Docetaxel and gemcitabine activity in NSCLC cell lines and in primary cultures from human lung cancer

Zoli, Wainer; Ricotti, Luca; Susino, M. Dal; Barzanti, F.; Frassineti, Giovanni Luca; Folli, Secondo; Tesei, Anna; Bacci, Francesco; Amadori, Dino

doi:10.1038/sj.bjc.6690737

Cited by 50 publications

(26 citation statements)

References 20 publications

(22 reference statements)

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“…For example, gemcitabine (2Ј,2Ј-difluoro-2Ј-deoxycytidine) is synergistic in vitro with cisplatin in non-small cell lung cancer cell lines and this interaction is most pronounced when gemcitabine precedes this drug (4,5). Similar results were obtained using PANC-1 and BxPc3 pancreatic cancer cells for which the most synergistic schedule is gemcitabine followed by cisplatin (6), whereas additive to slightly synergistic or antagonistic effects are observed with gemcitabine followed by topotecan, paclitaxel, and docetaxel in various non-small cell lung cancer cell lines (7)(8)(9).…”

Section: Introductionsupporting

confidence: 68%

Synergistic Cytotoxicity and Pharmacogenetics of Gemcitabine and Pemetrexed Combination in Pancreatic Cancer Cell Lines

Giovannetti¹,

Mey²,

Danesi³

et al. 2004

Clinical Cancer Research

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Purpose: Gemcitabine is an inhibitor of ribonucleotide reductase (RR) and DNA synthesis and is an effective agent in the treatment of pancreas cancer. The present study investigates whether the multitargeted antifolate pemetrexed would be synergistic with gemcitabine against MIA PaCa-2, PANC-1, and Capan-1 pancreatic cancer cell lines.Experimental Design: Cells were treated with gemcitabine and pemetrexed, and the type of drug interaction was assessed using the combination index. Cytotoxicity of gemcitabine was examined with inhibitors of (a) deoxycytidine kinase (dCK), which activates gemcitabine by phosphorylation, and (b) 5-nucleotidase (drug dephosphorylation) and cytidine deaminase (drug deamination), the main inactivating enzymes. The effects of gemcitabine and pemetrexed on cell cycle were analyzed by flow cytometry, and apoptosis was examined by fluorescence microscopy. Finally, quantitative, real-time PCR was used to study the pharmacogenetics of the drug combination.Results: Synergistic cytotoxicity and enhancement of apoptosis was demonstrated, mostly with the sequence pemetrexed3gemcitabine. Pemetrexed increased cells in S phase, the most sensitive to gemcitabine, and a positive correlation was found between the expression ratio of dCK:RR and gemcitabine sensitivity. Indeed, pemetrexed significantly enhanced dCK gene expression (؉227.9, ؉86.0, and ؉135.5% in MIA PaCa-2, PANC-1, and Capan-1 cells, respectively), and the crucial role of this enzyme was confirmed by impairment of gemcitabine cytotoxicity after dCK saturation with 2-deoxycytidine.Conclusions: These data demonstrate that the gemcitabine and pemetrexed combination displays scheduledependent synergistic cytotoxic activity, favorably modulates cell cycle, induces apoptosis, and enhances dCK expression in pancreatic cancer cells.

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Section: Introductionsupporting

confidence: 68%

Synergistic Cytotoxicity and Pharmacogenetics of Gemcitabine and Pemetrexed Combination in Pancreatic Cancer Cell Lines

Giovannetti¹,

Mey²,

Danesi³

et al. 2004

Clinical Cancer Research

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“…Following combined treatment, we determined SfAB. The results obtained were defined according to the following criteria: SfAB = SfA Â SfB indicated an additive effect, SfAB < fAxSfB, a synergistic effect, and SfAB > SfA Â SfB, an antagonistic effect, as described (21).…”

Section: Methodsmentioning

confidence: 99%

“…Normal test was used to test for statistical significance of the differences in the arg and pro allele status, and only those with P < 0.05 were considered significant. To quantify deviations from additive effects induced by sequential treatment of two drugs, a statistical Student's test was employed, as described (21). For a given drug dose, we determined survival fraction (Sf) of cells: SfA for the first drug used in sequential schemes and SfB for the second.…”

Section: Methodsmentioning

confidence: 99%

Evaluation of the Combined Effect of p53 Codon 72 Polymorphism and Hotspot Mutations in Response to Anticancer Drugs

Vikhanskaya

Siddique

Lee

et al. 2005

Clinical Cancer Research

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Mutations in p53 are common events during carcinogenesis and have been suggested to affect sensitivity to chemotherapy. Recently, the common polymorphism at codon 72, resulting in either an arginine (72R) or proline (72P) residue, was shown to differentially affect the response to anticancer drugs. Here, we have generated isogenic lung cancer cell lines to evaluate the effect of six p53 hotspot mutations (R175H, G245S, R248W, R249S, R273H, and R282W) in conjunction with the codon 72 polymorphism, for their response to a variety of anticancer drugs, either alone or in combination. The data indicate that 72R mutations do not confer general resistance to cisplatin, etoposide, gemcitabine, vinblastine, and taxol. For doxorubicin, cells expressing 249-72R were more resistant than the 249-72P cells. Combined treatment with cisplatin + etoposide resulted in an additive effect in cells expressing most 72R and 72P mutations, except for the 175-72R cells which were refractory to combined treatment. However, combined treatment with cisplatin + gemcitabine resulted in the absence of an additive effect in cells expressing the 273-72R and 282-72R mutants, unlike their 72P counterparts. Nonetheless, all p53 mutants (72R or 72P) equally inhibited p73-mediated transcriptional activity in lung cancer cells, suggesting that the selective resistance conferred by some 72R mutants to certain drugs is probably due to other p73-independent effects of these mutants. Together, the data show that the status of codon 72 polymorphism and p53 mutations can be used as a means for prediction of treatment response, although variables for each cancer type requires detailed evaluation.p53 is arguably the most critical tumor suppressor gene and mutations in the p53 gene are considered to represent the most common genetic alterations in human cancer (1 -3). About 90% of the p53 mutations are found in the central DNA-binding domain of p53 (1, 3). These mutations therefore affect the DNA-binding activity of p53, leading to the loss of p53-mediated transcriptional activation and hence, p53 functions such as apoptosis, and cell cycle arrest and repair (1,2). Besides the gene mutations, several reports have focused on p53 polymorphisms as risk factors for malignant disease. A polymorphic site at codon 72 in exon 4 encodes either an arginine amino acid (Arg 72R ) or a proline residue (Pro 72P ;. This polymorphism is located in a proline-rich region of the p53 protein that is required for the growth suppression and apoptosis mediated by p53 but not for cell cycle arrest (7 -9). The two polymorphic variants of wild-type p53 have been shown to have some differences in biochemical properties such as differential binding to components of the transcriptional machinery (10). Moreover, it has also been suggested that the 72R variant is much more susceptible to degradation by the human papillomavirus E6 protein (11) and recent analysis has shown that the 72R variant is more efficient in inducing cell death than the 72P variant in some cell types (12,13)...

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“…Gemcitabine and docetaxel applied simultaneously to lung cancer cell lines were antagonistic with one another, and were somewhat less than additive when gemcitabine preceded paclitaxel or vice versa [33]. Zoli et al [34] showed that gemcitabine given before docetaxel was modestly synergistic in non-small cell lung cancer cell lines. Docetaxel given before gemcitabine (with a washout period) engendered significant synergy, perhaps from synchronizing the cell line to the effects of gemcitabine.…”

Section: Gemcitabine and Docetaxel: Possible Synergy?mentioning

confidence: 99%

Gemcitabine and Docetaxel in Metastatic Sarcoma: Past, Present, and Future

Maki

2007

The Oncologist

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Objective. In the era of oral molecular kinase inhibitors, cytotoxic chemotherapy agents are somewhat overlooked, but remain the backbone of treatment for most cancers. Patients with non-gastrointestinal stromal tumor sarcomas, such as leiomyosarcoma, liposarcoma, and undifferentiated high-grade pleomorphic sarcoma (formerly called malignant fibrous histiocytoma), have received doxorubicin and ifosfamide as the backbone of their treatment for over 15 years or more. The goal of this article is to review the data that have led to the use of gemcitabine and docetaxel as a useful combination for patients with metastatic sarcomas, and to comment on possible synergy of the combination.Methods and results. The literature regarding the use of gemcitabine, docetaxel, or both, is reviewed, with emphasis on patients with metastatic sarcoma.Results. Activity of gemcitabine and docetaxel is observed in leiomyosarcoma and undifferentiated highgrade pleomorphic sarcoma. There is apparent schedule dependence of the combination in other cancers; it is unclear if schedule matters in patients with sarcomas. The dose and schedule of gemcitabine and docetaxel examined in phase II studies are probably too high for routine practice.Conclusions. The combination of gemcitabine and docetaxel is an effective option for patients with metastatic sarcoma, increasing the armamentarium for the practicing oncologist in treating this heterogeneous group of diseases. Given the low response rate to docetaxel as a single agent, it is likely that there is true clinical synergy of the combination. The Oncologist 2007;12: 999 -1006 Disclosure of potential conflicts of interest is found at the end of this article.

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Docetaxel and gemcitabine activity in NSCLC cell lines and in primary cultures from human lung cancer

Cited by 50 publications

References 20 publications

Synergistic Cytotoxicity and Pharmacogenetics of Gemcitabine and Pemetrexed Combination in Pancreatic Cancer Cell Lines

Synergistic Cytotoxicity and Pharmacogenetics of Gemcitabine and Pemetrexed Combination in Pancreatic Cancer Cell Lines

Evaluation of the Combined Effect of p53 Codon 72 Polymorphism and Hotspot Mutations in Response to Anticancer Drugs

Gemcitabine and Docetaxel in Metastatic Sarcoma: Past, Present, and Future

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