Pemetrexed for advanced stage nonsquamous non-small cell lung cancer: latest evidence about its extended use and outcomes

Tomasini, Pascale; Barlési, Fabrice; Mascaux, Céline; Greillier, L.

doi:10.1177/1758834016644155

Cited by 51 publications

(34 citation statements)

References 68 publications

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“…Despite improvements in diagnosis and combined treatments, the overall survival for NSCLC patients still remains unfavorable due to the toxicity and limited efficacy, thereby resulting in more than one-quarter of all lung cancer death [1]. The survival of advanced NSCLC still largely relied on systemic treatments [2]. The limited success rates in the treatment of advanced and metastatic NSCLC have presented challenges to current treatment paradigms.…”

Section: Introductionmentioning

confidence: 99%

Activation of ERK and Mutual Regulation of Stat3 and SP1 Contribute to Inhibition of PDK1 Expression by Atractylenolide-1 in Human Lung Cancer Cells

Xiao¹,

Zheng²,

Wu³

et al. 2017

Cell Physiol Biochem

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Background/Aims: Atractylodes macrocephula Koidz is an important ingredient in traditional Chinese herbs. One major bioactive compound, atractylenolide-1 (ATL-1), was reported to have anti-inflammatory and anti-tumor activities. However, the underlying molecular mechanism associated to this has not been well elucidated. Methods: Cell viability and cell cycle distribution were measured using 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) and flow cytometry assays, respectively. Western blot analysis was performed to examine the phosphorylation and protein expression of extracellular signaling-regulated kinase 1/2 (ERK1/2), signal transducer and activator of transcription 3 (Stat3), 3-phosphoinositide dependent protein kinase-1 (PDK1) and transcription factor SP1. QRT-PCR was used to examine the mRNA levels of PDK1 gene. Exogenously expressions of Stat3, PDK1 and SP1 were carried out by transient transfection assays. PDK1 promoter activity was measured by Secrete-Pair Dual Luminescence Assay Kit. A nude mice xenograft model was used to confirm the findings in vitro. Results: We showed that ATL-1 inhibited human lung cancer cell growth and induced cell cycle arrest. Furthermore, we found that ATL-1 stimulated phosphorylation of ERK1/2, inhibited phosphorylation and protein expressions of Stat3 and SP1; the latter were abrogated in the presence of MEK/ERK inhibitor PD98059. Moreover, ATL-1 reduced the protein, mRNA expression and promoter activity of PDK1. Intriguingly, exogenously expressed Stat3 and SP1 overcame ATL-1-inhibited SP1 and Stat3, and PDK1 protein expressions, respectively. Moreover, overexpression of PDK1 resisted the ATL-1-inhibited lung cancer cell growth. In consistent with the results in vitro, ATL-1 inhibited tumor growth, protein expressions of Stat3, SP1 and PDK1, and induced phosphorylation of ERK1/2 in vivo. Conclusion: In summary, our results show that ATL-1 inhibits lung cancer cell growth through activation of ERK1/2, followed by suppressing SP1 protein expression. ATL-1 also reduces phosphorylation and protein levels of Stat3. These are mutual regulation between Stat3 and SP1 proteins affected by ATL-1. This ultimately suppresses PDK1 gene expression. This study reveals a novel mechanism by which ATL-1 inhibits growth of lung cancer cells. Thus, targeting PDK1 pinpoints a potential in the lung cancer treatment.

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Section: Introductionmentioning

confidence: 99%

Activation of ERK and Mutual Regulation of Stat3 and SP1 Contribute to Inhibition of PDK1 Expression by Atractylenolide-1 in Human Lung Cancer Cells

Xiao¹,

Zheng²,

Wu³

et al. 2017

Cell Physiol Biochem

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“…In this trial, pemetrexed showed a similar clinical activity and a lower rate of myelosuppression compared to docetaxel [4] [5]. In a secondary analysis, pemetrexed was demonstrated to be more active in non-squamous cell tumours, leading to its restriction to patients with non-squamous histology [6].…”

Section: Introductionmentioning

confidence: 81%

Prospective Analysis of Patients Treated with Chemotherapy in Metastatic Adenocarcinoma of Lung—Single Centre Experience

Srinivasa¹,

Bhanu²,

Badarke³

et al. 2017

JCT

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Background: Lung cancer is the leading cause of cancer-related death worldwide with an estimated 1.6 million new cases diagnosed each year. According to standard guidelines in NSCLC, the effectiveness of combined chemotherapy regimen comprises of pemetrexed and platinum, and very few reports are available in Indian population. This study shows the experience with pemetrexed and platinum combination chemotherapy in metastatic NSCLC in first line setting. Methods: Total 61 patients with following inclusion criteria were recruited such as: 1) PS of 1 and 2; 2) NSCLC of non-squamous histology; 3) locally advanced or metastatic disease at diagnosis; 4) should have received minimum 3 cycles of pemetrexed and platinum as first line treatment and or continued for 6 cycles; 5) EGFR/ALK mutated or EGFR/ALK unknown patients but must have received upfront chemo. Primary endpoint of the present study is to assess Disease Control Rate (DCR) (CR + PR + SD). Progression Free Survival, OS and Toxicity assessment were secondary endpoints. Results: The mean number of average chemotherapy cycles was found to be 4.38. The range of chemotherapy was 2 -6 cycles. Disease control rate, defined as (CR + PR + SD), was seen in 44 (72.1%) patients. (PR in 26 (42.62%), SD 18 (29.5%)), Progressive disease (PD) was observed in 17 (27.9%) patients. Overall study showed that patients had PFS of 9.414 months (95% CI 6.709 -12.120) and OS of 13.437 months (95% CI 10.721 -16.153). Conclusion: Pemetrexed and platinum combination is effective and well-tolerated chemotherapy regimen in patients with metastatic adenocarcinoma lung cancer patients. Pemetrexed and cisplatin may be more effective in particular. Early switch over to TKIs is preferred immediately after obtaining molecular subtype result.How to cite this paper: Srinivasa, B

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“…Moreover, it is one of the recommended drugs for use in combination with platinum-based cisplatin or carboplatin for patients with stage IV non-squamous NSCLC. [13][14][15] PMX is a polar compound exhibiting poor oral bioavailability because of low intestinal permeability. 11 To address these problems, various strategies including the coadministration of a therapeutic agent and functional excipients (such as P-gp inhibitors), and/or enhancers of drug solubility or permeability, have been developed to circumvent the biological barriers in play, or to promote drug absorption across the GI tract by altering the physicochemical properties of the drugs.…”

Section: Introductionmentioning

confidence: 99%

Enhanced oral absorption of pemetrexed by ion-pairing complex formation with deoxycholic acid derivative and multiple nanoemulsion formulations: preparation, characterization, and in vivo oral bioavailability and anticancer effect

Pangeni

Choi

Panthi

et al. 2018

IJN

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ObjectiveThe current study sought to design an oral delivery system of pemetrexed (PMX), a multitargeted antifolate antimetabolite, by enhancing its intestinal membrane permeability.Materials and methodsPMX was ionically complexed with a permeation enhancer such as Nα-deoxycholyl-l-lysyl-methylester (DCK) and prepared as an amorphous solid dispersion by mixing with dispersants such as 2-hydroxypropyl-beta-cyclodextrin (HP-beta-CD) and poloxamer 188 (P188), forming an HP-beta-CD/PMX/DCK/P188; the complex was incorporated into multiple water-in-oil-in-water nanoemulsions in a supersaturated state (HP-beta-CD/PMX/DCK/P188-NE).ResultsAfter complex formation, the partition coefficient and in vitro membrane permeability of PMX were markedly increased, but it showed similar cytotoxic and inhibitory effects on cancer cell proliferation/migration. Furthermore, the intestinal membrane permeability and epithelial cell uptake of PMX were synergistically improved after HP-beta-CD/PMX/DCK/P188 was incorporated into a nanoemulsion with a size of 14.5±0.45 nm. The in vitro permeability of HP-beta-CD/PMX/DCK/P188-NE across a Caco-2 cell monolayer was 9.82-fold greater than that of free PMX, which might be attributable to the partitioning of PMX to the epithelial cells being facilitated via specific interaction of DCK with bile acid transporters, as well as the enhanced lipophilicity accompanied by surfactant-induced changes in the intestinal membrane structure and fluidity. Therefore, the oral bioavailability of HP-beta-CD/PMX/DCK/P188-NE in rats was evaluated as 26.8%±2.98% which was 223% higher than that of oral PMX. Moreover, oral HP-beta-CD/PMX/DCK/P188-NE significantly suppressed tumor growth in Lewis lung carcinoma cell-bearing mice, and the tumor volume was maximally inhibited by 61% compared with that in the control group.ConclusionThese results imply that HP-beta-CD/PMX/DCK/P188-NE is an effective and promising delivery system for enhancing the oral absorption of PMX. Thus, there is the potential for new medical applications, including applications in metronomic cancer treatment.

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Pemetrexed for advanced stage nonsquamous non-small cell lung cancer: latest evidence about its extended use and outcomes

Cited by 51 publications

References 68 publications

Activation of ERK and Mutual Regulation of Stat3 and SP1 Contribute to Inhibition of PDK1 Expression by Atractylenolide-1 in Human Lung Cancer Cells

Activation of ERK and Mutual Regulation of Stat3 and SP1 Contribute to Inhibition of PDK1 Expression by Atractylenolide-1 in Human Lung Cancer Cells

Prospective Analysis of Patients Treated with Chemotherapy in Metastatic Adenocarcinoma of Lung—Single Centre Experience

Enhanced oral absorption of pemetrexed by ion-pairing complex formation with deoxycholic acid derivative and multiple nanoemulsion formulations: preparation, characterization, and in vivo oral bioavailability and anticancer effect

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