gemcitabine

Overview

Gemcitabine (2’,2’-difluoro-2’-deoxycytidine, dFdC) is a deoxycytidine analog incorporated into DNA during replication, leading to chain termination and apoptosis. It also inhibits ribonucleotide reductase (RRM1). Gemcitabine is a backbone agent in pancreatic, biliary, urothelial, soft-tissue sarcoma, and lung-cancer regimens.

Evidence in the corpus

  • PDAC standard of care: gemcitabine combined with nab-paclitaxel is one of the two reference first-line regimens (vs folfirinox) in metastatic pancreatic adenocarcinoma. PMID:39214094, PMID:39753968
  • Sarcoma PDTO sensitivity: tested in the UCLA pediatric/adult sarcoma patient-derived organoid pharmacotyping screen — distinct subtype-specific response patterns observed across LMS, RMS, SYNS, and other sarcomas. PMID:39305899
  • Urothelial cancer (mUC): gemcitabine + cisplatin (GC) is the standard cytotoxic backbone in metastatic urothelial carcinoma; the CALGB 90601 cohort profiled cfDNA dynamics under GC ± bevacizumab. PMID:40256659
  • 143 metastatic gallbladder carcinoma patients received gemcitabine/platinum (mostly cisplatin) as first-line chemotherapy among 233 GBC cases profiled with MSK-IMPACT at MSK (2014–2021) PMID:36228155
  • Combined with saridegib (IPI-926, Smoothened inhibitor) in a co-clinical PAAD trial (NCT01130142); despite positive preclinical signal in GEM mice, the human phase II arm was halted for inferior survival, illustrating risks of preclinical-to-clinical translation without chronic-dosing validation PMID:23999436.
  • Cisplatin + gemcitabine is the standard chemotherapy backbone for R/M NPC; multiple anti-PD-1 combination trials add ICIs to this doublet PMID:24952746
  • Standard first-line therapy for advanced CCA (IHCH/EHCH/CHOL) in combination with cisplatin, with durvalumab addition showing incremental benefit; molecular profiling at diagnosis recommended per ESMO guidelines before targeted therapy sequencing PMID:25526346
  • Referenced as part of standard chemotherapy backbones for CCA treatment in the context of novel combination strategies with targeted agents such as futibatinib PMID:25608663
  • Antimetabolite; contraindicated throughout pregnancy (teratogenic) in young-onset NSCLC patients despite being a standard component of first-line NSCLC regimens PMID:27346245
  • Cisplatin + gemcitabine (neoadjuvant/first-line) administered in the WashU urothelial carcinoma WES cohort (n=32 patients, 72 tumors); 72 tumors from 32 patients profiled by WES showed only 28.4% shared mutations between matched pre- and post-chemotherapy samples, with gemcitabine-cisplatin driving clonal selection for L1CAM/integrin-pathway and APOBEC3A-enriched clones PMID:27749842
  • In the multi-institutional Phase II (Herman et al, n=49), gemcitabine (up to 3 weekly doses) combined with 33 Gy/5 fx SBRT achieved 79% 1-year local control and 13.9-month median OS in unresectable locally advanced PAAD, with only 2% acute and 6% late grade 3+ GI toxicity — the reference standard for SBRT-concurrent chemotherapy in pancreatic cancer PMID:27826200
  • Used in combination with docetaxel (16 cycles) in EWSR1::BEND2 bladder sarcoma after progression and nephrotoxicity on ISG/SSG IV protocol; disease approximately stable on docetaxel + gemcitabine; patient died at 26 months post-diagnosis PMID:28199314.

Resistance mechanisms

  • Resistance is associated with high RRM1 expression, low dCK expression, and altered nucleotide-pool homeostasis.

Cancer types (linked)

Sources

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This page was processed by crosslinker on 2026-05-14. - PMID:36228155

This page was processed by crosslinker on 2026-05-14. - PMID:23999436

This page was processed by crosslinker on 2026-05-14. - PMID:24952746

This page was processed by crosslinker on 2026-05-14. - PMID:25526346

This page was processed by crosslinker on 2026-05-14. - PMID:25608663

This page was processed by crosslinker on 2026-05-14. - PMID:27346245 - PMID:27749842 — Faltas et al. 2016, Nature Genetics. WashU UC WES cohort; cisplatin + gemcitabine clonal evolution, APOBEC3A enrichment, and L1CAM/integrin clonal selection. - PMID:27826200 — Tchelebi et al. 2016, Semin Radiat Oncol. SBRT in pancreatic cancer review; gemcitabine + SBRT 33 Gy/5 fx reference regimen (79% local control, 13.9 mo median OS).

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