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Biomedical subjects

S Parodi

Publications and source records attributed to S Parodi.

At least 37 records · Page 2Linked to original sources
PubMed1999

Drug metabolism polymorphisms as modulators of cancer susceptibility.

Recently, several molecular genetic bases of polymorphic enzyme activities involved in drug activation and detoxification have been elucidated. Many molecular epidemiology studies based on these premises have sought to gather information on the association of genetically determined metabolic variants with different risks of environmentally induced cancer. While rare alterations of tumor suppressor genes dramatically raise cancer risk for the single affected subjects, far more common and less dramatic differences in genes encoding for drug metabolism enzymes can be responsible for a relatively small, but rather frequent increase of cancer risk at the population level. This increase could be especially important in specific cases of occupational, pharmacological or environmental exposure. Examination of the current literature reveals that the most extensively investigated metabolic polymorphisms are those of P450 1A1 and P450 2D6 cytochromes, glutathione S-transferases (GSTs; M1 and, to a lesser extent, M3, P1 and T1) and N-acetyltransferases (NATs; NAT1 and NAT2). Making reference to these enzymes, we have assayed the current knowledge on the relations among polymorphisms of human xenobiotic-metabolizing enzymes and cancer susceptibilities. We have found intriguing models of susceptibility toward different types of cancer. We have reviewed and commented these models on light of the complex balance among different enzyme activities that, in each individual, determines the degree of each cancer susceptibility. Moreover, we have found techniques of molecular genetic analysis, more suitable than previous ones on phenotypic expression, now allowing better means to detect individuals at risk of cancer. According to the models presently available, a systematic screening of individuals at risk seems to make sense only in situations of well defined carcinogenic exposures and when performed by the polymorphism analysis of coordinated enzyme activities concurring to the metabolism of the carcinogen(s) in question. Genetic polymorphism analysis can allow for the detection of patients more prone to some types of specific cancers, or to the adverse effects of specific pharmaceutical agents. Considering the increasingly confirmed double-edged sword nature of metabolism polymorphism (both wild-type and variant alleles can predispose to cancer, albeit in different situations of exposure), individual susceptibility to cancer should be monitored as a function of the nature, and mechanism of action, of the carcinogen(s) to which the individual under study is known to be exposed, and with reference to the main target organ of the considered type of exposure.

Disease Susceptibility↗
PubMed1999

Cooperation between p53 and hMLH1 in a human colocarcinoma cell line in response to DNA damage.

We have studied the possible interactions between the mismatch repair system and p53 in a human colon cancer cell line, HCT-116 (known to have a homozygous mutation in mismatch repair gene hMLH1 on chromosome 3) and in a clone obtained after insertion of a single copy of chromosome 3 (HCT-116+ ch3). Loss of DNA mismatch repair activity resulted in resistance to cisplatin (DDP). p53 accumulated differently in these cell lines after treatment with DDP. Initially at similar high levels after DDP treatment, p53 maintained the increase in HCT-116 cells, even 72-96 h after drug exposure, whereas HCT-116+ch3 mismatch-proficient cell line p53 declined to basal levels after 48 h. The higher levels of p53 in mismatch-deficient HCT-116 cells were accompanied by increased transcriptional activity as assessed by the gel-retardation assay and by activation of a promoter containing a p53 DNA binding site. To better understand the role of p53, if any, in cell sensitivity to DDP, we disrupted p53 in both cell lines by stable transfection with the human papillomavirus type 16 E6 gene. HCT-116/E6 cells were more sensitive to DDP than the parental cell line, whereas HCT-116+ch3/E6 were fairly similar to HCT-116+ch3 with normal p53 function. Although in our system the transfer of the entire chromosome 3 was used (thus not excluding a possible role of other genes localized on this chromosome), our data indicate that p53 can cooperate with the mismatch repair system. In fact, the lack of hLMH1, at least in these cells, enhances the role of p53 in protecting the cells from DDP-induced DNA damage.

Adaptor Proteins, Signal Transducing↗
PubMed1999

Computer-aided analysis of mutagenicity and cell transformation data for assessing their relationship with carcinogenicity.

Using a computer-aided approach, the tests for Salmonella mutagenicity and transformation in established cell lines were compared for the qualitative bases of their carcinogenicity predictions. For this purpose, a database of 145 chemicals was prepared in which rodent carcinogenicity data and results of the Ames' and transformation tests were available. Using a software program for connectivity analysis (previously developed and validated by us), we assayed the molecular structures of these chemicals for the presence of fragments relatable to their positive (i.e., biophores) or negative (i.e., biophobes) response to the tests in question. These fragments were then studied for their association with genotoxic and nongenotoxic carcinogenicity. The philosophy adopted was that the type and number of molecular fragments chosen by the software to describe the chemicals correctly predicted by the tests could be related to the type of carcinogenic effects to which the tests themselves were sensitive. The classifications made by the software were interpreted by human expertise and the biophores found were compared with the acknowledged structural alerts to DNA reactivity as formalized by Ashby and co-workers [(1991): Mutat Res 257:229-306; (1993): Mutat Res 286: 3-74]. The results show that, in quantitative terms, the overall ability to predict carcinogenicity is about the same for both the Salmonella and transformation tests. However, in qualitative terms the transformation test appears to be sensitive to effects that are more heterogeneous than those inducing mutation, some of which are presumably related to nongenotoxic carcinogenic activities. This study illustrates a possible, innovative model of analysis of chemical structures that, using an automated approach along with the biologist's judgment, could contribute to the detection of complementarities among short-term test endpoints.

Animals↗
PubMed1999

In situ RT-PCR allows the detection of ornithine decarboxylase mRNA in paraffin embedded archival human hyperplastic breast tissues.

Expression of ornithine decarboxylase (ODC) is induced by c-Myc oncoprotein and is required for cell proliferation and tumour growth. We have studied the expression of ODC mRNA by in situ hybridisation and in situ RT-PCR in archival human hyperplastic breast tissues. A very low signal was detected by in situ hybridisation, while the in situ RT-PCR on human breast archival tissues demonstrated an over-expression of ODC mRNA in epithelial cells characterised by some degree of hyperplasia, maintaining the morphology of the archival tissue intact despite the multiple steps of fixation, permeabilization and thermal cycling.

Breast↗
PubMed1998

Inhibition of cancer cell growth and c-Myc transcriptional activity by a c-Myc helix 1-type peptide fused to an internalization sequence.

c-Myc is a nuclear protein with important roles in cell transformation, cell proliferation, and gene transcription. It has been previously shown that a 14-amino acid (aa) modified peptide (H1-S6A,F8A) derived from the helix 1 (H1) carboxylic region of c-Myc can interfere in vitro with specific c-Myc DNA binding. Here, we have linked the above Myc-derived 14-aa peptide to a 16-aa sequence from the third helix of Antennapedia (Int). It has been repeatedly reported that this 16-aa Antennapedia peptide is able to cross mammalian cell membranes and to work as a vector for short peptides. Using fluorescent (dansylated or rhodaminated) peptides, we have shown that the fusion peptide with the Antennapedia fragment (Int-H1-S6A,F8A) but not the c-Myc derived fragment alone (H1-S6A,F8A) was capable of internalization inside MCF-7 human breast cancer cells. Int-H1-S6A,F8A and H1-S6A,F8A were the only two peptides capable of inhibiting coimmunoprecipitation of the c-Myc/Max heterodimer in vitro. We have treated (continuously for 10-11 days) MCF-7 cells with four different peptides: Int, H1-S6A,F8A, Int-H1-S6A,F8A, and Int-H1wt [a peptide differing from Int-H1-S6A,F8A by 2 aa (S6 and F8) in the H1 region]. In intact MCF-7 cells, Int-H1-S6A,F8A was the only active peptide capable of inducing the following biological effects: (a) inhibition of cloning efficiency on plates; (b) inhibition of cell growth and induction of apoptosis in subconfluent/confluent cells; and (c) inhibition of transcription of two c-Myc-regulated genes (ODC and p53). Int-H1-S6A,F8A was active in the 1-10 microM range. Int-H1-S6A,F8A may represent a lead molecule for peptidomimetic compounds that have a similar three-dimensional structure but are more resistant to peptidases and, therefore, suitable for in vivo treatment of experimentally induced tumors.

Amino Acid Sequence↗
PubMed1998

Effect of fenretinide on plasma IGF-I and IGFBP-3 in early breast cancer patients.

Growing evidence substantiates the role of the insulin-like growth factor I (IGF-1) system in breast tumorigenesis. Retinoids have been shown to affect the IGF system several experimental models. We extended our previous data on plasma IGF-1 modulation by the synthetic retinoid fenretinide (4-HPR) and investigated the effect of the retinoid on plasma IGF binding protein (BP)-3, the major protein binding IGFs. IGF-1 and IGFBP-3 were measured on plasma samples obtained at randomization and after an interval of approximately 1 year, from 39 and 33 stage 1 breast cancer patients assigned to receive 4-HPR, and from 39 and 34 untreated controls, respectively. There was a significant decrease in plasma IGF-1 after 4-HPR administration, whereas no significant change was observed in controls. The effect of 4-HPR on IGF-1 levels was modified by menopausal status, inasmuch as the decrease in IGF-1 was particularly pronounced in pre-menopausal women, whereas the reverse was observed in untreated controls. By contrast, treatment induced an increase of IGFBP-3 with respect to controls. As a result of this dual effect, the bioavailability of IGF-1 for interaction with receptors at target levels further decreased in pre-menopausal 4-HPR treated patients compared with controls, suggesting that retinoid administration may result in lower concentrations of biologically active IGF-1. Our findings may have important implications for the clinical preventive activity of this retinoid.

Adult↗
PubMed1998

Performance status and comorbidity in elderly cancer patients compared with young patients with neoplasia and elderly patients without neoplastic conditions.

BACKGROUND: Elderly people constitute a heterogeneous group and are at an increased risk for the development of cancer. It is not clear whether comorbid conditions and functional status influence clinical decisions and the pattern of referral in elderly cancer patients. The current study investigated functional status measured by Eastern Cooperative Oncology Group performance status, comorbid conditions, and medication taken as well as social environment in three series of patients grouped according to age and diagnosis. METHODS: A total of 593 patients were involved: 138 neoplastic patients age > 70 years with breast, colon, or prostate carcinoma, 177 neoplastic patients age < 70 years with the same types of pathology, and 278 elderly patients with nonneoplastic conditions. Patients with neoplastic disease were recruited from cancer centers; patients with nonneoplastic disease were recruited from either geriatric or general medicine departments. Differences in the distribution of variables were analyzed by univariate and bivariate analyses. RESULTS: No significant differences in social environment, marital status, or education were observed. Statistical differences were noted when comparing the distribution of comorbidities, performance status, and medication taken, elderly neoplastic patients presented in poorer condition compared with younger patients but in better condition compared with elderly patients with nonneoplastic disease. CONCLUSIONS: The overall better health of older cancer patients compared with those without cancer needs to be assessed further. It is possible that cancer is more likely to be diagnosed in healthier elderly, or that primary care providers are reluctant to refer for cancer care patients in poor general health. Studies of comorbidity, function, and social resources are necessary to establish the impact of cancer on survival and quality of life of older patients and to determine the social resources necessary for adequate care.

Activities of Daily Living↗
PubMed1998

In vivo studies on genotoxicity of a soil fumigant, dazomet.

Dazomet is a soil fumigant effective against germinating weed seeds, nematodes, soil fungi, and soil insects. Dazomet is primarily used for preplanting control in tobacco and forest nursery crops and is now marketed for a wider range of open field and greenhouse crops (e.g., vegetables, fruits, ornamental plants, lawns, and turfs). Swiss CD1 male and female mice were intraperitoneally treated with dazomet in order to evaluate its potential genotoxicity. DNA damage activity, namely, DNA single-strand breaks, DNA adducts, and increased micronuclei frequency due to treatment with the soil fumigant was observed in the experimental animals. Dose-dependent DNA adduct formation was detected in the liver, kidneys, and lungs of mice. DNA adduct levels in these three organs were 6.0 +/- 0.4 (SD), 4.8 +/- 0.1 (SD), and 2.2 +/- 0.4 (SD) adducts/10(8) nucleotides, respectively, at the highest dose of the soil fumigant tested (90 mg/kg). No adduct formation was observed in control mice. A significant increase in DNA single-strand breaks was detected in the liver and kidneys of mice treated with 100 mg/kg of dazomet (P < 0.05). A significant increase in micronuclei frequency was observed in the bone marrow of mice treated with 100 mg/kg of dazomet (P < 0.05).

Animals↗
PubMed1998

Socioeconomic status and survival of gastric cancer patients.

Survival differences in cancer patients according to socioeconomic status (SES) have been reported for several organs, but the relationship with gastric cancer prognosis has not been conclusively defined. The present study analysed the survival of 122 incident, histologically confirmed gastric cancer patients diagnosed between 1985 and 1987 in Genoa, Italy and enrolled in a multicentric case-control study on gastric cancer occurrence and dietary habits. Adjusting for age at diagnosis, tumour stage, histopathological grading and surgery (i.e. curative gastric resection), Cox's proportional hazards regression model showed statistically significant hazard ratio (HR) (relative risk) estimates below unity for education (> 5 versus < or = 5 years of schooling, HR = 0.40, P = 0.003) and occupation (higher versus lower income job, HR = 0.59, P = 0.030). Also, the same final regression model revealed a positive prognostic effect for origin (Southern Italy migrants versus Genoa natives) (HR = 0.56, P = 0.039) and female gender (HR = 0.58, P = 0.020). High SES, origin from lower risk area for gastric cancer occurrence and female gender are positive prognostic categories for gastric cancer patients.

Adult↗
PubMed1998

Correlation between plasma transforming growth factor-beta 1 and second primary breast cancer in a chemoprevention trial.

The relationship between plasma transforming growth factor-beta 1 (TGF-beta 1) and second primary breast cancer was explored in a prevention trial of the synthetic retinoid fenretinide (N-(4-hydroxyphenyl)retinamide; 4-HPR). Plasma concentrations of TGF-beta 1 were measured by radioimmunoassay in plasma obtained at randomisation and after approximately 1 year of intervention in 28 women treated with 4-HPR and 27 untreated controls with stage I breast cancer. Baseline and 1 year growth factor concentrations were not significantly different between treated and control groups. After a median follow-up of 65 months, an increase in TGF-beta 1 over 1 year was the only significant, independent predictor of a shorter survival free from secondary primary breast cancer. Moreover, the change in TGF-beta 1 levels had a tendency to influence the treatment effect on second breast cancer incidence. Our data suggest that the role of plasma TGF-beta 1 as a surrogate endpoint of breast carcinogenesis should be assessed further.

Adult↗
PubMed1998

Relative survival in elderly cancer patients in Europe. EUROCARE Working Group.

In this paper different patterns of survival by age and gender are presented for 17 European countries which participated in the EUROCARE II programme. Survival data were available for 701,521 patients aged between 65 and 99 years from 44 population-based cancer registries. Age-standardised relative survival rates at 1 and 5 years from diagnosis were computed. Relative risks (RRs) of death for those aged between 65 and 99 years compared with those aged between 55 and 64 years were estimated by gender and country. In general, the elderly had a large survival disadvantage, particularly 1 year after diagnosis and in women. Poorer survival rates in the elderly were observed for patients from Eastern European countries for almost all sites. However, relative survival of the elderly with respect to younger patients was similar in the different geographic areas. The results are in agreement with other population-based studies, confirming a worse prognosis for the elderly in both sexes. This may be explained by changes in biology and the natural history of the tumour and the occurrence of severe comorbidities, potentially affecting preventive, diagnostic and therapeutic strategies. The lack of equality in providing adequate treatment to elderly cancer patients should be addressed as a matter of urgency by health-care providers.

Age Distribution↗
PubMed1998

32P-postlabeling detection of aromatic adducts in the white blood cell DNA of nonsmoking police officers.

Atmosphere in urban areas may be polluted by a number of combustion sources, including industries, vehicle traffic, and residential heating. Traffic police constitute a group of workers that is highly exposed to urban pollutants, especially those from motor vehicle exhaust. We conducted a biomonitoring study to simultaneously measure in 34 nonsmoking police officers and in 36 nonsmoking office workers, as referents, the individual benzo(a)pyrene [B(a)P] exposure using personal samplers and the formation of DNA adducts in peripheral WBCs using 32P-postlabeling techniques. Our results show that the police officers were exposed to significantly higher levels of B(a)P than were referents (P < 0.0001). No seasonal variation of the atmospheric levels of B(a)P was found throughout the year. The median relative adduct labeling x 10(-8) values of the controls and exposed police officers were 0.94 (range, 0.1-3.7) and 1.3 (range, 0.1-5.5), respectively, using the nuclease P1 technique. Although the DNA adduct levels of police officers were globally higher than those of referents (P < 0.05), the difference was entirely due to the summer difference [median values 0.80 (range, 0.1-1.8) and 2.8 (range, 0.7-5.5), respectively (P < 0.001)]. In winter, the DNA adduct levels were substantially identical, and in midseason, there was only a very small increase in police officers, with respect to controls (statistically not significant). Moreover, a more significant seasonal variation of bulky aromatic DNA adduct levels was observed in WBC DNA samples of police officers (P < 0.05) compared to those of referents. The seasonal variation of bulky aromatic adduct levels could be correlated with the reported seasonal variation of aryl hydrocarbon hydroxylase inducibility in human lymphocytes.

Adult↗
PubMed1998

32P-postlabeling detection of DNA adducts in mice treated with the herbicide Roundup.

Roundup is a postemergence herbicide acting on the synthesis of amino acids and other important endogenous chemicals in plants. Roundup is commonly used in agriculture, forestry, and nurseries for the control or destruction of most herbaceous plants. The present study shows that Roundup is able to induce a dose-dependent formation of DNA adducts in the kidneys and liver of mice. The levels of Roundup-related DNA adducts observed in mouse kidneys and liver at the highest dose of herbicide tested (600 mg/kg) were 3.0 +/- 0.1 (SE) and 1.7 +/- 0.1 (SE) adducts/10(8) nucleotides, respectively. The Roundup DNA adducts were not related to the active ingredient, the isopropylammonium salt of glyphosate, but to another, unknown component of the herbicide mixture. Additional experiments are needed to identify the chemical specie(s) of Roundup mixture involved in DNA adduct formation. Findings of this study may help to protect agricultural workers from health hazards and provide a basis for risk assessment.

Animals↗
PubMed1997

Mutation frequencies at codon 248 of the p53 tumour suppressor gene are not increased in colon cancer cell lines with the RER+ phenotype.

The replication-error positive (RER+) phenotype characterizes tumour cells with microsatellite instability. This 'mutator phenotype' is thought to induce spread mutations throughout the genome, thus increasing the risk of tumour development. Here we analyse spontaneously arising mutations at the tetranucleotide CCGG ( Msp I recognition site), at positions 14 067-14 070 of the p53 gene sequence, in three colon cancer cell lines, two with microsatellite instability and one without this characteristic. This restriction site covers hot-spot codon 248, which is often mutated in colon carcinomas. Using the Msp I RFLP-PCR assay we found that the mean mutation frequency at this site was not different among the cell lines considered. Taking the substitutions separately, none of the mutations involving codon 248 arose with significantly higher frequency in each of the RER+ cell lines (HCT116 and DLD1) compared with the RER-one (SW480). Only the CG transversion at nt 14 067 (codon 247) occurred with a slightly higher, but biologically insignificant, frequency in one of the RER+ cell lines (HCT116). Our in vitro data support the previously reported lack of correlation between microsatellite instability and p53 mutations in RER+ tumour specimens.

Base Sequence↗
PubMed1997

Mechanism of resistance to cisplatin in a human ovarian-carcinoma cell line selected for resistance to doxorubicin: possible role of p53.

A possible novel mechanism of cross-resistance to cisplatin (CDDP) in the doxorubicin-resistant ovarian-cancer cell line A2780-DX3, which displays atypical multidrug resistance, is presented. A2780-DX3 is found to be more resistant than the parental line A2780 in terms of CDDP-induced cytotoxicity and apoptosis. Resistance is not related to the amount of cross-links. Topoisomerase-II (topII) protein levels were similar in both cell lines, with lower cleavage activity in A2780-DX3 cells. The parental and the doxorubicin-resistant cells expressed the same level of c-erb2, which could be implicated in CDDP resistance. bcl2 was almost undetectable in both cell lines. At the same time, we found strong induction of p53, waf-1 and bax protein levels after CDDP treatment in the A2780, but not in the A2780-DX3, cell line. Treatment of both cell lines with mitomycin C (MMC), which acts with a mechanism different from CDDP, caused equal accumulation of p53 and induction of bax. We found that A2780-DX3 cells exhibit altered cellular localization of p53 protein in comparison with A2780. A significant proportion of p53 in A2780-DX3 cells was found in the cytoplasmic compartment, and CDDP treatment induced a functional p53 protein in the nucleus of A2780 much more strongly than in A2780-DX3, which coincides with an increase of transcriptional activity of p53 in treated A2780 cells. We propose that the cross-resistance to CDDP in the A2780-DX3 cell line may be due to inactivation of a CDDP-dependent p53-accumulation pathway.

Cisplatin↗