Search PubMed⌕ Search

Biomedical subjects

Giuseppe Giaccone

Publications and source records attributed to Giuseppe Giaccone.

At least 37 records · Page 2Linked to original sources
PubMed2005

Epidermal growth factor receptor and angiogenesis: Opportunities for combined anticancer strategies.

Tumor-induced angiogenesis is essential for malignant growth. This mini review focuses on the role of vascular endothelial growth factor (VEGF) and epidermal growth factor (EGF) and their receptors in this process, and the rationale to combine inhibitors of these growth factors as anticancer therapy. Concomitantly, targeting the VEGF(R) and the EGF(R) signaling pathway may circumvent the problem of acquired resistance to EGFR inhibitors. By targeting both pathways, the antiangiogenic effect may be more pronounced, which may lead to greater antitumor activity. Preliminary efficacy data from clinical trials encourage further exploration of this combined anticancer strategy.

Cells, Cultured↗
PubMed2005

Expression and localization of inhibitor of apoptosis proteins in normal human tissues.

The family of inhibitor of apoptosis (IAP) proteins can suppress apoptosis induced by a variety of triggers. Among the IAPs, cIAP1, cIAP2, and XIAP have been characterized as inhibitors of specific caspases, and their expression, together with that of survivin, has been shown in several studies to play a role as tumor marker and prognostic factor for the survival of patients with cancer. Although survivin is usually not expressed in normal adult tissues, cIAP1, cIAP2, and XIAP have been found broadly expressed at messenger RNA level within normal cells. Here, we report an immunohistochemical study in a comprehensive panel of normal human tissues, and we confirm at the protein level the wide expression of IAPs. These results are consistent with a physiological role of IAPs in normal cells. Moreover, we show that IAPs' expression levels and localization patterns differ depending on the cell lineage. The variable subcellular localization of the IAPs within different cell types suggests that compartmentalization may contribute to regulate their function. The physiological role of these proteins should be further investigated to help tailor IAP-targeted therapeutic strategies for patients with cancer and circumvent possible side effects.

Apoptosis Regulatory Proteins↗
PubMed2005

Proteasome inhibition and its clinical prospects in the treatment of hematologic and solid malignancies.

The proteasome is responsible for the degradation of intracellular proteins, including several involved in cell cycle control and the regulation of apoptosis. Preclinical studies have shown that the proteasome inhibitor bortezomib decreases proliferation, induces apoptosis, enhances the activity of chemotherapy and radiation, and reverses chemoresistance in a variety of hematologic and solid malignancy models in vitro and in vivo. Proteasome inhibition with bortezomib has specifically promoted apoptosis of tumor cells through the stabilization of p53, p21, p27, Bax, and IkappaBalpha, resulting in nuclear factor kappaB inhibition. Bortezomib was the first proteasome inhibitor to enter clinical trials. In two Phase II trials, SUMMIT and CREST, it was found that treatment with bortezomib, alone or in combination with dexamethasone, produced durable responses with meaningful survival benefits in patients with recurrent and/or refractory multiple myeloma. In the APEX Phase III trial, bortezomib produced significant survival benefits and improved response rates over high-dose dexamethasone at first recurrence and beyond in patients with multiple myeloma. Clinical trials evaluating the safety and activity of bortezomib alone or in combination regimens with dexamethasone, doxorubicin, melphalan, prednisone, and/or thalidomide in the treatment of patients with newly diagnosed multiple myeloma have shown encouraging results. Preliminary studies suggest that bortezomib may serve as induction therapy before stem cell transplantation. Proteasome inhibition with bortezomib also has shown activity with manageable toxicity in mantle cell and other lymphomas, leukemias, and solid malignancies, including nonsmall cell lung carcinoma. Further studies with bortezomib as monotherapy and in combination regimens in the treatment of solid and hematologic malignancies are warranted.

Antineoplastic Agents↗
PubMed2005

Epidermal growth factor receptor mutations and gene amplification in non-small-cell lung cancer: molecular analysis of the IDEAL/INTACT gefitinib trials.

PURPOSE: Most cases of non-small-cell lung cancer (NSCLC) with dramatic responses to gefitinib have specific activating mutations in the epidermal growth factor receptor (EGFR), but the predictive value of these mutations has not been defined in large clinical trials. The goal of this study was to determine the contribution of molecular alterations in EGFR to response and survival within the phase II (IDEAL) and phase III (INTACT) trials of gefitinib. PATIENTS AND METHODS: We analyzed the frequency of EGFR mutations in lung cancer specimens from both the IDEAL and INTACT trials and compared it with EGFR gene amplification, another genetic abnormality in NSCLC. RESULTS: EGFR mutations correlated with previously identified clinical features of gefitinib response, including adenocarcinoma histology, absence of smoking history, female sex, and Asian ethnicity. No such association was seen in patients whose tumors had EGFR amplification, suggesting that these molecular markers identify different biologic subsets of NSCLC. In the IDEAL trials, responses to gefitinib were seen in six of 13 tumors (46%) with an EGFR mutation, two of seven tumors (29%) with amplification, and five of 56 tumors (9%) with neither mutation nor amplification (P = .001 for either EGFR mutation or amplification v neither abnormality). Analysis of the INTACT trials did not show a statistically significant difference in response to gefitinib plus chemotherapy according to EGFR genotype. CONCLUSION: EGFR mutations and, to a lesser extent, amplification appear to identify distinct subsets of NSCLC with an increased response to gefitinib. The combination of gefitinib with chemotherapy does not improve survival in patients with these molecular markers.

Adult↗
PubMed2005

Randomized phase III study of cisplatin with or without raltitrexed in patients with malignant pleural mesothelioma: an intergroup study of the European Organisation for Research and Treatment of Cancer Lung Cancer Group and the National Cancer Institute of Canada.

PURPOSE: We conducted a phase III trial to determine whether first-line treatment with raltitrexed, a thymidine synthase inhibitor, and cisplatin results in superior outcome compared with cisplatin alone in patients with malignant pleural mesothelioma (MPM). PATIENTS AND METHODS: Eligible patients with histologically proven advanced MPM, not pretreated with chemotherapy, WHO performance status (PS) 0 to 2, and adequate hematological, renal, and hepatic function were randomly assigned to receive cisplatin 80 mg/m2 IV on day 1, alone (arm A) or combined with raltitrexed 3 mg/m2 (arm B). In patients with measurable disease, response was monitored using the Response Evaluation Criteria in Solid Tumors criteria. Health related quality of life (HRQOL) was measured using the European Organisation for Research and Treatment of Cancer QLQ-C30 and Lung Module (QLQ-LC13). RESULTS: Two hundred fifty patients were randomized: 80% male; median age, 58 years; and WHO PS, 0, 1, 2 in 25, 62, and 13% of cases, respectively. There were no toxic deaths. The main grade 3 or 4 toxicities observed were neutropenia and emesis, reported twice as often in the combination arm. Among 213 patients with measurable disease, response rate was 13.6% (arm A) versus 23.6% (arm B; P = .056). No difference in HRQOL was observed on any of the scales. Median overall and 1-year survival in arms A and B were 8.8 (95% CI, 7.8 to 10.8) v 11.4 months (95% CI, 10.1 to 15), respectively, and 40% v 46%, respectively (P = .048). CONCLUSION: A combination of raltitrexed and cisplatin improves overall survival compared with cisplatin alone. This study confirms that a combination of cisplatin and an antifolate is superior to cisplatin alone in patients with MPM, without harmful effect on HRQOL.

Adult↗
PubMed2005

Phase III study of adjuvant vaccination with Bec2/bacille Calmette-Guerin in responding patients with limited-disease small-cell lung cancer (European Organisation for Research and Treatment of Cancer 08971-08971B; Silva Study).

PURPOSE: Bec2 is an anti-idiotypic antibody that mimics GD3, a ganglioside that is expressed on the surface of tumor cells and is of neuroectodermal origin. We assessed whether Bec2/bacille Calmette-Guerin (BCG) vaccination prolongs survival in patients with limited-disease small-cell lung cancer (SCLC) after a major response to chemotherapy and chest radiation. PATIENTS AND METHODS: Patients were randomly assigned to receive five vaccinations of Bec2 (2.5 mg)/BCG vaccine or follow-up. Vaccination was given over a 10-week period. The sample size was targeted to detect an increase in median survival of 40% after random assignment, and stratification was by performance status, response, and institution. Quality of life was assessed by using the European Organisation for Research and Treatment of Cancer instrument. Humoral response was assessed in patients who received vaccination. RESULTS: A total of 515 patients were randomly assigned. The primary toxicities of vaccination were transient skin ulcerations and mild flu-like symptoms. There was no improvement in survival, progression-free survival, or quality of life in the vaccination arm. Median survival from randomization was 16.4 and 14.3 months in the observation and vaccination arms (P = .28), respectively. Among vaccinated patients, a trend toward prolonged survival was observed in those (one third) who developed a humoral response (P = .085). Multivariate analysis showed a positive impact on survival by prior treatment with concomitant chemoradiotherapy, prophylactic cranial irradiation, female sex, low lactate dehydrogenase, and normal platelets. CONCLUSION: Vaccination with Bec2/BCG has no impact on outcome of patients with limited-disease SCLC responding to combined-modality treatment. Vaccination strategies in SCLC may still be warranted using vaccines that produce a better immunologic response.

Adjuvants, Immunologic↗
PubMed2005

Dose-finding study of the multitargeted tyrosine kinase inhibitor SU6668 in patients with advanced malignancies.

PURPOSE: SU6668 is a tyrosine kinase inhibitor which targets platelet-derived growth factor receptor-beta, fibroblast growth factor receptor-1, vascular endothelial growth factor receptor-2, and KIT. We did a phase I study to define the maximum tolerated dose and to assess the pharmacokinetics of SU6668 administered orally thrice daily with food. PATIENTS AND METHODS: Patients with histologically proven, advanced, and progressive solid tumors were included at a starting dose level of 400 mg/m2 thrice daily. The early onset of dose-limiting toxicities (DLT) required dose reductions to 100 and 200 mg/m2 thrice daily. Pharmacokinetics was done on days 1, 28, and 56. RESULTS: Sixteen patients were included. Two of the first three patients developed DLTs, which consisted of grade 4 fatigue and grade 3 serositis-like pains. Six patients at dose level 100 mg/m2 thrice daily experienced no DLT. At dose level 200 mg/m2 thrice daily, two out of seven patients experienced DLTs consisting of grade 3 abdominal pain, grade 4 anorexia and grade 3 nausea/vomiting. Increasing doses resulted in a disproportional increase in area under the curve and C(max) (peak plasma concentration). Both variables, however, decreased significantly on days 28 and 56 compared with day 1 (P < 0.05). No objective responses were observed. Acute phase response, probably mediated by interleukin-6, was observed in serial blood samples. CONCLUSIONS: The maximum tolerated dose of SU6668 given orally, thrice daily under fed conditions, is 100 mg/m2. Because of the low plasma levels reached at this dose level, the efficacy of SU6668 as a single agent is not to be expected.

Administration, Oral↗
PubMed2005

Kahalalide F induces necrosis-like cell death that involves depletion of ErbB3 and inhibition of Akt signaling.

Kahalalide F (KF) is a novel marine-derived antitumor agent that is currently undergoing phase II clinical trials. The mechanism of action of KF is not well understood. In line with previous reports, we show that KF caused rapid and potent cytotoxicity in the breast cancer cell lines SKBR3 and BT474, characterized by cytoplasmic swelling and DNA clumping. Several markers of caspase-dependent apoptosis, such as phosphatidyl-serine externalization, cytochrome c release, and caspase-3 and poly-(ADP-ribose) polymerase cleavage were negative after KF exposure. Inhibitors of caspases or cathepsins failed to protect against KF cytotoxicity. Altogether, these data indicate that KF-induced cell death is a necrosis-like process. The sensitivity to KF in a panel of human tumor cell lines derived from breast (SKBR3, BT474, and MCF7), vulval (A431), non-small-cell lung (H460, A549, SW1573, and H292), and hepatic (Skhep1, HepG2, and Hep3B) carcinomas positively correlated with ErbB3 (HER3) protein levels. A KF-resistant subline of colon carcinoma cells, HT29/KF, expressed significantly reduced levels of all ErbB receptors, but short-term KF exposure of sensitive cell lines such as SKBR3 selectively induced down-regulation of ErbB3. On the other hand, stable transfection of an ErbB3-expressing plasmid increased the KF sensitivity of H460 cells, the most resistant cell line in our panel. Finally, we found that KF efficiently inhibited the phosphatidylinositol 3-kinase (PI3K)-Akt signaling pathway in sensitive cell lines and that ectopic expression of a constitutively active Akt mutant reduced KF cytotoxicity in this cell line. In summary, our results identify ErbB3 and the downstream PI3K-Akt pathway as important determinants of the cytotoxic activity of KF in vitro.

Antineoplastic Agents↗
PubMed2005

Epidermal growth factor receptor inhibitors in the treatment of non-small-cell lung cancer.

Remarkable developments in the systemic treatment of advanced non-small-cell lung cancer have taken place in the past few years. Targeted therapies have been largely employed in patients with far advanced disease, and some of them have demonstrated consistent activity in this setting. Epidermal growth factor receptor (EGFR) inhibitors cause dramatic response in approximately 10% of white patients who had received prior chemotherapy. Responses are higher in Asians. These findings are at least partly caused by the substantially higher incidence of EGFR mutations in Asians compared with whites. Studies of EGFR inhibitors in combination chemotherapy in front-line therapy of advanced non-small-cell lung cancer have, however, failed to improve survival, and better understanding of interactions between chemotherapeutic agents and EGFR inhibitors will be essential in the development of more effective strategies.

Antibodies, Monoclonal↗
PubMed2005

Cell death independent of caspases: a review.

Patterns of cell death have been divided into apoptosis, which is actively executed by specific proteases, the caspases, and accidental necrosis. However, there is now accumulating evidence indicating that cell death can occur in a programmed fashion but in complete absence and independent of caspase activation. Alternative models of programmed cell death (PCD) have therefore been proposed, including autophagy, paraptosis, mitotic catastrophe, and the descriptive model of apoptosis-like and necrosis-like PCD. Caspase-independent cell death pathways are important safeguard mechanisms to protect the organism against unwanted and potential harmful cells when caspase-mediated routes fail but can also be triggered in response to cytotoxic agents or other death stimuli. As in apoptosis, the mitochondrion can play a key role but also other organelles such as lysosomes and the endoplasmic reticulum have an important function in the release and activation of death factors such as cathepsins, calpains, and other proteases. Here we review the various models of PCD and their death pathways at molecular and organelle level and discuss the relevance of the growing knowledge of caspase-independent cell death pathways for cancer.

Animals↗
PubMed2005

Identification of multiple nuclear export sequences in Fanconi anemia group A protein that contribute to CRM1-dependent nuclear export.

The Fanconi anemia (FA) pathway plays an important role in maintaining genomic stability, and defects in this pathway cause cancer susceptibility. The FA proteins have been found to function primarily in a nuclear complex, although a cytoplasmic localization and function for several FA proteins has also been reported. In this study, we investigated the possibility that FANCA, FANCC and FANCG are subjected to active export out of the nucleus. After treatment with leptomycin B, a specific inhibitor of CRM1-mediated nuclear export, the accumulation of epitope-tagged FANCA in the nucleus increased, whereas FANCC was affected to a lesser extent and FANCG showed no response. CRM1-mediated export of FANCA was further confirmed using CRM1 cotransfection, which led to a dramatic relocalization of FANCA to the cytoplasm. Five functional leucine-rich nuclear export sequences (NESs) distributed throughout the FANCA sequence were identified and characterized using an in vivo export assay. Simultaneous inactivation of three of these NESs resulted in a discrete but reproducible increase of FANCA nuclear accumulation. However, these NES mutations did not affect the ability of FANCA to complement the mitomycin C or cisplatin sensitivity of FA-A lymphoblasts. Surprisingly, mutations in the other two NESs resulted in an almost complete relocation of the protein to cytoplasm, suggesting that these motifs overlap with domains that are crucial for nuclear import. Taken together, these findings indicate that FANCA can be actively exported out of the nucleus by CRM1, revealing a new mechanism to regulate the function of the FA protein complex.

Cell Line, Transformed↗
PubMed2005

A phase II study of paclitaxel in advanced bronchioloalveolar carcinoma (EORTC trial 08956).

PURPOSE: The incidence of bronchioloalveolar carcinoma (BAC) has risen steadily over the last decades along with the increasing frequency of adenocarcinomas. BAC is relatively resistant to commonly used chemotherapy regimens. A phase II study with single agent paclitaxel in patients with stages IIIB, IV or recurrent BAC was performed. EXPERIMENTAL DESIGN: Patients with BAC with at least one target bidimensionally measurable lesion staged as unresectable stages IIIB, IV or recurrent disease, not previously irradiated; ECOG performance status 0-2; life expectancy greater than 3 months; age range between 18 and 75, received paclitaxel at a dose of 200 mg/m2 i.v. as 3h continuous infusion on day 1 every 21 days. Treatment was continued until progression or up to a maximum of six cycles. RESULTS: Nineteen patients were eligible. Median number of cycles was 3 (range 0-6); 35% of patients received the planned six cycles of chemotherapy. One patient died of unrelated cause before the start of treatment. Both hematological and non-hematological toxicities were generally mild. Only one partial response (PR) was observed among the 18 eligible patients who started protocol treatment, with a response rate of 5.6% (95% CI: 0.1-27.3%). After an independent review, two PR were confirmed, for a response rate of 11.1% (95% CI: 1.4-34.7%); nine patients had stable disease (50.0%), three patients had progressive disease (11.1%) and four patients were not assessable (22.2%). Median survival was 8.6 months (95% CI: 5.8-14.5) and 1-year survival was 35.0% (95% CI: 14.1-55.8). Median progression free survival for all patients was 2.2 months (95% CI: 1.5-6.0). The study was terminated due to the low response rate. CONCLUSIONS: Paclitaxel as single agent in stages IIIB-IV BAC was well tolerated and manageable but of limited efficacy. BAC should not be excluded from trials of new forms of chemotherapy.

Adenocarcinoma, Bronchiolo-Alveolar↗
PubMed2005

Introduction.

Explore the source record for details and available documents.

Editorial↗
PubMed2005

Lung cancer.

Explore the source record for details and available documents.

Clinical Trials as Topic↗
PubMed2005

EGFR inhibitors: what have we learned from the treatment of lung cancer?

Tyrosine kinase inhibitors directed against the epidermal growth factor receptor (EGFR) are the first molecular-targeted agents to be approved in the US and other countries for the treatment of advanced non-small-cell lung cancer after failure of chemotherapy. Some patient characteristics, such as never-smoking, female gender, East Asian origin, adenocarcinoma histology, and bronchioloalveolar subtype, are associated with a greater benefit from treatment with EGFR inhibitors. Recently, studies have identified gene mutations targeting the kinase domain of the EGFR that are related to the response to inhibitors. Most EGFR mutations predict a higher benefit from treatment compared with wild-type receptors and are correlated with clinical features related to better outcome; some EGFR mutations, however, confer drug resistance. The analysis of material usually available from lung cancer patients, using techniques such as direct sequencing to determine EGFR mutational status, can be technically challenging. In this regard, high EGFR copy number and EGFR protein detected by immunohistochemistry can also be used to select those patients who would benefit from treatment. Prospective validation of biological and clinical markers of sensitivity needs to be performed.

Adenocarcinoma↗
PubMed2005

Treatment of malignant thymoma.

PURPOSE OF REVIEW: The present review reports findings in the field of epithelial tumors originating from the thymus from the past year and discusses these findings in the context of the literature. RECENT FINDINGS: Epithelial tumors of the thymus are relatively common tumors of the anterior superior mediastinum. Thymomas are usually slowly growing tumors, and their prognosis depends on the macroscopic and microscopic invasion of surrounding tissues. Thymic carcinomas are more aggressive and less common tumors than thymomas and have been increasing in frequency in recent years. Surgery is the mainstay treatment of thymic malignancies, and complete resection represents the best prognostic factor in this disease. Postoperative radiotherapy may be indicated in tumors with invasion of surrounding tissues, but it is controversial in early-stage thymomas. Combination chemotherapy has been employed in several small studies and in advanced disease has been demonstrated to produce a 50-80% objective response rate. Neoadjuvant chemotherapy or external beam radiotherapy have been used with success in patients with tumors that are not readily resectable. Novel antiproliferative systemic agents are being investigated, based on a better understanding of the biology of these tumors. SUMMARY: A better understanding of the clinical behavior of thymomas versus thymic carcinomas and systemic therapies targeted to biologically validated targets in these diseases will help improve efficacy of treatment.

Combined Modality Therapy↗
PubMed2005

Health economics: can we afford an unrestricted use of new biological agents in gastrointestinal oncology?

PURPOSE OF REVIEW: To review pharmacoeconomic studies in gastrointestinal oncology published after January 2003 and to assess whether the use of the new biologic agents should be restricted by cost considerations. RECENT FINDINGS: Chemotherapy is standard treatment for the most common gastrointestinal tumors. New biologic agents have recently been introduced with significant benefit. Given the high cost of these novel agents, the question arises as to whether these drugs should be made available without restrictions. For some drugs, results from economic evaluations are available, showing incremental cost-effectiveness ratios between 33 649 and 46 720 Euros. However, for the most expensive new drugs such as bevacizumab and cetuximab no data is available yet. However, it is expected that the incremental cost-effectiveness ratio will be much higher. In our opinion incremental cost-effectiveness ratios between 45 000 Euros and 50 000 Euros per quality adjusted life year gained, should be acceptable for gastrointestinal cancer patients. We strongly recommend to authorities to be more willing to reimburse new cancer drugs for patients to benefit and that the pharmaceutical companies will be more prudent in their price setting. SUMMARY: There are many new promising (biologic) agents available for patients with gastrointestinal cancer. The availability of these drugs for patients becomes more and more dependent on economic reasons.

Antineoplastic Agents↗