Modulation of drug cytotoxicity by iressa (ZD1839) in pancreatic cancer cell lines

Rosetti, Marco; Tesei, Anna; Ulivi, Paola; Fabbri, Francesco; Vannini, Ivan; Brigliadori, Giovanni; Granato, Anna Maria; Amadori, Dino; Zoli, Wainer

doi:10.4161/cbt.4.10.1995

Cited by 10 publications

(5 citation statements)

References 36 publications

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“…In head and neck cancer cells as well as xenografts, the combination of gemcitabine followed by gefitinib is superior to the reverse sequence (46). This observation has been supported in pancreatic cancer cells as well where treatment with gemcitabine prior to gefitinib produced additive to synergistic effects but antagonistic effects in response to the reverse sequence (52, 53). This schedule dependent cell killing may be attributable to the cell cycle effects of EGFR inhibitors since EGFR inhibitors upregulate the cyclin dependent kinase inhibitors, p27 (54, 55) and p21 (56) and thus produce G1 cell cycle arrest.…”

Section: Cellular Effects Of Radiation and Gemcitabinementioning

confidence: 78%

Improving Gemcitabine-Mediated Radiosensitization Using Molecularly Targeted Therapy: A Review

Morgan

Parsels

Maybaum

et al. 2008

Clinical Cancer Research

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In the last three decades, gemcitabine has progressed from the status of a laboratory cytotoxic drug to a standard clinical chemotherapeutic agent and a potent radiation sensitizer. In an effort to improve the efficacy of gemcitabine, additional chemotherapeutic agents have been combined with gemcitabine (both with and without radiation) but with toxicity proving to be a major limitation. Therefore, the integration of molecularly targeted agents, which potentially produce less toxicity than standard chemotherapy, with gemcitabine radiation is a promising strategy for improving chemoradiation. Two of the most promising targets, described in this review, for improving the efficacy of gemcitabine radiation are epidermal growth factor receptor and checkpoint kinase 1.Gemcitabine was first introduced into the clinic as a chemotherapeutic agent nearly 3 decades ago. Since then, both laboratory and clinical investigations have shown gemcitabine to be a potent radiation sensitizer. In this review, we will begin with a discussion of gemcitabine biochemistry and its mechanisms of interaction with radiation, highlighting observations that may lead to improving the design of clinical trials combining gemcitabine with radiation. Previous attempts to improve the efficacy of gemcitabine radiotherapy have included the addition of other chemotherapeutic agents (1 -3) such as cisplatin (4) and oxaliplatin (5). More recent studies have focused on the addition of molecularly targeted therapies, to gemcitabine, and radiation (6, 7). In this review, we will present our rationale for integrating checkpoint kinase 1 (Chk1)-and epidermal growth factor (EGFR) molecularly targeted agents with gemcitabine radiation therapy. Gemcitabine Biochemistry and RadiosensitizationThe antitumor activity of gemcitabine depends on a series of sequential phosphorylations. In the first rate-limiting step, deoxycytidine kinase converts gemcitabine to the monophosphorylated metabolite, dFdCMP [this has motivated the study of fixed-dose-rate infusion (10 mg/m 2 /min), which increases intracellular metabolites compared with bolus treatment (8, 9), but in the majority of trials, does not significantly improve survival (10)]. Subsequent phosphorylations lead to the accumulation of gemcitabine diphosphate and triphosphate (dFdCDP and dFdCTP) that are both active metabolites (Fig. 1). Whereas dFdCTP can interfere with DNA synthesis by competing with endogenous dCTP for misincorporation into replicating DNA, dFdCDP is a potent inhibitor of ribonucleotide reductase, reducing the synthesis of deoxynucleoside triphosphates, primarily dATP (in solid tumor cells).

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Section: Cellular Effects Of Radiation and Gemcitabinementioning

confidence: 78%

Improving Gemcitabine-Mediated Radiosensitization Using Molecularly Targeted Therapy: A Review

Morgan

Parsels

Maybaum

et al. 2008

Clinical Cancer Research

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“…DNA was extracted from pancreatic cell lines using the QIAmp DNA‐Mini kit (Qiagen, Hilden, Germany), in accordance with the manufacturer's instructions. Exons 18, 19, 20 and 21 of the EGFR gene and exons 5, 6, 7, 8 of the p53 gene were amplified by polymerase chain reaction and DNA sequencing, as previously described (Rengucci et al, 2001; Rosetti et al, 2005).…”

Section: Methodsmentioning

confidence: 99%

Iressa strengthens the cytotoxic effect of docetaxel in NSCLC models that harbor specific molecular characteristics

Rosetti

Zoli

Tesei

et al. 2007

Journal Cellular Physiology

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Non-small cell lung cancer (NSCLC) is the most lethal malignant tumor and is also considered one of the most chemoresistant cancers. Despite the benefits obtained from platinum-based therapy, the majority of patients treated will progress and die. In the continuing quest for personalized therapy based on the biomolecular characteristics of each single patient, clinical practice now seems to be oriented towards combining conventional drugs with molecular-targeted agents. In the present study, we evaluated the antitumor activity of docetaxel, one of the most widely used drugs for second-line treatment, and Iressa, an EGFR-targeting tyrosine kinase inhibitor, administered singly or in sequence. The study was performed on three human NSCLC cell lines (ChaGo-K1, CAEP and RAL) that exhibit different expression of proliferation and apoptosis-related markers, and do not harbor EGFR mutations. The efficacy of docetaxel and Iressa differed in the three cell lines and an important synergistic interaction was observed with the sequence 1-h docetaxel --> 72-h Iressa during which Iressa doubled the fraction of docetaxel-induced apoptotic cells, amplifying a caspase-dependent apoptosis and inhibiting docetaxel-induced p21 hyperexpression. Moreover, the important role of MAPK-dependent modulation of this molecular marker was shown using a specific inhibitor. The results from the present preclinical study demonstrate the cytotoxic activity of Iressa and its ability to increase taxane activity in a model that does not harbor EGFR-specific mutations, thus highlighting the importance of focusing on alternative molecular targets of Iressa activity.

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“…The synergism of gefitinib with cytotoxics has been tested in vitro on pancreatic cell lines and has showed a differential cytotoxic effect [95,96]. The authors of the study where no response was demonstrated suggested that only EGF receptors with specific mutations are responsive to gefitinib which was not the case in the tested two cell lines used in this study [96].…”

Section: Gefitinibmentioning

confidence: 90%

“…The authors of the study where no response was demonstrated suggested that only EGF receptors with specific mutations are responsive to gefitinib which was not the case in the tested two cell lines used in this study [96].…”

Section: Gefitinibmentioning

confidence: 94%

Pancreatic cancer: from molecular pathogenesis to targeted therapy

Strimpakos

Saif

Syrigos

2008

Cancer Metastasis Rev

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Pancreatic cancer is a deadly malignancy with still high mortality and poor survival despite the significant advances in understanding, diagnosis, and access to conventional and novel treatments. Though cytotoxic chemotherapy based on the purine analogue gemcitabine remains the standard approach in adjuvant and palliative setting the need for novel agents aiming at the main pathophysiological abnormalities and molecular pathways involved remains soaring. So far, evidence of clinical benefit, though small, exists only from the addition of the targeted agent erlotinib on the standard gemcitabine chemotherapy. Apart from the popular monoclonal antibodies and small molecules tyrosine kinase inhibitors, other novel compounds being tested in preclinical and clinical studies target mTOR, NF-kappaB, proteasome and histone deacetylase. These new drugs along with gene therapy and immunotherapy, which are also under clinical evaluation, may alter the unfavorable natural course of this disease. In this review we present the main pathophysiological alterations met in pancreatic cancer and the results of the florid preclinical and clinical research with regards to the targeted therapy associated to these abnormalities.

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Modulation of drug cytotoxicity by iressa (ZD1839) in pancreatic cancer cell lines

Cited by 10 publications

References 36 publications

Improving Gemcitabine-Mediated Radiosensitization Using Molecularly Targeted Therapy: A Review

Improving Gemcitabine-Mediated Radiosensitization Using Molecularly Targeted Therapy: A Review

Iressa strengthens the cytotoxic effect of docetaxel in NSCLC models that harbor specific molecular characteristics

Pancreatic cancer: from molecular pathogenesis to targeted therapy

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