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Giuseppe Giaccone

Publications and source records attributed to Giuseppe Giaccone.

82 records · Page 5Linked to original sources
PubMed2002

Novel approaches to the treatment of non-small cell lung cancer.

Prognosis of non-small cell lung carcinomas (NSCLC) remains poor, especially in advanced disease. The introduction of new cytotoxic agents in the past decade did only attain minor improvements in survival. It is rather clear that chemotherapy may have reached a plateau, and that it will be difficult to obtain better results in advanced NSCLC by chemotherapy alone. Novel treatment modalities are urgently needed in advanced NSCLC. Backed-up by advances in the understanding of tumor cell biology, a new generation of anticancer agents specifically directed at targets such as tyrosine kinases, farnesyl transferase, angiogenesis factors, matrixmetalloproteinases and oncogenes has been developed in recent years. In this review, we give a brief summary of the state-of-the-art treatment of NSCLC, highlighting its limitations. Novel systemic approaches are then discussed in detail with focus on their mechanistic rationale, stage of clinical development and possible drawbacks. Finally, perspectives of future applications and impact on the treatment of NSCLC are also discussed.

Angiogenesis Inhibitors↗
PubMed2002

Early results of a randomized phase III trial of platinum-containing doublets versus a nonplatinum doublet in the treatment of advanced non-small cell lung cancer: European Organization for Research and Treatment of Cancer 08975.

In the European Organization for Research and Treatment of Cancer randomized phase III trial (08975), 480 patients with advanced non-small cell lung cancer received the standard arm of cisplatin/paclitaxel or one of two experimental arms; gemcitabine/cisplatin or gemcitabine/paclitaxel. Cisplatin was given at 80 mg/m(2) on day 1, gemcitabine was administered at 1,250 mg/m(2) on days 1 and 8, and paclitaxel at 175 mg/m(2) as a 3-hour infusion on day 1, every 3 weeks. The cisplatin/paclitaxel and gemcitabine/cisplatin regimens were comparably active. The nonplatinum arm, gemcitabine/paclitaxel, was well tolerated, but had a trend toward lower median, 1-year, and progression-free survival compared with the standard arm. Further follow-up and analysis of quality of life may clarify this possible difference in treatment outcome.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2002

Continuous administration of irinotecan by hepatic arterial infusion: a phase I and pharmacokinetic study.

PURPOSE: The main advantage of administering chemotherapy by means of hepatic arterial infusion (HAI) is the achievement of a high concentration of the drug in the liver. Irinotecan (CPT-11) is an active agent for the treatment of advanced colorectal cancer and other tumor types, which frequently metastasize in the liver. We performed a Phase I and pharmacokinetic study to investigate CPT-11 by hepatic arterial administration in patients with liver metastases. PATIENTS AND METHODS: Patients with liver metastases received CPT-11 at doses ranging from 15 to 25 mg/m(2)/day for 5 days every 3 weeks by continuous HAI. All of the patients also received one cycle CPT-11 i.v. Primary end points of the study were to define the maximum tolerated dose (MTD) of hepatic arterial CPT-11 and to study its pharmacokinetics. RESULTS: Twenty patients were included. The MTD was 25 mg/m(2)/day and the dose-limiting toxicities were neutropenia and diarrhea. The metabolic ratio was significantly increased with HAI compared with i.v. administration (P = 0.015). The steady-state concentrations of total CPT-11 and CPT-11 carboxylate and lactone were all lower than those during i.v. infusion (P = 0.008, 0.013, and 0.004, respectively), whereas the levels of total SN-38, and SN-38 carboxylate, lactone, and glucuronide were similar. The total body clearance of CPT-11 was significantly higher with HAI (P = 0.008). CONCLUSIONS: The MTD of CPT-11 given by hepatic 5-day continuous infusion was 25 mg/m(2)/day. HAI of CPT-11 resulted in a higher metabolic ratio because of increased elimination of CPT-11. We recommend 20 mg/m(2)/day for additional Phase II studies.

Adult↗
PubMed2002

Paclitaxel triggers cell death primarily via caspase-independent routes in the non-small cell lung cancer cell line NCI-H460.

PURPOSE: Here we report on the role of mitochondria, death receptors (DRs), and caspases in exerting the cytotoxic effect of clinically relevant concentrations of paclitaxel in the non-small cell lung cancer cell line NCI-H460. EXPERIMENTAL DESIGN: We have characterized paclitaxel-induced cell death with annexin V, propidium iodide staining, and poly(ADP-ribose) polymerase cleavage assays. The involvement of the mitochondria pathway was studied by monitoring cytochrome c release and using H460 cells stable in overexpressing Bcl-2 or Bcl-x(L). DR dependency was analyzed in FADD dominant-negative or cytokine response modifier A-overexpressing cells, and a possible role for DR4 and DR5 was investigated by antagonistic antibodies. Caspase activity and cleavage assays and treatment with the synthetic inhibitor zVAD-fmk were used to determine the involvement of caspases. RESULTS: Paclitaxel-treated cells displayed several features of apoptosis, including annexin V staining and poly(ADP-ribose) polymerase cleavage. The sequence of events suggested the involvement of a DR, as indicated by an early role for Fas-associated death domain and caspase-8, followed by cleavage of Bid and the disruption of mitochondria; nonetheless, we failed to demonstrate the involvement of DR4 and DR5. Interestingly, inhibition of either one of these routes only resulted in a 30% reduction of cell death that was in line with the observed small effect of caspase inhibition by zVAD-fmk on H460 cell survival. CONCLUSION: Paclitaxel triggers cell death in H460 cells mainly via a currently unidentified caspase-independent mechanism in which the basic apoptotic machinery is merely coactivated. This finding is in sharp contrast with the largely caspase-dependent response elicited by DNA-damaging agents in these cells. We speculate on therapeutic implications.

Amino Acid Chloromethyl Ketones↗
PubMed2002

Apoptosis: target of cancer therapy.

Recent knowledge on apoptosis has made it possible to devise novel approaches, which exploit this process to treat cancer. In this review, we discuss in detail approaches to induce tumor cell apoptosis, their mechanism of action, stage of development, and possible drawbacks. Finally, the obstacles yet to be overcome and the perspectives for potential clinical use of apoptosis-triggering approaches in cancer therapy in the future are assessed.

Animals↗
PubMed2002

A phase I study of the natural killer T-cell ligand alpha-galactosylceramide (KRN7000) in patients with solid tumors.

PURPOSE: alpha-galactosylceramide (KRN7000) is a glycosphingolipid that has been shown to inhibit tumor growth and to prolong survival in inoculated mice through activation of natural killer (NK) T cells. We performed a dose escalation study of KRN7000 in advanced cancer patients. EXPERIMENTAL DESIGN: Patients with solid tumors received i.v. KRN7000 (50-4,800 micro g/m(2)) on days 1, 8, and 15 of a 4-weekly cycle. Patients were given 1 cycle and, in the absence of dose-limiting toxicity or progression, treatment was continued. Pharmacokinetics (PK) and immunomonitoring were performed in all patients. RESULTS: Twenty-four patients were entered into this study. No dose-limiting toxicity was observed over a wide range of doses (50-4,800 micro g/m(2)). PK was linear in the dose range tested. Immunomonitoring demonstrated that NKT cells (CD3+Valpha24+Vbeta11+) typically disappeared from the blood within 24 h of KRN7000 injection. Additional biological effects included increased serum cytokine levels (tumor necrosis factor alpha and granulocyte macrophage colony-stimulating factor) in 5 of 24 patients and a transient decrease in peripheral blood NK cell numbers and cytotoxicity in 7 of 24 patients. Importantly, the observed biological effects depended on pretreatment NKT-cell numbers rather than on the dose of KRN7000. Pretreatment NKT-cell numbers were significantly lower in patients compared with healthy controls (P = 0.0001). No clinical responses were recorded and seven patients experienced stable disease for a median duration of 123 days. CONCLUSION: i.v. KRN7000 is well tolerated in cancer patients over a wide range of doses. Biological effects were observed in several patients with relatively high pretreatment NKT-cell numbers. Other therapeutic strategies aiming at reconstitution of the deficient NKT-cell population in cancer patients may be warranted.

Adult↗
PubMed1999

10th Conference on DNA Topoisomerases in therapy.

The 10th Conference on DNA Topoisomerases in Therapy 6-8 October 1999 in Amsterdam, The Netherlands) covered basic research on DNA topoisomerases and aspects of topoisomerase-directed therapy. The understanding of basic aspects of enzyme functions and structures was discussed throughout the meeting, as this knowledge is fundamental to further developments of new and more effective therapeutic approaches. Several new crystal structures were presented, and implications for function and interaction with DNA and drugs were discussed. Knock-out mice for various topoisomerase genes have been produced and genes have been shown to differ in importance for development and survival. The interaction of topoisomerases with other proteins involved in DNA metabolism, chromosome stability and physiology were discussed. The main focus for cancer therapy was on camptothecins (CPT) and related compounds stabilizing covalent DNA-intermediates of topoisomerase I. Reports on recent clinical trials of first-generation, water-soluble CPT-analogs (topotecan and irinotecan) confirmed earlier findings of activity in several solid tumors and hematological malignancies. Improvements in efficacy and toxicity profiles are being sought in orally absorbable compounds and other drug formulations (e.g. in liposomes). Several new CPT-analogs at preclinical stages of development might also provide a greater stability of the lactone ring, higher DNA-binding affinity, and improved water solubility. New drugs have also been developed from a number of new non-CPT compounds, which inhibit the activity of DNA-topoisomerases but do not stabilize the DNA-linked form of the enzymes. Another focus of the meeting was on therapeutic targeting of microbial DNA topoisomerases. The antibiotic potential of the quinolones has been extended to gram-positive pathogens, particularly Streptococcus pneumoniae. The cloning and biochemical characterization of the DNA-topoisomerases of eukaryotic parasites such as Plasmodium falciparum or Candida albicans have been completed and the search for specific inhibitors targeting these enzymes is under way. Copyright 1999 Harcourt Publishers Ltd.

Journal Article↗
PubMedDate not supplied

The expression of TUCAN, an inhibitor of apoptosis protein, in patients with advanced non-small cell lung cancer treated with chemotherapy.

BACKGROUND: TUCAN is a caspase recruitment domain (CARD)-containing protein involved in tumor biology by regulating apoptosis and the NFkappaB pathway. Inhibition of caspase-9 may cause drug resistance. The pattern of expression, localization and prognostic value of TUCAN in the tumors of patients with non-small cell lung cancer (NSCLC) treated with chemotherapy were assessed in this study. MATERIALS AND METHODS: Using immunohistochemistry, the expression and localization of TUCAN was evaluated in forty-nine tumor specimens from patients with NSCLC who underwent neoadjuvant chemotherapy (32 stage IIB or IIIA), or palliative chemotherapy (17 stage IIIB or IV). The correlation between TUCAN expression and subcellular localization, major patient characteristics, response to the treatment and overall survival were assessed. RESULTS: TUCAN expression was detectable in 34 out of 49 (69%) tumor specimens. Among the positively-stained specimens, three patterns of localization were observed: 5 samples (11%) showed exclusive nuclear localization, 13 samples (27%) contained only cytoplasmic staining and 15 (31%) showed both cytoplasmic and nuclear localization. There was no significant correlation between the localization of TUCAN and response to chemotherapy. Although TUCAN expression was not correlated with outcome, interestingly, exclusive cytoplasmic localization of TUCAN predicted shorter survival (p = 0.027). CONCLUSION: Our results suggest that differential localization of TUCAN may be a prognostic factor for NSCLC, despite the lack of predictive value for response to chemotherapy.

Adult↗