Gemcitabine

Gemcitabine is an inhibitor of DNA synthesis [1].

DNA synthesis is a natural creation of deoxyribonucleic acid (DNA) molecules and plays an important role in cell growth.

Gemcitabine is an active chemotherapeutic agents that disrupt DNA replication. In tumor cells, gemcitabine activated checkpoint kinase 2 (Chk2) and ataxia-telangiectasia mutated kinase (ATM), which regulated apoptosis, DNA repair and cell-cycle arrest. Also, gemcitabine activated the Rad9-Hus1-Rad1 complex and the protein kinases ATM and ATR and checkpoint kinase 1 (Chk1), which blocked cell-cycle progression and influence DNA repair [1]. Gemcitabine is a DNA synthesis inhibitor with anti-tumor activity. In human osteosarcoma cell lines HOS and MG63, gemcitabine inhibited DNA synthesis and induced apoptosis [2].

In C3H mice inoculated with murine osteosarcoma cell line LM8, gemcitabine induced cell apoptotics and reduced the size of primary tumor. Also, it inhibited metastatic lesions in the lung [2]. In C57Bl/6 mice infected with LP-BM5 murine leukemia virus, gemcitabine significantly inhibited disease progression. Also, gemcitabine reduced spleen size, provirus levels and plasma IgM [3].

References:
[1].  Karnitz LM, Flatten KS, Wagner JM, et al. Gemcitabine-induced activation of checkpoint signaling pathways that affect tumor cell survival. Mol Pharmacol, 2005, 68(6): 1636-1644.
[2].  Ando T, Ichikawa J, Okamoto A, et al. Gemcitabine inhibits viability, growth, and metastasis of osteosarcoma cell lines. J Orthop Res, 2005, 23(4): 964-969.
[3].  Clouser CL, Holtz CM, Mullett M, et al. Analysis of the ex vivo and in vivo antiretroviral activity of gemcitabine. PLoS One, 2011, 6(1): e15840.

Comparison of Efficacy of Adjuvant MEC (Methotrexate, Epirubicin and Cisplatin) and GC (Gemcitabine and Cisplatin) in Advanced Upper Tract Urothelial Carcinoma.[Pubmed:28373455]

Anticancer Res. 2017 Apr;37(4):1875-1883.

AIM: To evaluate the efficacy of methotrexate, epirubicin and cisplatin (MEC) or Gemcitabine and cisplatin (GC) as adjuvant chemotherapy in advanced upper tract urothelium carcinoma (UTUC). PATIENTS AND METHODS: From 2002 January to 2008 December, a total of 70 patients with advanced UTUC received radical nephroureterctomy at our Institute with MEC and GC as adjuvant chemotherapy. Disease-free survival (DFS), cancer-specific survival (CSS) and overall survival (OS) among the two groups were evaluated. RESULTS: The MEC (n=30) and GC group (n=40) were compared and showed no significant differences in DFS (p=0.859), CSS (p=0.722) and OS (p=0.691). Positive lymph nodes, preoperative creatinine >1.5, old age, a high ECOG state and low BMI are all the independent risk factors of poor prognosis in advanced UTUC. CONCLUSION: In patients with UTUC, MEC has a non-inferior efficacy to GC in consideration of cancer recurrence, cancer-specific survival and overall survival.

Gemcitabine Conjugated Chitosan and Double Antibodies (Abc-GC-Gemcitabine Nanoparticles) Enhanced Cytoplasmic Uptake of Gemcitabine and Inhibit Proliferation and Metastasis In Human SW1990 Pancreatic Cancer Cells.[Pubmed:28366930]

Med Sci Monit. 2017 Apr 3;23:1613-1620.

BACKGROUND Pancreatic cancer is considered a chemoresistant neoplasm with extremely dismal prognosis and Gemcitabine treatment is associated with many side effects and poor overall survival. The study aimed at developing a new nanobioconjugate, which specifically delivered Gemcitabine and anti-EGFR antibody into pancreatic cancer cells. MATERIAL AND METHODS The novel nanodrug is based on chitosan platform, which is non-toxic, biocompatibility and biodegradable. We measured the effects of proliferation and metastasis on SW1990 by CCK-8 assay, colony formation assay, wound healing assay and Transwell assay. The expression of related proteins were evaluated by Western blot. RESULTS We synthesized Abc-GC-Gemcitabine nanoparticles successfully with the encapsulation rate of nanobioconjugates was 91.63% and the drug loadings was 9.97%. Both GC-Gemcitabine microspheres solution (GC group) and Abc-GC-Gemcitabine microspheres solution (Abc group) inhibited cells proliferation, colony formation, migration and invasion in SW1990 cells dramatically. Moreover, Abc-GC-Gemcitabine microspheres expressed more significant inhibited action than GC-Gemcitabine microspheres efficiently CONCLUSIONS Our data suggested that Abc-GC-Gemcitabine nanoparticles could have promising potential in treating metastasized and chemoresistant pancreatic cancer by enhancing the drug efficacy and minimizing off target effects.

Long-term results and recurrence patterns from SCALOP: a phase II randomised trial of gemcitabine- or capecitabine-based chemoradiation for locally advanced pancreatic cancer.[Pubmed:28376080]

Br J Cancer. 2017 May 9;116(10):1264-1270.

BACKGROUND: SCALOP, a randomised, phase II trial, tested the activity and safety of Gemcitabine (GEM)-based and capecitabine (CAP)-based chemoradiation (CRT) for locally advanced pancreatic cancer (LAPC). Here we present the long-term outcomes. METHODS: Eligibility: histologically proven LAPC 7 cm. Following 12 weeks of induction GEMCAP chemotherapy (three cycles: GEM 1000 mg m(-2) days 1, 8, 15; CAP 830 mg m(-2) days 1-21 q28 days) patients with stable/responding disease, tumour 6 cm, and WHO Performance Status 0-1 were randomised to receive one cycle GEMCAP followed by CAP (830 mg m(-2) b.d. on weekdays only) or GEM (300 mg m(-2) weekly) with radiation (50.4 Gy per 28 fractions). RESULTS: One-hundred fourteen patients (28 UK centres) were registered between 24 December 2009 and 25 October 2011, and 74 were randomised (CAP-RT=36; GEM-RT=38). At the time of this analysis, 105 of the 114 patients had died and the surviving 9 patients had been followed up for a median of 10.9 months (IQR: 2.9-18.7). Updated median OS was 17.6 months (95% CI: 14.6-22.7) in the CAP-CRT arm and 14.6 months (95% CI: 11.1-16.0) in the GEM-CRT arm (intention-to-treat adjusted hazard ratio (HR): 0.68 (95% CI: 0.38-1.21, P=0.185)); median progression-free survival (PFS) was 12.0 months (95% CI: 10.0-15.2) in the CAP-CRT arm and 10.4 months (95% CI: 8.8-12.7) in the GEM-CRT arm (intention-to-treat adjusted HR: 0.60 (95% CI: 0.32-1.14, P=0.120)). In baseline multivariable model, age 65 years, better performance status, CA19.9<613 IU l(-1), and shorter tumour diameter predicted improved OS. CAP-CRT, age 65 years, better performance status, CA19.9 <46 IU ml(-1) predicted improved OS and PFS in the pre-radiotherapy model. Nine-month PFS was highly predictive of OS. CONCLUSIONS: CAP-CRT remains the superior regimen. SCALOP showed that patients with CA19.9 <46 IU ml(-1) after induction chemotherapy are more likely to benefit from CRT.

Nab-Paclitaxel and Gemcitabine in Advanced Pancreatic Cancer: The One-year Experience of the National Cancer Institute of Naples.[Pubmed:28373469]

Anticancer Res. 2017 Apr;37(4):1975-1978.

BACKGROUND: Pancreas adenocarcinoma is the sixth cause of cancer-related death worldwide with an increasing mortality in the Western countries. Recently, the association between nab-paclitaxel (nab-P) and Gemcitabine (GEM) has significantly improved progression-free and overall survival. PATIENTS AND METHODS: Patients affected by metastatic pancreas adenocarcinoma were treated at the Department of Abdominal Oncology of the National Cancer Institute of Naples from July 2015 to July 2016 with nab-P at 125 mg per square meter of body-surface area followed by GEM at 1,000 mg per square meter on days 1, 8 and 15 every 4 weeks. Computed tomography (CT) was performed every three months of therapy. Toxicity was graded with National Cancer Institute-Common Toxicity Criteria (NCI-CTC) v4.0. Objective responses were evaluated with Response Evaluation Criteria in Solid Tumors (RECIST). Analysis of time-to-progression is only descriptive. Pain was evaluated with a visual analogue scale (VAS). RESULTS: Twenty-three patients were treated. Median age was 67 years (range=45-81); 8 patients were >/=70 years old. Performance status (PS) Eastern Cooperative Oncology Group (ECOG) was 2 in 8 patients, 1 in 10 and 0 in 5. Twelve patients presented with diffuse hepatic metastases, 4 with carcinosis, 7 with more than one organ involvement. Nab-P was reduced at 100 mg per square meter in all patients. The most common G3/G4 adverse events were neutropenia (13.0% G4, 8.6% G3; none was febrile), neuropathy (30.4% G3) and asthenia (G3 17.3%). The disease control rate was 43.4% (partial response+stable disease (PR+SD) 10/23). The median time-to-progression was 7.9 months (95% confidence interval (CI)=5.8-11.2). After three months of therapy the PS improved in 14 patients, as well as pain in 18 patients. CONCLUSION: We present an experience with nab-P and GEM association in a series with poor PS and highly metastatic disease relatively to a previous randomized study. The schedule is feasible, with nab-P at 100 mg per square meter achieving a good disease control rate, as well as a clinical benefit.

Gemcitabine (LY 188011) is a pyrimidine nucleoside analog antimetabolite and an antineoplastic agent. Gemcitabine inhibits DNA synthesis and repair, resulting in autophagyand apoptosis. Gemcitabine inhibits the growth of BxPC-3, Mia Paca-2, PANC-1, PL-45 and AsPC-1 cells with IC50s of 37.6 nM, 42.9 nM, 92.7 nM, 89.3 nM and 131.4 nM, respectively.

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