Beyond Pancreatic Cancer: Irinotecan and Gemcitabine in Solid Tumors and Hematologic Malignancies

Lima, Caio Max S. Rocha; Urbanic, James J.; Lal, Asheesh; Kneuper-Hall, Rayna; Brunson, Chris Y.; Green, Mark R.

doi:10.1016/s0093-7754(01)80007-5

Cited by 8 publications

(3 citation statements)

References 44 publications

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“…We used gemcitabine, a well known chemotherapeutic agent used to treat several tumours, including pancreatic cancer [36], to modulate the viability of the cells contained in the different P k . All P k were prepared simultaneously on the same morning and gemcitabine was tested at scalar concentrations of 5 μM (flask P2 ), 50 μM ( P3 ), 500 μM ( P4 ), and 1000 μM ( P5 ).…”

Section: Methodsmentioning

confidence: 99%

Cell Counting and Viability Assessment of 2D and 3D Cell Cultures: Expected Reliability of the Trypan Blue Assay

et al. 2017

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BackgroundWhatever the target of an experiment in cell biology, cell counting and viability assessment are always computed. The Trypan Blue (TB) assay was proposed about a century ago and is still the most widely used method to perform cell viability analysis. Furthermore, the combined use of TB with a haemocytometer is also considered the standard approach to estimate cell population density. There are numerous research articles reporting the use of TB assays to compute cell number and viability of 2D and 3D cultures. However, the literature still lacks studies regarding the reliability of the TB assay in terms of assessment of its repeatability and reproducibility.MethodsWe compared the TB assay's measurements obtained by two biologists who analysed 105 different samples in double-blind for a total of 210 counts performed. We measured: (a) the repeatability of the count performed by the same operator; (b) the reproducibility of counts performed by the two operators.ResultsThere were no significant differences in the results obtained with 2D and 3D cell cultures: we estimated an approximate variability of 5% when the TB assay was used to assess the viability of the culture, and a variability of around 20% when it was used to determine the cell population density.ConclusionsThe main aim of this study was to make researchers aware of potential measurement errors when TB is used with a haemocytometer for counting and viability measurements in 2D and 3D cultures. We believe that these results can help researchers to determine whether the expected reliability of the TB assay is compliant with their applications.

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Section: Methodsmentioning

confidence: 99%

Cell Counting and Viability Assessment of 2D and 3D Cell Cultures: Expected Reliability of the Trypan Blue Assay

et al. 2017

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“…The triphosphate, once incorporated into DNA, is a potent inhibitor of DNA synthesis and induces apoptosis . GEM has significant activity against a broad spectrum of tumors when used as a single agent and can show synergistic antitumor activity in combination with DNA‐damaging agents .…”

Section: Introductionmentioning

confidence: 99%

Triplex-forming oligonucleotides targeting c-MYC potentiate the anti-tumor activity of gemcitabine in a mouse model of human cancer

et al. 2013

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Antimetabolite chemotherapy remains an essential cancer treatment modality, but often produces only marginal benefit due to the lack of tumor specificity, the development of drug resistance, and the refractoriness of slowly-proliferating cells in solid tumors. Here, we report a novel strategy to circumvent the proliferation-dependence of traditional antimetabolite-based therapies. Triplex-forming oligonucleotides (TFOs) were used to target site-specific DNA damage to the human c-MYC oncogene, thereby inducing replication-independent, unscheduled DNA repair synthesis (UDS) preferentially in the TFO-targeted region. The TFO-directed UDS facilitated incorporation of the antimetabolite, gemcitabine (GEM), into the damaged oncogene, thereby potentiating the anti-tumor activity of GEM. Mice bearing COLO 320DM human colon cancer xenografts (containing amplified c-MYC) were treated with a TFO targeted to c-MYC in combination with GEM. Tumor growth inhibition produced by the combination was significantly greater than with either TFO or GEM alone. Specific TFO binding to the genomic c-MYC gene was demonstrated, and TFO-induced DNA damage was confirmed by NBS1 accumulation, supporting a mechanism of enhanced efficacy of GEM via TFO-targeted DNA damage-induced UDS. Thus, coupling antimetabolite chemotherapeutics with a strategy that facilitates selective targeting of cells containing amplification of cancer-relevant genes can improve their activity against solid tumors, while possibly minimizing host toxicity.

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“…Nab-paclitaxel [Abraxane] is an albumin-bound cremophor-free formulation of paclitaxel, which in combination with gemcitabine, has been shown to improve overall survival compared with gemcitabine alone in patients with metastatic pancreatic cancer 4. Irinotecan, an agent that is hydrolyzed to SN-38, an inhibitor of topoisomerase I, lacks significant activity in pancreatic cancer as a single agent and the combination of irinotecan plus gemcitabine failed to improve survival compared with gemcitabine alone 5. Although irinotecan may be synergistic when used in combination with oxaliplatin and fluorouracil, its overall contribution to FOLFIRINOX might be at the cost of significant toxicity.…”

mentioning

confidence: 99%

The Brown University Oncology Group Experience With FOLFOX + Nab-paclitaxel [FOLFOX-A] for Metastatic and Locally Advanced Pancreatic, BrUOG-292 and BrUOG-318

Breakstone

Almhanna

Raufi

et al. 2022

American Journal of Clinical Oncology

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Objectives: To evaluate response rate, toxicity, and efficacy of the novel combination of nab-paclitaxel, oxaliplatin, 5-fluorouracil, and leucovorin [FOLFOX-A] in patients with advanced pancreatic ductal adenocarcinoma [PDAC]. Methods: BrUOG-292 and BrUOG-318 were two concurrently run, prospective, single-arm phase II studies evaluating FOLFOX-A as first-line therapy in patients with metastatic and locally advanced/borderline resectable PDAC respectively. The FOLFOX-A regimen consisted of 5-fluorouracil, 1200 mg/m2/d as a continuous intravenous (IV) infusion over 46 hours, leucovorin 400 mg/m2 IV, oxaliplatin 85 mg/m2 IV, and nab-paclitaxel 150 mg/m2 IV on day 1 every 14 days up to a maximum of 12 cycles. Patients with locally advanced or borderline resectable disease were permitted to stop treatment after 6 cycles and receive radiation therapy and/or surgical exploration if feasible. The primary end point was overall response rate [ORR]. Secondary end points were median progression-free survival [PFS], median overall survival [OS], and safety. Results: Seventy-eight patients with previously untreated PDAC were enrolled between June 2014 and November 2019; 76 patients were evaluable. The median follow-up was 40 months and 32 months, respectively. overall response rate was 34%. Among the patients enrolled on BrUOG-292 [48 patients], the PFS was 5 months and OS was 11 months, respectively. For those enrolled on BrUOG 318 [28 patients], the PFS was 11 months and OS was 22 months. Treatment-related toxicities included grade 3 fatigue [40%], diarrhea [14%], and neuropathy [2%]. Conclusions: The combination of FOLFOX-A has promising activity in PDAC and may represent an alternative to FOLFIRINOX when reduction of gastrointestinal toxicity is required.

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Beyond Pancreatic Cancer: Irinotecan and Gemcitabine in Solid Tumors and Hematologic Malignancies

Cited by 8 publications

References 44 publications

Cell Counting and Viability Assessment of 2D and 3D Cell Cultures: Expected Reliability of the Trypan Blue Assay

Cell Counting and Viability Assessment of 2D and 3D Cell Cultures: Expected Reliability of the Trypan Blue Assay

Triplex-forming oligonucleotides targeting c-MYC potentiate the anti-tumor activity of gemcitabine in a mouse model of human cancer

The Brown University Oncology Group Experience With FOLFOX + Nab-paclitaxel [FOLFOX-A] for Metastatic and Locally Advanced Pancreatic, BrUOG-292 and BrUOG-318

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