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Clinical application and drug resistance mechanism of gemcitabine

Xuanrui Zhang1, Bing Qi1, Jing Chen1

  • 1College of Life Sciences, North China University of Science and Technology, Tangshan, Hebei, China.

Frontiers in Cell and Developmental Biology
|November 26, 2025
PubMed

Insights

Gemcitabine resistance in cancer is driven by metabolic issues, DNA repair, and tumor microenvironment changes. New strategies include advanced drug delivery, combination therapies, and precision medicine for better treatment outcomes.

Area of Science:

  • Oncology
  • Pharmacology
  • Biochemistry

Background:

  • Gemcitabine, a nucleoside analog, shows broad-spectrum antitumor activity by inhibiting DNA synthesis.
  • Clinical efficacy of gemcitabine is significantly hampered by the development of drug resistance.
  • Understanding gemcitabine resistance mechanisms is crucial for improving cancer treatment.

Purpose of the Study:

  • To systematically review the multifaceted mechanisms underlying gemcitabine drug resistance.
  • To explore innovative therapeutic strategies, including novel drug delivery systems and combination therapies.
  • To highlight the potential of cutting-edge technologies for personalized gemcitabine treatment.

Main Methods:

  • Review of existing literature on gemcitabine resistance mechanisms.
  • Analysis of metabolic abnormalities (e.g., deoxycytidine kinase downregulation, hENT1 deficiency).
  • Investigation of enhanced DNA repair pathways (e.g., RRM1/RRM2 overexpression) and tumor microenvironment factors.

Main Results:

  • Gemcitabine resistance is associated with metabolic alterations, increased DNA repair capacity, and immunosuppressive tumor microenvironments.
  • New drug delivery systems (liposomes, albumin nanoparticles) and combination therapies (targeted drugs, immune checkpoint inhibitors) show promise.
  • Single-cell sequencing and AI-driven drug sensitivity prediction offer new avenues for precision oncology.

Conclusions:

  • Addressing gemcitabine resistance requires a comprehensive approach targeting metabolic, DNA repair, and microenvironment pathways.
  • Future directions involve integrating advanced drug delivery, combination therapies, and precision medicine tools.
  • A proactive "prevention-monitoring-intervention" system utilizing multi-omics biomarkers and integrated medicine is proposed for dynamic cancer management.
Keywords:
combination therapygemcitabineprecision medicineresistance mechanismtumor microenvironment

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