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Biomedical subjects

G Giaccone

Publications and source records attributed to G Giaccone.

At least 217 records · Page 12Linked to original sources
PubMed1993

A68 is a component of paired helical filaments of Gerstmann-Sträussler-Scheinker disease, Indiana kindred.

Gerstmann-Sträussler-Scheinker disease in the Indiana kindred is pathologically characterized by prion protein amyloid deposits and neurofibrillary tangles (NFT) with paired helical filaments (PHF). Using antibodies to various domains of the tau molecule, we investigated the composition of PHF in this family by immunocytochemistry and immunoblot analysis. The results indicate that A68 is a component of NFT in this family as it is in Alzheimer's disease, and suggest that post-translational modifications of tau leading to formation of A68 are not unique to Alzheimer's disease.

Aged↗
PubMed1993

Antiemetic activity of oral lorazepam in addition to methylprednisolone and metoclopramide in the prophylactic treatment of vomiting induced by cisplatin. A double-blind, placebo-controlled study with crossover design.

AIMS AND BACKGROUND: It has been suggested that lorazepam has a definite role as an antiemetic drug in antiemetic cocktails. In this study we examined the antiemetic efficacy of metoclopramide (200 mg) and methylprednisolone (1000 mg) with or without lorazepam. METHODS: Sixty patients treated with cisplatin-containing regimens were entered into a randomized, double-blind study with cross-over. Lorazepam 2.5 mg or placebo were administered orally the evening before therapy and just after the beginning of fluid infusion for chemotherapy. Degree of nausea and number of vomiting episodes, together with somnolence, were recorded on a data flow sheet and visual-analogue scales. RESULTS: 100 cycles (50 patients) are evaluable. In 39 cycles there was no nausea and vomiting, in 74 cycles acceptable control of emesis was reached (0-2 episodes of vomiting), without significant differences among the two arms. However, nausea was shorter in lorazepam arm (p < 0.01), and 80% of the patients preferred treatment with lorazepam (p < 0.003). Anxiety was reduced in the patients treated with lorazepam (p < 0.4). CONCLUSIONS: Lorazepam improves tolerability to cisplatin-containing chemotherapy, mainly by influencing the psychological status of the patient and favoring the amnestic process.

Adult↗
PubMed1993

Ubiquitinated neurites are associated with preamyloid and cerebral amyloid beta deposits in patients with hereditary cerebral hemorrhage with amyloidosis Dutch type.

Hereditary cerebral hemorrhage with amyloidosis Dutch type (HCHWA-D) is characterized clinically by recurrent strokes and pathologically by deposition of amyloid beta (A beta) in cerebral vessel walls and, to a lesser extent, in the neuropil. Distinct from Alzheimer's disease, amyloid formation in HCHWA-D is not associated with neurofibrillary changes. Since a central issue in the pathophysiology of Alzheimer's disease and related conditions is the role of A beta in the neurodegenerative process, we investigated HCHWA-D brains for the presence of neuritic abnormalities using antibodies to ubiquitin and to phosphorylated neurofilaments. The study showed that amyloid deposits in the vessel walls and in the neuropil were surrounded by abnormal ubiquitinated neurites, suggesting that A beta deposition induces neuritic changes.

Aged↗
PubMed1993

Cytotoxic effects of anticancer agents on subconfluent and multilayered postconfluent cultures.

The cytotoxic effects of conventional (doxorubicin, 5-fluorouracil, cisplatin) and investigational (2',2'-difluorodeoxycytidine, hexadecylphosphocholine, EO9, rhizoxin) anticancer drugs were studied in subconfluent and multilayered postconfluent cultures of human colon and ovarian carcinoma cell lines. Chemosensitivity was assessed 4 days after a 24-h drug exposure with the sulphorhodamine B assay. Except for rhizoxin, all drugs tested yielded an EC50 (drug concentration producing absorbance readings 50% lower than those of non-treated wells) in postconfluent cultures that were higher than an EC50 obtained with subconfluent cultures. Compared with subconfluent cultures, postconfluent cultures showed decreased cellular nucleotide concentrations and ATP/ADP ratios, in addition to an increased percentage of G0/G1 cells. The activity of DT-diaphorase, a reductase involved in the bioactivation of EO9, was similar in sub- and postconfluent cultures. These results indicate similarity of the postconfluent model presented with those obtained with in vivo models and more complex in vitro techniques.

Antineoplastic Agents↗
PubMed1993

Cortisol is transported by the multidrug resistance gene product P-glycoprotein.

The physiology of the multidrug transporter P-glycoprotein (Pgp) is still poorly understood. We now show evidence that cell lines with a high expression of Pgp display a reduced accumulation of cortisol and an ATP-dependent outward transport of the hormone. Cortisol efflux from Pgp negative cells does not have such an active component. Further we show that the steroid hormones cortisol, testosterone, and progesterone cause an immediate, dose-dependent increase of daunorubicin accumulation in Pgp overexpressing cells. These effects are particularly apparent for the more lipophilic steroids. These results demonstrate that Pgp may function as a transporter for cortisol and suggest a physiological role of the protein in steroid handling by organs such as the adrenal.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1993

Beta PP participates in PrP-amyloid plaques of Gerstmann-Sträussler-Scheinker disease, Indiana kindred.

Gerstmann-Sträussler-Scheinker disease in the Indiana kindred is pathologically characterized by deposits of PrP-amyloid, neurofibrillary tangles and degenerating neurites. The aim of this study was to investigate seven patients of different ages for beta PP and A beta immunoreactivities associated with PrP-amyloid deposits and degenerating neurites. In one asymptomatic individual with PrP-amyloid deposits, Alz50 and A beta immunoreactivities were absent. In six symptomatic patients, the degenerating neurites surrounding PrP-amyloid deposits were labeled by Alz50 and by antibodies to synaptophysin, ubiquitin and the N- and C-terminal domains of beta PP. In one symptomatic, senile patient, A beta immunoreactivity was present in the extracellular space, often in association with PrP-amyloid deposits. The analysis of the immunohistochemical findings suggested that in the Indiana kindred the intracellular accumulation of beta PP, synaptophysin and ubiquitinated material most probably revealed a reaction of neurites to PrP-amyloid, whereas the extracellular deposition of A beta was likely an age-related phenomenon.

Aged↗
PubMed1993

Maintenance chemotherapy in small-cell lung cancer: long-term results of a randomized trial. European Organization for Research and Treatment of Cancer Lung Cancer Cooperative Group.

PURPOSE: The present study investigates the role of short chemotherapy (five cycles) versus prolonged (12 cycles) chemotherapy in small-cell lung cancer (SCLC). PATIENTS AND METHODS: Six hundred eighty-seven patients with SCLC were registered in a multicenter study to receive five cycles of chemotherapy consisting of cyclophosphamide 1 g/m2 on day 1, doxorubicin 45 mg/m2 on day 1, and etoposide 100 mg/m2 on days 1, 3 and 5 (CDE), every 3 weeks. Four hundred thirty-four nonprogressing patients after five cycles of chemotherapy were randomized either to receive seven further cycles of the same chemotherapy or to follow-up. RESULTS: The response rate of 585 assessable patients was 79%, with 36% attaining a complete response. Toxicity was mainly hematologic, with 16 toxic deaths (2.4% of all eligible patients), 13 of which were due to sepsis. Median survival time from registration of all patients was 326 days (396 and 267 days for limited and extensive disease, respectively) with 3.2% of patients alive at 5 years. No difference in survival between the two arms was observed, with the same number of 5-year survivors in both arms. The patients randomized to the maintenance arm had a progression-free survival (PFS) duration approximately 2 months longer than the patients randomized to follow-up (median of 177 days v 114 days from randomization; P = .0004). Among patients with a partial response who were randomized to receive maintenance chemotherapy, 12 achieved a complete response after 12 cycles. More patients in the follow-up arm than in the maintenance arm received subsequent treatment on progression and responded more frequently to that treatment. Twelve patients developed second malignancies (seven non-small-cell lung cancers). CONCLUSION: Prolonged chemotherapy does not offer a better chance of cure than short chemotherapy (five cycles) and does not prolong survival in patients with SCLC. Short, combination chemotherapy appears to be a reasonable choice for standard treatment of SCLC and for attempts to improve the cure rate of this disease.

Adult↗
PubMed1992

Characterization of a topoisomerase II gene rearrangement in a human small-cell lung cancer cell line.

BACKGROUND: Small-cell lung cancer (SCLC) is a highly chemosensitive tumor, but the recurrent disease that is common after initial response is often unresponsive to further chemotherapy. Although the mechanisms of drug resistance in SCLC have not been established, studies suggest that alterations of the nuclear enzyme DNA topoisomerase II may reduce the sensitivity of the cell to drug action. This enzyme is recognized as a primary target for cytotoxic activity of important antitumor agents. PURPOSE: In this study, we attempted to determine if altered forms of DNA topoisomerase II are responsible for reduced drug sensitivity. METHODS: We characterized a rearrangement of the topoisomerase II p170 gene (also known as TOP2) in a relatively chemoresistant SCLC cell line, NCI-H69, and compared topoisomerase II expression and activity in this line with those in the chemosensitive NCI-H187 cell line. Fragments of complementary DNA from the topoisomerase II gene were generated by polymerase chain reaction. Immunodetection was accomplished by using the monoclonal antibody 7E6 against the human topoisomerase II p170 isoform. Using DNA probes corresponding to different complementary DNA regions, we showed that the rearrangement was localized at the 3' terminus of one allele of the topoisomerase II gene. RESULTS: In addition to the normal 6.2-kilobase (kb) topoisomerase II messenger RNA (mRNA), the NCI-H69 line expressed a 7.4-kb topoisomerase II transcript, presumably encoded by the rearranged allele. Moreover, this transcript, although longer than the normal mRNA, lacked a substantial portion of the 3'-terminal p170 gene coding sequence. Topoisomerase II activity in nuclear extracts, as determined by the P4 phage DNA-unknotting assay, was more easily detected and measured at lower NaCl concentrations in NCI-H69 than in NCI-H187 cells. CONCLUSION: These results are consistent with the hypothesis that the chemoresistant NCI-H69 cell line may express, in addition to the normal enzyme, an altered topoisomerase II enzyme possibly encoded by the 7.4-kb mRNA, which in turn may be transcribed from the rearranged gene allele. IMPLICATION: These observations emphasize the role of topoisomerase II in determining drug sensitivity and suggest that such gene rearrangements may contribute to resistance of SCLC cells to topoisomerase II inhibitors.

Alleles↗
PubMed1992

Prion protein preamyloid and amyloid deposits in Gerstmann-Sträussler-Scheinker disease, Indiana kindred.

Gerstmann-Sträussler-Scheinker disease (GSS) is a familial neurological disorder pathologically characterized by amyloid deposition in the cerebrum and cerebellum. In GSS, the amyloid is immunoreactive to antisera raised against the prion protein (PrP) 27-30, a proteinase K-resistant peptide of 27-30 kDa that is derived by limited proteolysis from an abnormal isoform of a neuronal sialoglycoprotein of 33-35 kDa designated PrPSc. Polyclonal antibodies raised against synthetic peptides homologous to residues 15-40 (P2), 90-102 (P1), and 220-232 (P3) of the amino acid sequence deduced from hamster PrP cDNA were used to investigate immunohistochemically the distribution of PrP and PrP fragments in the brains of two patients from the Indiana kindred of GSS. Two types of anti-PrP-immunoreactive deposits were found: (i) amyloid deposits, which were exclusively labeled by anti-P1 antiserum to residues 90-102 of PrP, and (ii) preamyloid deposits, which were labeled by all anti-PrP antisera but did not exhibit the tinctorial and optical properties of amyloid. The latter appeared as diffuse immunostaining of the neuropil that targeted to areas in which amyloid deposits were most abundant. They were partially resistant to proteinase K digestion and consisted ultrastructurally of amorphous, flaky, electron-dense material. These findings substantiate our previous observation that the major amyloid component in the GSS Indiana kindred is an internal fragment of PrP and indicate that full-length abnormal isoforms of PrP and/or large PrP fragments accumulate in brain regions most affected by amyloid deposition. These findings support the view that in the GSS Indiana kindred a stepwise degradation of PrP occurs in situ in the process of amyloid fibril formation.

Aged↗
PubMed1992

Neuromedin B is present in lung cancer cell lines.

Previously, high levels of gastrin-releasing peptide and its mRNA were detected in classic small cell lung cancer cell lines. Here the ability of lung cancer cell lines to synthesize neuromedin B (NMB), a structurally similar mammalian bombesin-like peptide, was investigated. By radioimmunoassay, NMB (0.1-0.7 pmol/mg of protein) was detected in 23 of 33 lung cancer cell lines. In contrast, gastrin-releasing peptide (0.1-12.9 pmol/mg of protein) was detected in 16 of 32 cell lines. Using gel filtration and high pressure liquid chromatography techniques, the main peak of immunoreactive NMB coeluted with synthetic NMB. By Northern analysis, a 0.8-kilobase mRNA species was present, using poly(A) mRNA derived from two of three lung cancer cell lines. Using a more sensitive S1 nuclease protection assay, NMB mRNA was present in most of the 15 lung cancer cell lines examined. These data suggest that NMB may be a regulatory peptide in lung cancer.

Blotting, Northern↗
PubMed1992

Multidrug sensitivity phenotype of human lung cancer cells associated with topoisomerase II expression.

Patterns of drug sensitivities in relation to topoisomerase II gene expression and activity were studied in eight human lung cancer cell lines not selected in vitro for drug resistance. The cytotoxicities of doxorubicin, etoposide, teniposide, cisplatin, camptothecin, and 5-fluorouracil were measured and, remarkably, these unselected cell lines were shown to have a common pattern of multidrug sensitivity, i.e., a multidrug sensitivity phenotype. In fact, drug sensitivities were significantly correlated with each other in the studied cell lines, the correlation being best for the topoisomerase II-targeted agents and cisplatin, less strong with camptothecin, and weak with 5-fluorouracil. Almost 1-log range difference of topoisomerase II gene expression was found in these cell lines, and this was not explained by the cell-doubling time or cell cycle distribution. The level of topoisomerase II gene expression was positively and highly correlated with the cell sensitivity to epipodophyllotoxins, doxorubicin, and cisplatin in seven cell lines. Although weaker, an association was also observed between topoisomerase II gene expression and camptothecin cytotoxicity, while no association was observed with 5-fluorouracil. However, a non-small cell lung cancer cell line with neuroendocrine properties had very low levels of expression of the topoisomerase II gene, despite being highly sensitive to all drugs tested. The levels of topoisomerase I gene expression were not found to be correlated with the cytotoxicity of any drug tested. A specific enzymatic activity assay and a teniposide-stimulated DNA cleavage assay showed that the extent of active topoisomerase II present in nuclear extracts paralleled the level of topoisomerase II gene expression. Furthermore, in addition to the normal transcript, an abnormally sized topoisomerase II message and a rearrangement of the topoisomerase II gene were detected in a poorly sensitive small cell lung cancer cell line. Therefore, low levels of topoisomerase II gene expression, and possibly mutations, may predict a reduced sensitivity of unselected human lung cancer cell lines to several drugs, including agents with a cellular target other than topoisomerase II. It is hypothesized that topoisomerase II might be involved in a common pathway of cell death induced by drugs in tumor cell lines which present a multidrug sensitivity phenotype.

Adenocarcinoma↗
PubMed1992

Phase II study of ACNU as second-line treatment in small-cell lung cancer. EORTC Lung Cancer Cooperative Group.

A total of 24 patients presenting with small-cell lung cancer either resistant to or relapsing within 3 months after first-line treatment were entered in a phase II study of 1-(4-amino-2-methyl-5-pyrimidinyl)-methyl-(2-chloroethyl)-3- nitrosourea hydrochloride (ACNU). ACNU was given i.v. at a dose of 75 mg/m2 every 6 weeks. We observed a partial response of 7 months' duration in one patient and one case of stable disease that lasted for 6 months; all other subjects exhibited progressive disease. Two patients developed brain metastases during treatment. The toxicity of ACNU consisted mainly of bone marrow suppression, especially thrombocytopenia. At this dose and on this schedule, ACNU shows minimal activity as second-line treatment in small-cell lung cancer.

Carcinoma, Small Cell↗
PubMed1992

The differential diagnosis of primary lung cancer: inter-observer agreement and contribution of specific diagnostic procedures.

In order to investigate inter-observer variability in the differential diagnosis of primary lung cancer among women and the contribution of specific diagnostic procedures to this diagnosis, a group of 449 suspect cases of this disease was studied. Based on a standard dossier (including clinical data and the reports, if present, of radiology, bronchoscopy and histology) six different physicians independently judged, for each woman, at each diagnostic step, the presence of a primary lung cancer. A final consensus was organized in order to define the true cases. Radiology and especially histology seem to give the most important contribution to the diagnosis. On the other hand bronchoscopy seems to be useful mainly as a guide for biopsy. A predictive value of 90% was found when both radiology and bronchoscopy were positive; in the other cases histology seems to be needed to reach an adequate discrimination. Inter-rater agreement increases with an increasing amount of information but is not very high even when histology is available.

Bronchoalveolar Lavage Fluid↗
PubMed1992

Epirubicin in previously untreated patients with small cell lung cancer: a phase II study by the EORTC Lung Cancer Cooperative Group.

Epirubicin 110 mg/m2 was administered intravenously every 3 weeks to 41 elderly and/or unfit, previously untreated patients with small cell lung cancer (SCLC). There were three complete responses, 16 partial responses and 14 treatment failures, with a response rate of 57% in 33 evaluable patients. The main toxicity was haematological, characterised by leukopenia and, less frequently, thrombocytopenia and anaemia. There were three toxic deaths due to infection occurring during leukopenia. Non-haematological side effects were alopecia, nausea, stomatitis and diarrhoea. WHO grade 2 cardiac toxicity was seen in 3 patients after a cumulative dose of more than 740 mg/m2. In conclusion epirubicin is an active agent in untreated SCLC.

Aged↗
PubMed1992

Increased expression of differentiation markers can accompany laminin-induced attachment of small cell lung cancer cells.

We investigated the interaction between human lung cancer cells, laminin, and several differentiating agents. When grown on laminin coated substrate eight out of 11 small cell lung cancer (SCLC) cell lines exhibited attachment to laminin and three had extensive outgrowth of long neurite-like processes. Of seven non-small cell lung cancer cell lines, selected for their in vitro anchorage-independent growth, attachment was observed in only three cell lines, and process formation was far less extensive than in SCLC cell lines. Among several differentiating agents, only dcAMP, which alone induced attachment and some process formation, increased laminin-mediated attachment and process formation of two SCLC cell lines, NCI-N417 a variant cell line, and NCI-H345, a classic cell line. The expression of several neuroendocrine and neuronal markers was investigated in these two SCLC cell lines. The expression of the light subunit of neurofilaments increased in NCI-N417 within 3 to 4 days of seeding, while NCI-H345 exhibited approximately 5 fold increase in expression of the GRP gene and a 3 fold increase expression of the beta-actin gene. The expression of a number of other neuroendocrine and neuronal markers did not change following growth on laminin. The doubling times remained unchanged independent of the presence of and attachment to laminin while topoisomerase II gene expression levels in NCI-N417 cells decreased approximately 5 fold when cells were growing on laminin.

Acetamides↗
PubMed1992

Growth, morphology and chemosensitivity studies on postconfluent cells cultured in 'V'-bottomed microtiter plates.

This study assessed the growth pattern, cellular organisation and chemosensitivity of established human tumour cell lines growing as postconfluent cultures in 'V'-bottomed, 96-well microtiter plates. Cross-sections of the colon (HT29, SW620, SW1116), ovarian (A2780) and head and neck (UM-SCC-22B) carcinoma microcultures allowed in situ evaluation of the cellular organisation in the wells. After 5 days of growth, every cell line had reached confluence, but each of them displayed a specific pattern of cell stacking which ranged from two to ten layers. Postconfluent HT29 cells displayed morphologic features suggestive of some degree of enterocytic differentiation. Growth and cytotoxicity could be studied reliably and reproducibly in this system with the sulforhodamine B protein assay. Against HT29 postconfluent cultures, the EC50's (drug concentrations producing absorbance readings 50% lower than those of non-treated wells) of 5-fluorouracil and of the ether lipid, hexadecylphosphocholine, were 1 mM and 50 microM respectively. The possibility to perform chemosensitivity tests using semiautomated microtiter plate technology supports further evaluation of this system as an alternative antitumour drug testing model.

Breast Neoplasms↗
PubMed1992

Epirubicin in malignant mesothelioma: a phase II study of the European Organization for Research and Treatment of Cancer Lung Cancer Cooperative Group.

PURPOSE: The doxorubicin analog, epirubicin (EPI), was tested in patients with malignant mesothelioma. PATIENTS AND METHODS: Sixty-three patients with malignant mesothelioma were given EPI 110 mg/m2 every 3 weeks. Histology was reviewed and confirmed by a pathology panel. On the basis of unconvincing or wrong histology, insufficient material or cytology only, nine cases were considered ineligible for the study. None of the patients had received prior chemotherapy. RESULTS: The main side effects were myelosuppression, alopecia, and gastrointestinal toxicity. Tumor response, assessed by computed tomographic (CT) scans, was assessable in 48 patients. Seven patients (15%) achieved a partial response that lasted a median of 37 weeks; 19 patients had stable disease, and 22 patients progressed on treatment. Median survival time was 40 weeks from the start of chemotherapy, and the median survival of responding patients was 87 weeks. One responding patient is still alive and free of relapse 4 years from the start of chemotherapy. CONCLUSION: We conclude that further testing of EPI in malignant mesothelioma is warranted.

Adult↗