Phase I and pharmacologic study of weekly gemcitabine and paclitaxel in chemo-naïve patients with advanced non-small-cell lung cancer

Pas, Tommaso De; Braud, Filippo de; Danesi, Romano; Sessa, C.; Catania, Chiara; Curigliano, Giuseppe; Fogli, Stefano; Tacca, M. Del; Zampino, G.; Sbanotto, Alberto; Rocca, Antonello La; Cinieri, Saverio; Marrocco, E.; Milani, Andrea; Goldhirsch, Aron

doi:10.1023/a:1008319923516

Cited by 27 publications

(22 citation statements)

References 16 publications

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“…An IC 50 dose was not achieved in the NRP-1 transfected cells at this time point, even at supratherapeutic doses. The survival advantage was even more dramatic (Pp0.005) at 50 000 nM, a therapeutically relevant concentration within the range of the peak plasma levels achieved following bolus gemcitabine chemotherapy (De Pas et al, 2000;Fogli et al, 2002). At this dose, at least 30% more of the NRP-1-transfected cells survived compared to control cells.…”

Section: Effect Of Nrp-1 Overexpression On Susceptibility To Anoikismentioning

confidence: 92%

Overexpression of neuropilin-1 promotes constitutive MAPK signalling and chemoresistance in pancreatic cancer cells

et al. 2005

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Neuropilin-1 (NRP-1) is a novel co-receptor for vascular endothelial growth factor (VEGF). Neuropilin-1 is expressed in pancreatic cancer, but not in nonmalignant pancreatic tissue. We hypothesised that NRP-1 expression by pancreatic cancer cells contributes to the malignant phenotype. To determine the role of NRP-1 in pancreatic cancer, NRP-1 was stably transfected into the human pancreatic cancer cell line FG. Signal transduction was assessed by Western blot analysis. Susceptibility to anoikis (detachment induced apoptosis) was evaluated by colony formation after growth in suspension. Chemosensitivity to gemcitabine or 5-fluorouracil (5-FU) was assessed by MTT assay in pancreatic cancer cells following NRP-1 overexpression or siRNA-induced downregulation of NRP-1. Differential expression of apoptosis-related genes was determined by gene array and further evaluated by Western blot analysis. Neuropilin-1 overexpression increased constitutive mitogen activated protein kinase (MAPK) signalling, possibly via an autocrine loop. Neuropilin-1 overexpression in FG cells enhanced anoikis resistance and increased survival of cells by 430% after exposure to clinically relevant levels of gemcitabine and 5-FU. In contrast, downregulation of NRP-1 expression in Panc-1 cells markedly increased chemosensitivity, inducing 450% more cell death at clinically relevant concentrations of gemcitabine. Neuropilin-1 overexpression also increased expression of the antiapoptotic regulator, MCL-1. Neuropilin-1 overexpression in pancreatic cancer cell lines is associated with (a) increased constitutive MAPK signalling, (b) inhibition of anoikis, and (c) chemoresistance. Targeting NRP-1 in pancreatic cancer cells may downregulate survival signalling pathways and increase sensitivity to chemotherapy.

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Section: Effect Of Nrp-1 Overexpression On Susceptibility To Anoikismentioning

confidence: 92%

Overexpression of neuropilin-1 promotes constitutive MAPK signalling and chemoresistance in pancreatic cancer cells

et al. 2005

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“…The worst nonhematological toxicity was grade 3 elevation in serum transaminases and grade 2 neurosensory toxicity in 8% and 5% of cycles, respectively. This study demonstrated that the weekly administration of paclitaxel and gemcitabine is well tolerated, and has promising antitumor activity in NSCLC at the recommended dose of 100 mg/m 2 paclitaxel and 1500 mg/m 2 gemcitabine (De Pas et al, 2000).…”

Section: Genetics and Drug Response In Non-small Cell Lung Cancermentioning

confidence: 70%

“…patients with stage III-IV NSCLC demonstrated objective responses at all dose levels, with an overall response rate of 43% in 30 evaluable patients (De Pas et al, 2000). Hematological toxicity included grade 4 neutropenia, grade 3 thrombocytopenia, and febrile neutropenia.…”

Section: Genetics and Drug Response In Non-small Cell Lung Cancermentioning

confidence: 99%

Pharmacogenetics of Anticancer Drug Sensitivity in Non-Small Cell Lung Cancer

et al. 2003

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“…The interaction between paclitaxel and gemcitabine has extensively been studied [15][16][17][18]. Some investigators have reported no pharmacokinetic interactions between the two drugs.…”

Section: Introductionmentioning

confidence: 99%

Intra-patient alternated dose escalation of paclitaxel and gemcitabine versus paclitaxel followed by fixed dose rate infusion of gemcitabine in fit elderly non-small cell lung cancer patients

et al. 2007

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Phase I and pharmacologic study of weekly gemcitabine and paclitaxel in chemo-naïve patients with advanced non-small-cell lung cancer

Abstract: The weekly administration of GEM and TAX is very well tolerated, and has shown promising antitumor activity in NSCLC. In view of the cumulative toxicity and of the pharmacokinetic profile of GEM, doses of 1500 mg/m2 of GEM and 100 mg/m2 of TAX are recommended for phase II studies.

Cited by 27 publications

References 16 publications

Overexpression of neuropilin-1 promotes constitutive MAPK signalling and chemoresistance in pancreatic cancer cells

Overexpression of neuropilin-1 promotes constitutive MAPK signalling and chemoresistance in pancreatic cancer cells

Pharmacogenetics of Anticancer Drug Sensitivity in Non-Small Cell Lung Cancer

Intra-patient alternated dose escalation of paclitaxel and gemcitabine versus paclitaxel followed by fixed dose rate infusion of gemcitabine in fit elderly non-small cell lung cancer patients

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