Clinical-benefit response in advanced non-small-cell lung cancer: A multicentre prospective randomised phase III study of single agent gemcitabine versus cisplatin–vindesine

Vansteenkiste, Johan; Vandebroek, J.; Nackaerts, Kristiaan; Weynants, P.; Valcke, Y.; Verresen, D.; Devogelaere, R.; Mariën, Steven; Humblet, Yves; Dams, N L

doi:10.1023/a:1012208711013

Cited by 95 publications

(45 citation statements)

References 31 publications

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“…Gemcitabine (2V ,2V -difluorodeoxycytidine, dFdC) is a nucleoside analogue that shows activity against solid tumors and hematologic malignancies both as a single agent (1,2) and in combination with other chemotherapeutic agents (3,4). The cellular metabolism of gemcitabine is similar to that of normal deoxyribonucleosides (5).…”

Section: Introductionmentioning

confidence: 99%

Increased expression of the large subunit of ribonucleotide reductase is involved in resistance to gemcitabine in human mammary adenocarcinoma cells

Jordheim

Guittet

Lepoivre

et al. 2005

Molecular Cancer Therapeutics

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Resistance to cytotoxic nucleoside analogues is a major problem in cancer treatment. The cellular mechanisms involved in this phenomenon have been studied for several years, and some factors have been identified. However, this resistance seems to be multifactorial and more studies are needed to gain better insight into this domain. For this purpose, we developed a gemcitabine-resistant cell line (MCF7 1K) from the human mammary adenocarcinoma MCF7 strain by prolonged exposure to gemcitabine in vitro. MCF7 1K cells are highly resistant to gemcitabine (533-fold) and cross-resistance is observed with araC (47-fold), triapine (14-fold), and hydroxyurea (6.7-fold). Quantitative real-time reverse transcription-PCR and Western blot analysis showed an increase in the gene and protein expression of the large subunit of ribonucleotide reductase, R1. Ribonucleotide reductase activity was also significantly increased in the gemcitabine-resistant cells. Study of genomic DNA showed 12-fold increase in R1 gene dosage in MCF7 1K cells. In contrast, the gene and protein expression of the small subunit of ribonucleotide reductase, R2, were not modified in this cell line. These results show that gemcitabine resistance can be associated with genetic modifications of target genes in malignant cells, and suggest that the large subunit of human ribonucleotide reductase is involved in the cellular response to gemcitabine. [Mol Cancer Ther 2005;4(8):1268 -76]

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Section: Introductionmentioning

confidence: 99%

Increased expression of the large subunit of ribonucleotide reductase is involved in resistance to gemcitabine in human mammary adenocarcinoma cells

Jordheim

Guittet

Lepoivre

et al. 2005

Molecular Cancer Therapeutics

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“…Gemcitabine (2Ј,2Ј-difluorodeoxycytidine) is a nucleoside analogue that shows activity against hematologic malignancies and solid tumors alone (1)(2)(3)(4) or in combination with other chemotherapeutic agents (5)(6)(7). The cellular metabolism of gemcitabine is similar to that of physiologic nucleosides (reviewed in Ref.…”

Section: Introductionmentioning

confidence: 99%

Characterization of a Gemcitabine-Resistant Murine Leukemic Cell Line

Jordheim

Cros

Gouy

et al. 2004

Clinical Cancer Research

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Resistance to cytotoxic nucleoside analogues is a major problem in cancer treatment. The cellular mechanisms involved in this phenomenon have been studied for several years, and some factors have been identified. Various strategies to overcome resistance have been suggested, but none has yet shown efficacy in vivo. We developed a gemcitabineresistant cell line (L1210 10K) from the murine leukemic L1210 strain (L1210 wt) by continuous exposure to increasing concentrations of gemcitabine. L1210 10K is highly resistant to gemcitabine (14,833-fold), 1-␤-D-arabinofuranosylcytosine (ara-C; 2,100-fold), troxacitabine (>200-fold), and cladribine (160-fold) and slightly resistant to trimidox (7.22-fold), but does not display cross-resistance to fludarabine or nonnucleoside anticancer drugs. Deoxycytidine kinase mRNA was not detected by quantitative real-time reverse transcription-PCR in L1210 10K cells, whereas expression of thymidine kinase 1 and ribonucleotide reductase subunit R2 gene was moderately reduced. L1210 10K cells also demonstrated in vivo resistance to nucleoside analogues: gemcitabine-or ara-C-treated mice carrying L1210 10K had significantly shorter survival than gemcitabine-or ara-C-treated mice carrying L1210 wt (P < 0.05). UA911, a mononucleotide prodrug (pronucleotide) of ara-C was found to significantly sensitize L1210 10K cells in vitro. These results suggest that reduced deoxycytidine kinase expression is a mechanism of resistance to gemcitabine that is relevant in vivo and can be circumvented by a prodrug approach.

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“…The details of the study have been described previously [2]. Briefly, between May 1996 and April 1999, 169 patients with advanced NSCLC with Karnofsky performance status o60% were randomised to either single agent therapy with the ''new drug'' gemcitabine or cisplatin-vindesine, the most commonly used regimen in Belgium at that time.…”

Section: Study Databasementioning

confidence: 99%

“…The outcome data on CB response and survival were collected for all patients enrolled in the described prospective multicentre randomised trial [2]. Patients were enrolled at different institutions throughout Belgium, both academic and general hospitals.…”

Section: Cost-effectiveness and Cost-utility Evaluationmentioning

confidence: 99%

Cost–utility analysis of chemotherapy in symptomatic advanced nonsmall cell lung cancer

Dooms

Lievens²,

Vansteenkiste³

2006

Eur Respir J

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When using chemotherapy in patients with a short life expectancy, outcomes such as symptom improvement or clinical benefit receive increasing attention. Outcomes of subjective benefit to the patient can be rated as a utility in order to perform health economic analyses and comparisons with other treatment conditions. A cost-utility analysis has been performed alongside a prospective randomised clinical trial comparing single agent gemcitabine to cisplatin-based chemotherapy in symptomatic advanced nonsmall cell lung cancer patients.Global quality of life as well as resource utilisation data were collected during first-line chemotherapy for both treatment arms. Incremental costs, utilities and cost-utility ratio were calculated.Per patient, an incremental cost of J1,522 was obtained for gemcitabine compared to cisplatinvindesine, mainly as a consequence of the direct cost of the cytotoxic drugs. When combined with utilities, this resulted in an incremental cost-utility ratio for gemcitabine of J13,836 per qualityadjusted life year gained.In conclusion, although the least expensive strategy is cisplatin-vindesine, the greater clinical benefit of gemcitabine, resulting in an acceptable incremental cost-utility ratio as compared with other healthcare interventions, balances its higher cost. The gains in subjective outcome achieved with palliative chemotherapy are critical from both a clinical and a health economic point of view.

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Clinical-benefit response in advanced non-small-cell lung cancer: A multicentre prospective randomised phase III study of single agent gemcitabine versus cisplatin–vindesine

Cited by 95 publications

References 31 publications

Increased expression of the large subunit of ribonucleotide reductase is involved in resistance to gemcitabine in human mammary adenocarcinoma cells

Increased expression of the large subunit of ribonucleotide reductase is involved in resistance to gemcitabine in human mammary adenocarcinoma cells

Characterization of a Gemcitabine-Resistant Murine Leukemic Cell Line

Cost–utility analysis of chemotherapy in symptomatic advanced nonsmall cell lung cancer

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