Biweekly Gemcitabine/Nab-Paclitaxel as First-line Treatment for Advanced Pancreatic Cancer

Kokkali, Stefania; Tripodaki, Elli; Drizou, Maria; Stefanou, Dimitra; Magou, Elpida; Zylis, Dimosthenis; Kapiris, Matthaios; Nasi, Despoina; Georganta, C.; Ardavanis, Alexandros

doi:10.21873/invivo.11289

Cited by 6 publications

(4 citation statements)

References 21 publications

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“…Ketolysis is an avenue for cells to obtain energy when hungry or stressed (31). OXCT1 is a key enzyme in ketone body metabolism that catalyzes the first and rate-determining step of ketolysis (12,24,(32)(33)(34). It promotes ketone metabolism, thereby increasing ATP production.…”

Section: Discussionmentioning

confidence: 99%

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OXCT1 Enhances Gemcitabine Resistance Through NF-κB Pathway in Pancreatic Ductal Adenocarcinoma

Ding

Liu

et al. 2021

Front. Oncol.

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BackgroundPancreatic ductal adenocarcinoma (PDAC) is a type of malignant tumor with a five-year survival rate of less than 10%. Gemcitabine (GEM) is the most commonly used drug for PDAC chemotherapy. However, a vast majority of patients with PDAC develop resistance after GEM treatment.MethodsWe screened for GEM resistance genes through bioinformatics analysis. We used immunohistochemistry to analyze 3-oxoacid CoA-transferase 1 (OXCT1) expression in PDAC tissues. The survival data were analyzed using the Kaplan–Meier curve. The expression levels of the genes related to OXCT1 and the NF-κB signaling pathway were quantified using real−time quantitative PCR and western blot analyses. We performed flow cytometry to detect the apoptosis rate. Colony formation assay was performed to measure the cell proliferation levels. The cytotoxicity assays of cells were conducted using RTCA. The downstream pathway of OXCT1 was identified via the Gene Set Enrichment Analysis. Tumor growth response to GEM in vivo was also determined in mouse models.ResultsBioinformatics analysis revealed that OXCT1 is the key gene leading to GEM resistance. Patients with high OXCT1 expression exhibited short relapse-free survival under GEM treatment. OXCT1 overexpression in PDAC cell lines exerted inhibitory effect on apoptosis after GEM treatment. However, the down-regulation of OXCT1 showed the opposite effect. Blocking the NF-κB signaling pathway also reduced GEM resistance of PDAC cells. Tumor growth inhibition induced by GEM in vivo reduced after OXCT1 overexpression. Moreover, the effect of OXCT1 on GEM refractoriness in PDAC cell lines was reversed through using an NF-κB inhibitor.ConclusionOXCT1 promoted GEM resistance in PDAC via the NF-κB signaling pathway both in vivo and in vitro. Our results suggest that OXCT1 could be used as a potential therapeutic target for patients with PDAC.

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Section: Discussionmentioning

confidence: 99%

“…Therefore, at present, chemotherapy is an important means for the treatment of advanced PDAC (11). However, considerable drug resistance against gemcitabine (GEM), which is used as the first-line treatment for PDAC (12), develops after a certain period of its use. This gives rise to great challenges for PDAC treatment.…”

Section: Introductionmentioning

confidence: 99%

OXCT1 Enhances Gemcitabine Resistance Through NF-κB Pathway in Pancreatic Ductal Adenocarcinoma

Ding

Liu

et al. 2021

Front. Oncol.

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“…To our knowledge, the largest prospective clinical cohort study published so far [ 19 ], including 1174 patients with advanced unresectable PAC, showed median PFS of 4.6 months with first-line gemcitabine monotherapy, 5.6 months with NPG, and 6.3 months with FOLFIRINOX, and a median OS of 6.8 months with first-line gemcitabine monotherapy, 9.1 months with NPG, and 11.3 months with FOLFIRINOX, which are very similar to the respective large randomized trials [ 7 – 9 ]. Also, a Greek group reported a median survival of 10 months with a modified biweekly NPG regimen in patients treated for advanced PAC in years 2014–2017 [ 20 ].…”

Section: Discussionmentioning

confidence: 99%

Observational Study of Clinical Practice in Patients with Pancreatic Adenocarcinoma in Greece

Papaxoinis

Athanasiadis

Sgouros

et al. 2020

Journal of Oncology

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Background. During the last decade, significant improvement was made in systemic therapy of pancreatic adenocarcinoma (PAC). The impact of this progress in everyday clinical practice has not been fully described yet. The aim of the study was to investigate the pattern followed by Greek Medical Oncologists regarding the treatment of patients with PAC. Methods. This observational, noninterventional multicenter study recorded clinical data from the files of 200 active patients (alive and under treatment or follow-up) for a two-year period (November 2015 until November 2017) from 20 oncology centers around Greece. Results. In total, 51 (25.5%) patients underwent radical surgical resection of PAC, and 40 (78.4%) of them received adjuvant and 1 (2.0%) neoadjuvant chemotherapy. The median time to recurrence was 7.9 months, and median overall survival (OS), 20.2 months. First-line chemotherapy was administered to 193 (96.5%) patients. The majority of patients were treated with the combination of nab-paclitaxel-gemcitabine (NPG), 5-fluorouracil, leucovorin, irinotecan, oxaliplatin (FOLFIRINOX), or gemcitabine monotherapy. Of them, 39.5% responded to the treatment. Median OS and PFS were 14.1 months and 7.0 months, respectively. Second-line treatment was administered to 112 patients. The majority received NPG, FOLFIRINOX/capecitabine, oxaliplatin, irinotecan (CAPOXIRI), or 5-fluorouracil, leucovorin, oxaliplatin (FOLFOX)/capecitabine, oxaliplatin (CAPOX). Median OS with second-line treatment was 8.6 months, and median PFS, 5.5 months. The most common chemotherapy sequences were NPG as first-line followed by FOLFIRINOX/CAPOXIRI as second-line, NPG followed by FOLFOX/CAPOX, NPG followed by other regimens, and FOLFIRINOX/CAPOXIRI followed by NPG. Conclusion. This study described the significant improvement in prognosis of PAC patients receiving palliative chemotherapy and the relatively high rate of receipt of second-line chemotherapy, according to real-world data. However, due to the nonrandomized nature of the study, any comparison between different chemotherapy regimens should be regarded with caution.

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“…Gemcitabine (GEM, also known as Gemzar) is a pyrimidine nucleoside antimetabolite drug used as monotherapy or in combination with chemotherapeutic agents or radiotherapy to treat pancreatic, ovarian, breast, and non-small-cell lung cancers . The uptake mechanisms of GEM include nucleoside transporter (NT) proteins such as human equilibrative nucleoside transporter 1 (hENT1) and human concentrative nucleoside transporter (hCNT) 1 and 3 proteins to permeate through the plasma membrane .…”

Section: Introductionmentioning

confidence: 99%

Integrin-Mediated Targeted Cancer Therapy Using c(RGDyK)-Based Conjugates of Gemcitabine

et al. 2021

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Metrics & MoreArticle Recommendations * sı Supporting Information ABSTRACT: c(RGDyK)-based conjugates of gemcitabine (GEM) with the carbonate and carbamate linkages in the 6-OH group of GEM were synthesized for the targeted delivery of GEM to integrin α v β 3 , overexpressing cancer cells to increase the stability as well as the tumor delivery of GEM and minimize common side effects associated with GEM treatment. Competitive cell uptake experiments demonstrated that conjugate TC113 could be internalized by A549 cells through integrin α v β 3 . Among the synthesized conjugates, TC113 bearing the carbamate linker was stable in human plasma and was further assessed in an in vivo pharmacokinetic study. TC113 appeared to be relatively stable, releasing GEM slowly into blood, while it showed potent antiproliferative properties against WM266.4 and A549 cells. The encouraging data presented in this study with respect to TC113 provide a promising keystone for further investigation of this GEM conjugate with potential future clinical applications.

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Biweekly Gemcitabine/Nab-Paclitaxel as First-line Treatment for Advanced Pancreatic Cancer

Abstract: Biweekly gemcitabine/nab-paclitaxel seems to have a similar safety and efficacy profile as the original regimen.

Cited by 6 publications

References 21 publications

OXCT1 Enhances Gemcitabine Resistance Through NF-κB Pathway in Pancreatic Ductal Adenocarcinoma

OXCT1 Enhances Gemcitabine Resistance Through NF-κB Pathway in Pancreatic Ductal Adenocarcinoma

Observational Study of Clinical Practice in Patients with Pancreatic Adenocarcinoma in Greece

Integrin-Mediated Targeted Cancer Therapy Using c(RGDyK)-Based Conjugates of Gemcitabine

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