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Biomedical subjects

G Giaccone

Publications and source records attributed to G Giaccone.

At least 127 records · Page 7Linked to original sources
PubMed1999

Expression of DNA topoisomerase IIalpha and topoisomerase IIbeta genes predicts survival and response to chemotherapy in patients with small cell lung cancer.

Drug resistance is a major problem in patients with small cell lung cancer; in fact, most die of resistant disease, despite an initial response. Several markers of drug resistance have been described in preclinical models, but the mechanism of drug resistance in lung cancer patients remains unknown. The objective of this study was to evaluate the role of the expression of a number of markers of drug resistance, proliferation, and apoptosis in relation to response to chemotherapy and survival in patients with small cell lung cancer. Tumor samples were derived from 93 previously untreated patients who were randomized in a Phase III study to receive cyclophosphamide, epirubicine, and etoposide or cyclophosphamide, epirubicine and vincristine alternating with carboplatin and etoposide. Paraffin-embedded samples, derived from the primary tumor site prior to chemotherapy, were analyzed by immunohistochemistry for expression of markers implicated in drug resistance [topoisomerase (topo) IIalpha, topo IIbeta, and multidrug resistance-associated protein], apoptosis (p53, p21, and bcl-2), or proliferation (Ki67). Response prediction was analyzed by chi2 test and logistic regression analysis; overall and disease-free survival curves were compared by log-rank test and Cox regression analysis. Shorter survival was observed in patients with extensive disease (P = 0.037) and poorer performance status (P = 0.028) and in patients whose tumors expressed high topo IIalpha levels (P = 0.01) and high Ki67 (P = 0.024). By multivariate analysis, the following factors were found to be predictive for worse survival: high expression levels of topo IIalpha, Ki67, and bcl-2; male sex; and extensive disease. High topo IIbeta expression was found to be predictive for lower overall and complete response rate. No relationship between apoptotic pathway markers or MRP and response to chemotherapy was observed. In conclusion, high expression of topo IIalpha was predictive of worse survival, and high expression of topo IIbeta was predictive of lower response rates. Furthermore, lower survival probability was observed in patients with bcl-2-positive tumors. Immunohistochemical assessment of these markers in diagnostic biopsies may give important prognostic information and may help selecting patients in the worse prognostic categories for new therapeutic strategies.

Antigens, Neoplasm↗
PubMed1998

Clinical resistance to topoisomerase-targeted drugs.

This review describes topoisomerase (topo)-mediated drug resistance and topo expression in human tissues and cancers. In some in vitro studies a relation has been observed between topo I, IIalpha or IIbeta expression and sensitivity to topo inhibitors. Drug resistance to topo inhibitors may, however, be multifactorial. Several topo inhibitors are substrates for drug membrane transporters. As most topo inhibitors are cell cycle specific, disturbances in cell cycle regulation can also confer resistance, and downstream events following DNA damage induced by topo inhibitors may be involved in regulating cell death or survival. Several studies in patient specimens have shown a relation between topo IIalpha expression and the proliferative state of the tumor, higher topo IIalpha levels being seen in more highly proliferating tumor types. In contrast, topo IIbeta appears to be expressed in both proliferating and quiescent cells. Furthermore, higher topo I levels were observed in some tumors when compared to their normal counterparts. In some studies a reduced topo IIalpha level was seen in samples taken after chemotherapy treatment, as compared with specimens prior to treatment. No unequivocal relation was observed, however, between expression or activity of the topo genes and response to chemotherapy; nonetheless only a few studies have properly addressed this question. This review summarizes the results of the clinical studies performed so far, and analyzes the critical issues in performing studies on patient material.

Antineoplastic Agents↗
PubMed1998

Brain-only metastases of small cell lung cancer; efficacy of whole brain radiotherapy. An EORTC phase II study.

BACKGROUND AND PURPOSE: To evaluate the efficacy of WBRT as a single treatment modality in patients with brain metastases of small cell lung cancer. PATIENTS AND METHODS: The patients had brain metastases of small cell lung cancer without any sign of tumour outside the brain and were treated with 10 x 3.0 Gy WBRT. Response and neurological functions were evaluated after 6, 18 and 36 weeks. RESULTS: Twenty of 22 eligible patients were evaluable for response. In six patients a complete response was seen and in five patients a partial response was seen giving a response rate of 50% (95% CI 28-72%). Response duration was 5.4 months (range 63-260 days) and median survival was 4.7 months (range 14-743 days). In the majority of patients the first site of progression after WBRT was in the central nervous system. Twelve of the patients had stabilization or improvement of the neurological function. CONCLUSION: WBRT for brain metastases of small cell lung cancer gives a 50% response rate with stabilization or improvement of neurological function. Response duration and survival are short.

Adult↗
PubMed1998

Determinants of CPT-11 and SN-38 activities in human lung cancer cells.

Irinotecan (CPT-11) is a semisynthetic camptothecin derivative with a broad spectrum of anti-tumour activity. Carboxylesterase (CE) catalyses the conversion of CPT-11 to SN-38 (7-ethyl-10-hydroxycamptothecin), the active form of CPT-11. The antiproliferative effects of CPT-11 and SN-38, CE-activity and topoisomerase I protein expression were investigated in five human small-cell lung cancer (SCLC) cell lines and four human non-small-cell lung cancer (NSCLC) cell lines. Antiproliferative activity, expressed as IC50 values, was determined using the MTT assay. CPT-11 was significantly more active in SCLC than in NSCLC cell lines (P = 0.0036), whereas no significant difference between histological types was observed with SN-38. A significant correlation (r2 = 0.52, P = 0.028) was observed between CE activity and chemosensitivity to CPT-11 but not to SN-38, and significantly higher CE activity was observed in SCLC compared with NSCLC cell lines (P = 0.025). Western blotting experiments showed topoisomerase I protein expressions within a factor of 2, and a granular nuclear staining was detectable in all cell lines by immunocytochemistry of cytospins. No correlation was observed between protein expression and sensitivity to CPT-11 or SN-38. Cellular and medium concentrations of CPT-11 and SN-38 were measured by high-performance liquid chromatography (HPLC) in one SCLC cell line with high CE activity and high sensitivity to CPT-11, and one NSCLC cell line with low sensitivity to CPT-11 and CE activity. Intracellular concentrations of CPT-11 and SN-38 were higher in the SCLC cell line, and this was associated with an increase in cellular uptake of CPT-11 compared with the medium, and an increased intracellular formation of SN-38. In conclusion, CE activity appears to be associated with higher sensitivity to CPT-11 in human lung cancer cell lines and may partly explain the difference in the in vitro sensitivity to CPT-11 between SCLC and NSCLC cells. The assessment of CE activity in clinical material of lung cancer patients undergoing treatment with CPT-11 may be warranted. However, other mechanisms may influence sensitivity to CPT-11, possibly including drug transport.

Antineoplastic Agents, Phytogenic↗
PubMed1998

CPT-11 sensitivity in relation to the expression of P170-glycoprotein and multidrug resistance-associated protein.

The relevance of P170-glycoprotein (P-gp) and multidrug resistance-associated protein (MRP) for the sensitivity to CPT-11 was investigated in human malignant cell lines as well as in human tumour xenografts. In vitro, the P-gp-positive sublines BRO/mdr1.1 (transfected with MDR1) and 2780AD were slightly cross-resistant against carboxylesterase-activated CPT-11. Cross-resistance against SN-38 was present in 2780AD cells, but not in BRO/mdr1.1 cells. The P-gp modulators BIBW22BS, verapamil and dexniguldipine partly reversed the resistance against CPT-11 in the P-gp-positive sublines. BIBW22BS was the most effective modulator in the reversal of the resistance against carboxylesterase-activated CPT-11 as well as against SN-38 in the 2780AD subline. In contrast to doxorubicin and vincristine, the BRO/mdr1.1 xenografts were at least as sensitive to CPT-11 as the BRO xenografts. The 2780AD xenografts were slightly less sensitive than the parent tumours, but there was no difference in topoisomerase I DNA unwinding activity. Therefore, the high retention of the multidrug-resistant phenotype of 2780AD cells in vivo may be the cause of the low cross-resistance against CPT-11. The MRP-positive subline GLC4/ADR was cross-resistant against carboxylesterase-activated CPT-11 and SN-38. GLC4/ADR cells, however, demonstrated a twofold lower topoisomerase I activity than GLC4 cells. Cross-resistance against the camptothecin derivatives was not apparent in the MRP-transfected subline of SW1573/S1. In conclusion, P-gp-positive cells show a low cross-resistance against CPT-11/SN38, which is only apparent with high P-gp expression in vivo. MRP does not seem to play a role in the sensitivity to CPT-11.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1998

Characterization of human soft-tissue sarcoma xenografts for use in secondary drug screening.

We have established ten transplantable human soft-tissue sarcoma (STS) xenografts grown as subcutaneous tumours in the nude mouse. Nine xenografts originated from patients that needed chemotherapy in the course of their disease. The xenografts were tested for their sensitivity to maximum tolerated doses of five anti-cancer agents. Growth of treated tumours was expressed as a percentage of control tumour growth and a growth inhibition > 75% was measured for doxorubicin in 20% of the STS xenografts, for cyclophosphamide in 30%, for ifosfamide in 20%, for vincristine in 20%, whereas etoposide was not effective in the STS xenografts. In three out of ten STS xenografts MDR1 mRNA was detectable, but this was not related to the resistance against doxorubicin, vincristine or etoposide. Topoisomerase IIalpha mRNA expression levels did not reflect sensitivity to doxorubicin or etoposide. In all STS tissues, however, these levels were lower than topoisomerase IIalpha mRNA in a drug-sensitive human ovarian cancer xenograft. Glutathione concentrations and the activities of glutathione S-transferase, glutathione peroxidase and glutathione reductase were not related to resistance against the alkylating agents or doxorubicin. Of interest, in all STS tissues, glutathione S-transferase pi was the predominant isoenzyme present. In conclusion, chemosensitivity of the STS xenografts reflects clinical response rates in phase II trials on the same compounds in adult STS patients. Relatively low levels of topoisomerase IIalpha mRNA may partly account for intrinsic resistance against, for example, doxorubicin. Additional factors must contribute to moderate responsiveness to alkylating agents.

Animals↗
PubMed1998

Prognostic role of clinical, pathological and biological characteristics in patients with locally advanced breast cancer.

Forty-two patients with clinical stage IIIA or IIIB breast cancer were treated with neoadjuvant chemotherapy followed by mastectomy and radiotherapy. The median follow-up was 32 months (range 10-72 months) and the median time to progression was 17 months (range 10-30 months). A multivariate analysis showed that a longer disease-free survival (DFS) was related to more chemotherapy cycles given (P = 0.003), a better pathological response to chemotherapy (P = 0.04) and fewer positive axillary lymph nodes (P = 0.05). A better overall survival (OS) was related to more chemotherapy cycles given (P = 0.03) and better pathological response to chemotherapy (P = 0.04). In patients with residual tumour after neoadjuvant chemotherapy, high levels of staining for Ki-67 was correlated with a worse DFS (P = 0.008). Other biological characteristics, including oestrogen receptor status, microvessel density (CD31 staining), P-glycoprotein (P-gp) staining and nuclear accumulation of p53, were not independent prognostic factors for either DFS or OS. If both P-gp and p53 were expressed, DFS and OS were worse in the uni- and multivariate analysis. The preliminary results of this phase II study suggest that coexpression of P-gp/p53 and a high level of staining for Ki-67 after chemotherapy are associated with a worse prognosis, and that prolonged neoadjuvant chemotherapy and the attainment of a pathological complete remission are important factors in determining outcome for patients with this disease.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1998

Prognostic factors in patients with pleural mesothelioma: the European Organization for Research and Treatment of Cancer experience.

PURPOSE: Identification of prognostic factors in patients with malignant pleural mesothelioma based on prospectively collected international data. PATIENTS AND METHODS: From October 1984 to October 1993, 204 eligible adult patients with malignant pleural mesothelioma were entered into five consecutive prospective European Organization for Research and Treatment of Cancer (EORTC) phase II clinical trials designed to assess the efficacy of various anticancer drugs (mitoxantrone, epidoxorubicin, etoposide, and paclitaxel). The Cox model was used to assess 13 factors related to biology and disease history with respect to survival. RESULTS: The median survival duration was 12.6 months from diagnosis and 8.4 months from trial entry. In the multivariate analysis, poor prognosis was associated with a poor performance status, a high WBC count, a probable/possible histologic diagnosis of mesothelioma, male gender, and having sarcomatous tissue as the histologic subtype. Taking these five factors into consideration, patients were classified into two groups: a good-prognosis group (1-year survival rate, 40%; 95% confidence interval [CI], 30% to 50%) and a poor-prognosis group (1-year survival, 12%; 95% CI, 4% to 20%). CONCLUSION: These results may help to design new clinical trials in pleural mesothelioma by selecting more homogenous groups of patients.

Age Factors↗
PubMed1998

Randomized study of paclitaxel-cisplatin versus cisplatin-teniposide in patients with advanced non-small-cell lung cancer. The European Organization for Research and Treatment of Cancer Lung Cancer Cooperative Group.

PURPOSE: To compare two cisplatin based chemotherapy schedules in patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: A total of 332 patients with advanced NSCLC were randomized to receive cisplatin 80 mg/m2 on day 1 either in combination with teniposide 100 mg/m2 on days 1, 3, and 5 (arm A) or paclitaxel 175 mg/m2 by 3-hour infusion on day 1 (arm B); cycles were repeated every 3 weeks. RESULTS: Fifteen patients were ineligible; patient characteristics were well balanced between the two arms: 71% were male, 71% had less than 5% weight loss, 89% had a World Health Organization (WHO) performance status of 0 to 1, 51% had adenocarcinoma, and 61% had stage IV disease. Hematologic toxicity was significantly more severe in arm A (leukopenia, neutropenia, and thrombocytopenia grade 3 or 4: 66% v 19%, 83% v 55%, 36% v 2% in arms A and B, respectively), which resulted in more febrile neutropenia (27% v 3% in arms A and B, respectively), dose reductions, and treatment delays. There were a total of nine toxic deaths, six due to neutropenic sepsis: five in arm A and one in arm B. In contrast, arthralgia/myalgia (grade 2 or 3, 4% v 17%), peripheral neurotoxicity (grade 2 or 3, 6% v 29%), and hypersensitivity reactions (1% v 7%, all grades) were significantly more frequent in arm B. The frequency and severity of other toxicities were comparable between the two arms. Responses were one complete and 44 partial on arm A (28%) and two complete and 61 partial (41%) on arm B (P = .018). There was no significant difference in survival, with median and 1-year survivals 9.9 versus 9.7 months and 41% versus 43%, respectively in arm A and B. Progression-free survival was 4.9 and 5.4 months in arm A and B, respectively. Selected centers participated in a quality-of-life (QoL) assessment, which was performed by the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 and LC-13 administered at baseline and every 6 weeks thereafter. Arm B achieved a better score at week 6 for emotional, cognitive and social functioning, global health status, fatigue, and appetite loss, which was lost at 12 weeks. In conclusion, arm B appears superior to arm A with regard to response rate, side effects, and QoL. CONCLUSION: Although survival was not improved, arm B offers a better palliation for advanced NSCLC patients than arm A.

Adult↗
PubMed1998

Fatal familial insomnia: genetic, neuropathologic, and biochemical study of a patient from a new Italian kindred.

Fatal familial insomnia (FFI) is an inherited prion disease linked to a mutation at codon 178 of the PRNP gene that results in aspartic acid to asparagine substitution, in coupling phase with methionine at position 129. The disease is characterized clinically by insomnia with disturbances of the autonomic, endocrine, and motor systems and neuropathologically by selective degeneration of the thalamus. Phenotypic variability is well known and has been linked to homozygosity or heterozygosity at PRNP codon 129. We report the clinical, neuropathologic, and biochemical findings and genomic analysis of a patient with FFI from a new Italian kindred. Although homozygous for methionine at codon 129, this patient showed some clinical and pathologic features most commonly found in heterozygotes.

Blotting, Western↗
PubMed1998

An antibody raised against a conserved sequence of the prion protein recognizes pathological isoforms in human and animal prion diseases, including Creutzfeldt-Jakob disease and bovine spongiform encephalopathy.

Antibodies to the prion protein (PrP) have been critical to the neuropathological and biochemical characterization of PrP-related degenerative diseases in humans and animals. Although PrP is highly conserved evolutionarily, there is some sequence divergence among species; as a consequence, anti-PrP antibodies have a wide spectrum of reactivity (from strong immunopositivity to lack of reactivity) when challenged with PrP from diverse species. We have produced an antibody (anti-PrP95-108) raised against a synthetic peptide corresponding to residues 95 to 108 of human PrP and have characterized it by epitope mapping, Western immunoblot analysis, and immunohistochemistry. The antibody recognizes not only human PrP isoforms but also pathological PrP from all species tested (ie, cattle, sheep, hamsters, and mice). This is probably due to the fact that the epitope recognized by this antibody includes residues 100 to 108 of human PrP, a sequence that is also present in PrP of several other species. Thus, this reagent is valuable not only for the study of human prion diseases but also for analysis of the possible relationship between human and animal disorders.

Amino Acid Sequence↗
PubMed1998

An update on European randomized studies in non-small cell lung cancer.

Less than 25% of non-small cell lung cancer (NSCLC) patients present with surgically resectable stage I and II disease, and the majority of patients will eventually die of disseminated disease. Cisplatin-based chemotherapy has been shown to prolong survival and improve quality of life in patients with stage III and IV disease. In recent years, new chemotherapeutic agents (eg, gemcitabine, paclitaxel, docetaxel, vinorelbine, and irinotecan) have shown definite activity in advanced NSCLC. The activity of these agents has led to phase II studies combining them with cisplatin, producing response rates that are generally in excess of 35%. Randomized trials suggest that survival is improved when combinations of gemcitabine/cisplatin, vinorelbine/cisplatin, and paclitaxel/cisplatin are compared with cisplatin alone or cisplatin/etoposide. The following report reviews the ongoing trials in NSCLC.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1998

Gemcitabine and paclitaxel combinations in non-small cell lung cancer.

Gemcitabine and paclitaxel are new cytotoxic agents that have been used both as single agents and in combination, particularly with cisplatin, in the therapy of non-small cell lung cancer (NSCLC) with promising results. The lack of overlapping toxicities and different mechanisms of action of gemcitabine and paclitaxel make the combination of these drugs appealing in the treatment of NSCLC. A number of phase I and II trials are evaluating the use of this combination of cytotoxic agents as first-line therapy and as second-line therapy in patients with advanced NSCLC. In ongoing phase II trials using a 21-day schedule, the combination of gemcitabine and paclitaxel therapy appears to be well-tolerated, with response rates ranging from 29% to 58% and hematologic toxicities that are mild to moderate in severity. Other reported toxicities included alopecia, fatigue, and flu-like symptoms, which were also mild to moderate. However, grade 2/3 neurotoxicity was also reported. In conclusion, preliminary results from these early phase II trials of gemcitabine/paclitaxel combination therapy in advanced NSCLC are encouraging.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1997

Diffuse thalamic degeneration in fatal familial insomnia. A morphometric study.

A morphometric investigation disclosed most thalamic nuclei severely degenerated in two patients with fatal familial insomnia. Associative and motor nuclei lost 90% neurons, and limbic-paralimbic, intralaminar and reticular nuclei lost 60%. These findings point to the disorganization of most thalamic circuits as a condition necessary for the sleep-wake rhythm being affected.

Adult↗
PubMed1997

FHIT and FRA3B 3p14.2 allele loss are common in lung cancer and preneoplastic bronchial lesions and are associated with cancer-related FHIT cDNA splicing aberrations.

We evaluated primary lung cancers, tumor cell lines, and preneoplastic bronchial lesions for molecular genetic abnormalities in the candidate tumor suppressor gene FHIT, which spans the FRA3B fragile site at 3p14.2. 3p14.2 allele loss was very frequent in 32 lung cancer cell lines [100% of small cell lung cancer and 88% of non-small cell lung cancer (NSCLC)] and 108 primary NSCLC cancers (45%), with numerous breakpoints indicating involvement of several distinct regions in the FRA3B site. 3p14 allele loss was least frequent in the adenocarcinoma subtype and occurred at the relatively late carcinoma in situ stage of preneoplastic bronchial lesions found in NSCLC patients. Homozygous deletions within the FHIT/FRA3B region were found in 6 of 135 (4.4%) thoracic cancer cell lines. Northern blot showed low or absent FHIT expression in most thoracic cancer cell lines tested, whereas reverse transcription-PCR showed that 59-62% exhibited aberrant FHIT transcripts but nearly always (93-100%) also expressing the wild-type transcripts. Aberrant transcripts included precise deletions of FHIT exons, insertion of non-FHIT sequences between exons and insertions replacing exons. Complete open reading frame single-strand conformational polymorphism analysis of 102 lung cancer cDNAs revealed only one nonsplicing mutation. Normal cells including bronchial epithelium, lung, and trachea expressed wild-type FHIT transcript and a variant transcript deleted for exon 8 but not the other aberrant transcripts, arguing against exon 8-deleted FHIT transcripts being tumor specific. Our findings support the conclusion that FHIT/FRA3B abnormalities are associated with lung cancer pathogenesis but that FHIT abnormalities differ from the types of mutations and lack of wild-type transcript found in classic tumor suppressor genes, and functional studies are needed to define the role of FHIT in thoracic tumorigenesis.

Acid Anhydride Hydrolases↗