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Analysis of institutional authors

Tamarit, LAuthorVayá, IAuthorMiranda, MaCorresponding AuthorAndreu, ICorresponding Author

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October 28, 2024
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Cellular photo(geno)toxicity of gefitinib after biotransformation

Publicated to: Frontiers in pharmacology. 14 1208075- - 2023-01-01 14(), DOI: 10.3389/fphar.2023.1208075

Authors:

El Ouardi, Meryem; Tamarit-Mayo, Lorena; Vayá Pérez, Ignacio; Miranda, Miguel A.; Andreu, Inmaculada
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Affiliations

Hosp Univ & Politecn La Fe, Unidad Mixta Invest UPV IIS La Fe - Author

Abstract

Gefitinib (GFT) is a selective epidermal growth factor receptor (EGFR) inhibitor clinically used for the treatment of patients with non-small cell lung cancer. Bioactivation by mainly Phase I hepatic metabolism leads to chemically reactive metabolites such as O-Demethyl gefitinib (DMT-GFT), 4-Defluoro-4-hydroxy gefitinib (DF-GFT), and O-Demorpholinopropyl gefitinib (DMOR-GFT), which display an enhanced UV-light absorption. In this context, the aim of the present study is to investigate the capability of gefitinib metabolites to induce photosensitivity disorders and to elucidate the involved mechanisms. According to the neutral red uptake (NRU) phototoxicity test, only DF-GFT metabolite can be considered non-phototoxic to cells with a photoirritation factor (PIF) close to 1. Moreover, DMOR-GFT is markedly more phototoxic than the parent drug (PIF = 48), whereas DMT-GFT is much less phototoxic (PIF = 7). Using the thiobarbituric acid reactive substances (TBARS) method as an indicator of lipid photoperoxidation, only DMOR-GFT has demonstrated the ability to photosensitize this process, resulting in a significant amount of TBARS (similar to ketoprofen, which was used as the positive control). Protein photooxidation monitored by 2,4-dinitrophenylhydrazine (DNPH) derivatization method is mainly mediated by GFT and, to a lesser extent, by DMOR-GFT; in contrast, protein oxidation associated with DMT-GFT is nearly negligible. Interestingly, the damage to cellular DNA as revealed by the comet assay, indicates that DMT-GFT has the highest photogenotoxic potential; moreover, the DNA damage induced by this metabolite is hardly repaired by the cells after a time recovery of 18 h. This could ultimately result in mutagenic and carcinogenic effects. These results could aid oncologists when prescribing TKIs to cancer patients and, thus, establish the conditions of use and recommend photoprotection guidelines.
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Keywords

4 defluoro 4 hydroxygefitinibAnticancer drugArticleAssayCarcinogenicityCell deathCell dnaCell viabilityCellsChlorpromazineComet assayControlled studyCytotoxicityDemorpholinopropylgefitinibDna damageDrug metaboliteDrug transformationErlotinibGefitinibGenotoxicityHacat cell lineHumanHuman cellIc50In vitro studyIn-vitroKeratinocyteKetoprofenLipid peroxidationMetabolismMutagenicityNorgefitinibPhotodamage to biomoleculesPhotosensitivityPhotosensitizationPhotosensitized reactionPhototoxicityThiobarbituric acid reactive substanceTyrosine kinaseTyrosine kinase inhibitorUltraviolet a radiationUnclassified drug

Quality index

Bibliometric impact. Analysis of the contribution and dissemination channel

Independientemente del impacto esperado determinado por el canal de difusión, es importante destacar el impacto real observado de la propia aportación.

Según las diferentes agencias de indexación, el número de citas acumuladas por esta publicación hasta la fecha 2026-04-02:

  • WoS: 3
  • Scopus: 3
  • Europe PMC: 2
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Impact and social visibility

From the perspective of influence or social adoption, and based on metrics associated with mentions and interactions provided by agencies specializing in calculating the so-called "Alternative or Social Metrics," we can highlight as of 2026-04-02:

  • The use, from an academic perspective evidenced by the Altmetric agency indicator referring to aggregations made by the personal bibliographic manager Mendeley, gives us a total of: 10.
  • The use of this contribution in bookmarks, code forks, additions to favorite lists for recurrent reading, as well as general views, indicates that someone is using the publication as a basis for their current work. This may be a notable indicator of future more formal and academic citations. This claim is supported by the result of the "Capture" indicator, which yields a total of: 10 (PlumX).

With a more dissemination-oriented intent and targeting more general audiences, we can observe other more global scores such as:

  • The Total Score from Altmetric: 2.
  • The number of mentions on the social network X (formerly Twitter): 3 (Altmetric).

It is essential to present evidence supporting full alignment with institutional principles and guidelines on Open Science and the Conservation and Dissemination of Intellectual Heritage. A clear example of this is:

  • The work has been submitted to a journal whose editorial policy allows open Open Access publication.
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Leadership analysis of institutional authors

There is a significant leadership presence as some of the institution’s authors appear as the first or last signer, detailed as follows: First Author (El Ouardi, M) and Last Author (Andreu Ros, María Inmaculada).

the authors responsible for correspondence tasks have been Marín García, Mª Luisa and Andreu Ros, María Inmaculada.

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Awards linked to the item

This research was funded by the MICINN (Grant PID2020-115010RB-I00 funded by MCIN/AEI/10.13039/501100011033, RYC-2015-17737 and FPU predoctoral fellowship for ME.).
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