the liberation of 5-FU in intestine tract under the action of thymidine phosphorylase, capecitabine was thus designed as a prodrug of doxifluridine that could not be the substrate for thymidine phosphorylase in the intestine with an oral bioavailability of about 100%, C max of 3.9 mg/L, t max of 1.5–2 h, and AUC of 5.96 mg·h/L ( Walko and Lindley, 2005 ; Rehman et al, 2022 ).…”

Section: Nucleoside Analogues For the Treatment Of Gi Malignanciesmentioning

confidence: 99%

Advanced prodrug strategies in nucleoside analogues targeting the treatment of gastrointestinal malignancies

Yao

et al. 2023

Front. Cell Dev. Biol.

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Gastrointestinal malignancies are common digestive system tumor worldwide. Nucleoside analogues have been widely used as anticancer drugs for the treatment of a variety of conditions, including gastrointestinal malignancies. However, low permeability, enzymatic deamination, inefficiently phosphorylation, the emergence of chemoresistance and some other issues have limited its efficacy. The prodrug strategies have been widely applied in drug design to improve pharmacokinetic properties and address safety and drug-resistance issues. This review will provide an overview of the recent developments of prodrug strategies in nucleoside analogues for the treatment of gastrointestinal malignancies.

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“…The mechanistic basis was unclear: impact on several transporters, modifications to intracellular pH, or something else [ 68 ]. Future studies are thus warranted as a series are accumulating on such possible interactions [ 69 ].…”

Section: Ppis and Oncologic Treatment Efficacymentioning

confidence: 99%

Long-Term Use of Proton Pump Inhibitors in Cancer Patients: An Opinion Paper

Raoul

Edeline

Simmet

et al. 2022

Cancers

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Multikinase inhibitors (MKIs), and particularly tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (CPIs), are currently some of the major breakthroughs in cancer treatment. Proton pump inhibitors (PPIs) revolutionised the treatment of acid-related diseases, but are frequently overused for epigastric pain or heartburn. However, long-term acid suppression from using PPIs may lead to safety concerns, and could have a greater impact in cancer patients undergoing therapy, like bone fractures, renal toxicities, enteric infections, and micronutrient deficiencies (iron and magnesium). Moreover, acid suppression may also affect the pharmacokinetics of drugs (at least during acid suppression) and decrease the absorption of many molecularly-targeted anticancer therapies, which are mostly weak bases with pH-dependent absorption. This type of drug-drug interaction may have detrimental effects on efficacy, with major clinical impacts described for some orally administrated targeted therapies (erlotinib, gefitinib, pazopanib, palbociclib), and conflicting results with many others, including capecitabine. Furthermore, the long-term use of PPIs results in severe alterations to the gut microbiome and recent retrospective analyses have shown that the benefit of using CPIs was suppressed in patients treated with PPIs. These very expensive drugs are of great importance because of their efficacy. As the use of PPIs is not essential, we must apply the precautionary principle. All these data should encourage medical oncologists to refrain from prescribing PPIs, explaining to patients the risks of interaction in order to prevent inappropriate prescription by another physician.

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Performance of capecitabine in novel combination therapies in colorectal cancer

Cited by 12 publications

References 123 publications

ACY1 Downregulation Enhances the Radiosensitivity of Cetuximab-Resistant Colorectal Cancer by Inactivating the Wnt/β-Catenin Signaling Pathway

ACY1 Downregulation Enhances the Radiosensitivity of Cetuximab-Resistant Colorectal Cancer by Inactivating the Wnt/β-Catenin Signaling Pathway

Advanced prodrug strategies in nucleoside analogues targeting the treatment of gastrointestinal malignancies

Long-Term Use of Proton Pump Inhibitors in Cancer Patients: An Opinion Paper

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