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Method To Visualize the Intratumor Distribution and Impact of Gemcitabine in Pancreatic Ductal Adenocarcinoma by Multimodal Imaging
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- Strittmatter, Nicole (författare)
- AstraZeneca, R&D, Clin Pharmacol & Safety Sci, Imaging & Data Analyt, Cambridge CB4 0WG, England
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- Richards, Frances M. (författare)
- Univ Cambridge, Canc Res UK Cambridge Inst, Cambridge CB2 0RE, England.;Astra Zeneca, Oncol R&D, Translat Med, Cambridge CB4 0WG, England
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- Race, Alan M. (författare)
- Philipps Univ Marburg, Inst Med Bioinformat & Biostat, D-35032 Marburg, Germany
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- AstraZeneca, R&D, Clin Pharmacol & Safety Sci, Imaging & Data Analyt, Cambridge CB4 0WG, England Univ Cambridge, Canc Res UK Cambridge Inst, Cambridge CB2 0RE, England;Astra Zeneca, Oncol R&D, Translat Med, Cambridge CB4 0WG, England (creator_code:org_t)
- 2022-01-10
- 2022
- Engelska.
- Ingår i: Analytical Chemistry. - : American Chemical Society (ACS). - 0003-2700 .- 1520-6882. ; 94:3, s. 1795-1803
- Tidskriftsartikel (refereegranskat)
Abstract
Ämnesord
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- Gemcitabine (dFdC) is a common treatment for pancreatic cancer; however, it is thought that treatment may fail because tumor stroma prevents drug distribution to tumor cells. Gemcitabine is a pro-drug with active metabolites generated intracellularly; therefore, visualizing the distribution of parent drug as well as its metabolites is important. A multimodal imaging approach was developed using spatially coregistered mass spectrometry imaging (MSI), imaging mass cytometry (IMC), multiplex immunofluorescence microscopy (mIF), and hematoxylin and eosin (H&E) staining to assess the local distribution and metabolism of gemcitabine in tumors from a genetically engineered mouse model of pancreatic cancer (KPC) allowing for comparisons between effects in the tumor tissue and its microenvironment. Mass spectrometry imaging (MSI) enabled the visualization of the distribution of gemcitabine (100 mg/kg), its phosphorylated metabolites dFdCMP, dFdCDP and dFdCTP, and the inactive metabolite dFdU. Distribution was compared to small-molecule ATR inhibitor AZD6738 (25 mg/kg), which was codosed. Gemcitabine metabolites showed heterogeneous distribution within the tumor, which was different from the parent compound. The highest abundance of dFdCMP, dFdCDP, and dFdCTP correlated with distribution of endogenous AMP, ADP, and ATP in viable tumor cell regions, showing that gemcitabine active metabolites are reaching the tumor cell compartment, while AZD6738 was located to nonviable tumor regions. The method revealed that the generation of active, phosphorylated dFdC metabolites as well as treatment-induced DNA damage primarily correlated with sites of high proliferation in KPC PDAC tumor tissue, rather than sites of high parent drug abundance.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Radiologi och bildbehandling (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Radiology, Nuclear Medicine and Medical Imaging (hsv//eng)
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