Preclinical models in oncological pharmacology: limits and advantages

Pagano, Ester; Bergamo, Alberta; Carpi, Sara; Donnini, Sandra; Villarosa, Monica Notarbartolo Di; Serpe, Loredana; Lisi, Lucia

doi:10.36118/pharmadvances.2021.05

Cited by 3 publications

(3 citation statements)

References 81 publications

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“…The temperature for conducting experiments using zebrafish is lower than the human body temperature, which may affect the observed processes. Also, drug administration through direct absorption from the zebrafish medium may impact the precision in compound dosing [ 24 ]. The model also poses technical difficulties: due to its small size, manipulation of the equipment and implantation of cells is highly challenging.…”

Section: Discussionmentioning

confidence: 99%

Assessment of an Anticancer Effect of the Simultaneous Administration of MM-129 and Indoximod in the Colorectal Cancer Model

Kwiatkowska,

Hermanowicz,

Czarnomysy

et al. 2023

Cancers

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(1) Background: The purpose of the given study was to examine the antitumor activity of the simultaneous administration of MM-129, a 1,2,4-triazine derivative, and indoximod (IND), the kynurenine pathway inhibitor, toward colon cancer. (2) Methods: The efficiency of the co-administration of the studied compounds was assessed in xenografted zebrafish embryos. Then, the effects of the combined administration of compounds on cellular processes such as cell viability, apoptosis, and intracellular signaling pathways were evaluated. In vitro studies were performed using two colorectal cancer cell lines, namely, DLD-1 and HT-29. (3) Results: The results indicated that the simultaneous application of MM-129 and indoximod induced a stronger inhibition of tumor growth in zebrafish xenografts. The combination of these compounds intensified the process of apoptosis by lowering the mitochondrial potential, enhancing the externalization of phosphatidylserine (PS) and activation of caspases. Additionally, the expression of protein kinase B (AKT) and indoleamine 2,3-dioxygenase-(1IDO1) was disrupted under the applied compound combination. (4) Conclusions: Simultaneous targeting of ongoing cell signaling that promotes tumor progression, along with inhibition of the kynurenine pathway enzyme IDO1, results in the enhancement of the antitumor effect of the tested compounds against the colon cancer cells.

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Section: Discussionmentioning

confidence: 99%

Assessment of an Anticancer Effect of the Simultaneous Administration of MM-129 and Indoximod in the Colorectal Cancer Model

Kwiatkowska,

Hermanowicz,

Czarnomysy

et al. 2023

Cancers

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“…Multiwell microtiter plates are the backbone of in vitro life sciences and drug discovery research. Enormous infrastructure exists to facilitate their use and includes liquid handling and signal detection instruments compatible with a wide range of cell types (primary cells, cell lines, and organoids), formats (monolayer, sandwich culture, spheroids, and 3D scaffold), and readouts (fluorescence, high content imaging, soluble and cell extracted biomarkers, and omics) [ 28 ]. However, these in vitro systems have limitations when replicating human biology, a fundamental one being that they allow only fixed concentration bolus drug exposure.…”

Section: Discussionmentioning

confidence: 99%

A microfluidic system that replicates pharmacokinetic (PK) profiles in vitro improves prediction of in vivo efficacy in preclinical models

et al. 2022

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Test compounds used on in vitro model systems are conventionally delivered to cell culture wells as fixed concentration bolus doses; however, this poorly replicates the pharmacokinetic (PK) concentration changes seen in vivo and reduces the predictive value of the data. Herein, proof-of-concept experiments were performed using a novel microfluidic device, the Microformulator, which allows in vivo like PK profiles to be applied to cells cultured in microtiter plates and facilitates the investigation of the impact of PK on biological responses. We demonstrate the utility of the device in its ability to reproduce in vivo PK profiles of different oncology compounds over multiweek experiments, both as monotherapy and drug combinations, comparing the effects on tumour cell efficacy in vitro with efficacy seen in in vivo xenograft models. In the first example, an ERK1/2 inhibitor was tested using fixed bolus dosing and Microformulator-replicated PK profiles, in 2 cell lines with different in vivo sensitivities. The Microformulator-replicated PK profiles were able to discriminate between cell line sensitivities, unlike the conventional fixed bolus dosing. In a second study, murine in vivo PK profiles of multiple Poly(ADP-Ribose) Polymerase 1/2 (PARP) and DNA-dependent protein kinase (DNA-PK) inhibitor combinations were replicated in a FaDu cell line resulting in a reduction in cell growth in vitro with similar rank ordering to the in vivo xenograft model. Additional PK/efficacy insight into theoretical changes to drug exposure profiles was gained by using the Microformulator to expose FaDu cells to the DNA-PK inhibitor for different target coverage levels and periods of time. We demonstrate that the Microformulator enables incorporating PK exposures into cellular assays to improve in vitro–in vivo translation understanding for early therapeutic insight.

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“…Transformed cell lines are robust and therefore more successful in transfection studies, allowing the stable introduction of genes in instances requiring the expression of a specific reporter, inducible expression of an extrinsic protein or as an overexpression system. Conversely specific methods of gene suppression (antisense RNA, small interfering RNA) allow the inhibition of gene activity more easily [35].…”

Section: Contextualising In Vitro and Preclinical Modelling Platformsmentioning

confidence: 99%

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Preclinical models in oncological pharmacology: limits and advantages

Cited by 3 publications

References 81 publications

Assessment of an Anticancer Effect of the Simultaneous Administration of MM-129 and Indoximod in the Colorectal Cancer Model

Assessment of an Anticancer Effect of the Simultaneous Administration of MM-129 and Indoximod in the Colorectal Cancer Model

A microfluidic system that replicates pharmacokinetic (PK) profiles in vitro improves prediction of in vivo efficacy in preclinical models

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