Chemotherapy in stage-IV NSCLC

Reck, Martin; Gatzemeier, U.

doi:10.1016/j.lungcan.2004.07.972

Cited by 17 publications

(13 citation statements)

References 39 publications

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“…Extensive clinical studies showed that chemotherapy increases survival in the adjuvant setting and in patients with advanced, metastatic disease (1). Nonetheless, in stage IV metastatic disease, objective clinical responses are observed in f25% to 30% of patients, with a median survival of 8 to 10 months, thus emphasizing the need for new effective drugs and combination regimens (2).…”

Section: Introductionmentioning

confidence: 99%

Sequence-dependent, synergistic antiproliferative and proapoptotic effects of the combination of cytotoxic drugs and enzastaurin, a protein kinase Cβ inhibitor, in non-small cell lung cancer cells

Morgillo¹,

Martinelli²,

Troiani³

et al. 2008

Molecular Cancer Therapeutics

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Enzastaurin, an acyclic bisindolymaleimide, is a potent and selective competitive inhibitor of protein kinase CB, which has been shown to inhibit cancer cell proliferation and angiogenesis in human cancer cell lines. Gemcitabine and pemetrexed are two cytotoxic drugs that are currently used in non-small cell lung cancer (NSCLC) therapy. In this study, we have investigated whether the addition of enzastaurin to gemcitabine or to pemetrexed is able to increase their antitumor activity to establish an effective schedule of combined treatment. The effects on cancer cell proliferation, cell cycle distribution, intracellular mitogenic and antiapoptotic signaling pathways, and induction of apoptosis were evaluated in three different combination sequences (concomitant treatment, sequential treatment with the cytotoxic drug followed by enzastaurin, or sequential treatment with enzastaurin followed by the cytotoxic drug) in a panel of human NSCLC cell lines. The combination of enzastaurin with either gemcitabine or pemetrexed caused different antiproliferative and proapoptotic effects depending on the treatment schedule. A synergistic antiproliferative and proapoptotic activity was only obtained when chemotherapy was followed by treatment with enzastaurin. These effects were accompanied by the arrest of the surviving cancer cells in the S phase, thus limiting their ability to proceed through the cell cycle, and by a maximum inhibition in the activated, phosphorylated forms of Akt and mitogen-activated protein kinase. In contrast, the concomitant treatments or the sequential treatments, in which enzastaurin was given before chemotherapy, resulted in significant antagonistic effects.

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Section: Introductionmentioning

confidence: 99%

Sequence-dependent, synergistic antiproliferative and proapoptotic effects of the combination of cytotoxic drugs and enzastaurin, a protein kinase Cβ inhibitor, in non-small cell lung cancer cells

Morgillo¹,

Martinelli²,

Troiani³

et al. 2008

Molecular Cancer Therapeutics

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“…Extensive clinical studies demonstrated that chemotherapy increases survival in the adjuvant setting (Arriagada et al, 2004) and in patients with advanced disease (Reck and Gatzemeier, 2004). Nonetheless, response rates remain lower than 15%, and median survival is less than 6 months, thus emphasizing the need for new effective drugs and combination regimens (Rosell and Crinò, 2002).…”

Section: Introductionmentioning

confidence: 99%

Cellular and Pharmacogenetics Foundation of Synergistic Interaction of Pemetrexed and Gemcitabine in Human Non–Small-Cell Lung Cancer Cells

Giovannetti¹,

Mey²,

Nannizzi³

et al. 2005

Mol Pharmacol

165

122

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Gemcitabine and pemetrexed are effective agents in the treatment of non-small-cell lung cancer (NSCLC), and the present study investigates cellular and genetic aspects of their interaction against A549, Calu-1, and Calu-6 cells. Cells were treated with pemetrexed and gemcitabine, and their interaction was assessed using the combination index. The role of drug metabolism in gemcitabine cytotoxicity was examined with inhibitors of deoxycytidine kinase (dCK), 5Ј-nucleotidase, and cytidine deaminase, whereas the role of pemetrexed targets, thymidylate synthase (TS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyltransferase (GARFT) in drug chemosensitivity was analyzed in cytotoxicity rescue studies. The effect of gemcitabine and pemetrexed on Akt phosphorylation was investigated with enzyme-linked immunosorbent assay, whereas quantitative polymerase chain reaction (PCR) was used to study target gene-expression profiles and its modulation by each drug. Synergistic cytotoxicity was demonstrated, and pemetrexed significantly decreased the amount of phosphorylated Akt, enhanced apoptosis, and increased the expression of dCK in A549 and Calu-6 cells, as well as the expression of the human nucleoside equilibrative transporter 1 (hENT1) in all cell lines. PCR demonstrated a correlation between dCK expression and gemcitabine sensitivity, whereas expression of TS, DHFR, and GARFT was predictive of pemetrexed chemosensitivity. These data demonstrated that 1) gemcitabine and pemetrexed synergistically interact against NSCLC cells through the suppression of Akt phosphorylation and induction of apoptosis; 2) the gene expression profile of critical genes may predict for drug chemosensitivity; and 3) pemetrexed enhances dCK and hENT1 expression, thus suggesting the role of gene-expression modulation for rational development of chemotherapy combinations.Despite recent advances in early diagnosis and treatment, non-small-cell lung cancer (NSCLC) is a disease with a grim prognosis. Extensive clinical studies demonstrated that chemotherapy increases survival in the adjuvant setting (Arriagada et al., 2004) and in patients with advanced disease (Reck and Gatzemeier, 2004). Nonetheless, response rates remain lower than 15%, and median survival is less than 6 months, thus emphasizing the need for new effective drugs and combination regimens (Rosell and Crinò, 2002). However, the rationale for chemotherapy combinations has remained mostly empirical, determined from the antitumor activity of each agent and the lack of overlapping toxicities, despite many attempts to discover preclinical models for rational selection of drug interactions.Gemcitabine (2Ј,2Ј-difluorodeoxycytidine) is a deoxycytidine analog with a broad spectrum of anticancer activity against several solid tumors in preclinical models, and it is M.D.T. was supported by unrestricted research grants from Eli Lilly (Florence, Italy). R. Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.doi:10.1124/...

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“…Palliative chemotherapy, the standard treatment in this situation, leads to a median survival of approximately 10 months. Several drugs are active, and although a platinum-based doublet is generally regarded as the current standard [5], the best chemotherapy regimen in NSCLC patients is debated [6]. There is an intensive hunt for molecular markers predicting chemotherapy response in NSCLC patients [7,8].…”

Section: Introductionmentioning

confidence: 99%

Cyclin D1 (CCND1) A870G gene polymorphism modulates smoking-induced lung cancer risk and response to platinum-based chemotherapy in non-small cell lung cancer (NSCLC) patients

et al. 2006

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Chemotherapy in stage-IV NSCLC

Cited by 17 publications

References 39 publications

Sequence-dependent, synergistic antiproliferative and proapoptotic effects of the combination of cytotoxic drugs and enzastaurin, a protein kinase Cβ inhibitor, in non-small cell lung cancer cells

Sequence-dependent, synergistic antiproliferative and proapoptotic effects of the combination of cytotoxic drugs and enzastaurin, a protein kinase Cβ inhibitor, in non-small cell lung cancer cells

Cellular and Pharmacogenetics Foundation of Synergistic Interaction of Pemetrexed and Gemcitabine in Human Non–Small-Cell Lung Cancer Cells

Cyclin D1 (CCND1) A870G gene polymorphism modulates smoking-induced lung cancer risk and response to platinum-based chemotherapy in non-small cell lung cancer (NSCLC) patients

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