Interactions of iron-anthracycline complexes with living cells: a microspectrofluorometric study.

The interaction of iron-anthracycline complexes with tumor cells has been studied using microspectrofluorometry. The anthracyclines used were adriamycin, 4'-O-tetrahydropyranyladriamycin and daunorubicin. In every case, a 1:3 Fe(III)-anthracycline complex is formed. The three daunorubicin molecules that bind to one Fe(III) are not chemically modified through complexation with iron. In the case of the Fe(III)-adriamycin and Fe(III)-4'-O-tetrahydropyranyladriamycin complexes, about one of the three anthracycline molecules is chemically modified, yielding a highly lipophilic derivative, the 7,8-dehydro-9,10-desacetyladriamycin. The others molecules remain unchanged, i.e., highly hydrophilic in the case of adriamycin. These two species have a different fluorescent spectrum and can be identified inside the cell, using microspectrofluorometry. In the case of the Fe(III)-adriamycin complex, the lipophilic derivative is more rapidly internalized in the cell than the hydrophilic one. Diffusion into the plasmic membrane is the limiting step for the uptake of anthracycline by cells; this means that the plasmic membrane speeds up the dissociation of the Fe(III)-anthracycline complex.

Influence of methoxy and nitro groups in the oxidative metabolism of naphtho[2,1-b]furan.

In the present study, we have investigated the role of methoxy and nitro groups in the oxidative metabolism of naphtho[2,1-b]furan. Hepatic microsomes were used to investigate the aerobic metabolism of naphtho[2,1-b]furan (compound A), 2-nitro-naphtho[2,1-b]furan (compound B) and 7-methoxy-naphtho [2,1-b]furan (compound C) and comparison of the metabolites formed was made using HPCL analysis and NMR, mass and UV-visible spectrometry. The different metabolic pathways investigated were compared with the previously reported metabolism of 7-methoxy-2-nitro-naphtho[2,1-b]furan (compound D). Naphtho[2,1-b]furan yield metabolites of both the furan and benzene rings, while metabolites formed from 7-methoxy-naphtho[2,1-b]furan and 2-nitro-naphtho [2,1-b]furan were derived entirely as a result of enzymic attack on the first benzene ring.

Microsomal metabolism of dibenz[a,c]anthracene, dibenz[a,h]anthracene and dibenz[a,j]anthracene to bis-dihydrodiols and polyhydroxylated products.

Polar, ethyl acetate soluble metabolites formed in incubations of dibenz[a,c]anthracene (DB[a,c]A), dibenz[a,h]anthracene (DB[a,h]A) and the related DB[a,h]A 3,4-diol and dibenz[a,j]anthracene (DB[a,j]A) with 3-methylcholanthrene (3-MC)-induced rat liver microsomal preparations have been separated by HPLC and examined using fluorescence, UV and NMR spectroscopy. Metabolites with spectral properties consistant with their identification as the 3,4:8,9-bis-diol of DB[a,j]A and a 1,2,3,4,12,13-hexol derived from DB[a,c]A were found. DB[a,h]A was metabolized to three polar products identified as the 3,4:10,11-bis-diol and the related 1,2,3,4,8,9- and 1,2,3,4,10,11-hexols, which were also formed, together with the related 1,2,3,4-tetrol, from the DB[a,h]A 3,4-diol. The possible role of bis-diols in the metabolic activation of these three dibenzanthracenes is discussed.

[Value of fine-needle aspiration and extemporaneous examination in thyroid surgery. A prospective study of 1235 fine-needle aspirations and extemporaneous examinations in 846 patients]. / Intérêt de la cytoponction et de l'examen extemporané en chirurgie thyroïdienne. Etude prospective à propos de 1,235 cytoponctions et examens extemporanés réalisés chez 846 patients.

We report a prospective study conducted from 1993 through 1995 in 846 patients (mainly women) consulting for a thyroid nodule. There were 465 multinodular goiters and 373 single nodules. The clinical diagnosis was obvious in 8 patients who were excluded. Pre-operative fine-needle aspiration was performed in 1235 patients and per-operative extemporaneous examinations in 569. These two simple reliable examinations, with few significant complications in skillful hands, are complementary. Fine-needle aspiration gives reliable histology data for thyroid nodules and should always be included in the pre-operative workup. Extemporaneous pathology examination of the surgical specimen provides information for adapted surgery and avoids morbidity due to reoperation.

[Influence of Body Mass Index on management and prognosis of women with endometrial cancer]. / Influence de l'indice de masse corporelle sur la prise en charge et le pronostic des patientes avec carcinome endométrial.

OBJECTIVE: The aim of this study was to evaluate the outcome of surgery, postoperative morbidity and prognosis of patients with endometrial cancer in function of the body mass index (BMI). PATIENTS AND METHODS: The study cohort consisted of consecutive women undergoing surgery for endometrial cancer in our institution between January 2000, and September 2012. Individual records of all patients were reviewed and analyzed. Patient BMI was categorized as underweight, normal, overweight and obese. RESULTS: A total of 192 patients were evaluated. Patients were followed for one to 153months with a mean of 52.56months. The mean BMI and the range of each of the BMI categories were 16.97kg/m(2) (14-18), 22.97kg/m(2) (20-24.9), 27.61kg/m(2) (25.7-29.4), 37.34kg/m(2) (30-71). Women with higher BMI were more frequently affected by hypertension (8.3%, 31.43%, 58.13% and 59.7% respectively, P<0.0001) and diabetes (16.67%, 4.3%, 13.9% and 29.85% respectively, P=0.02). Women with normal BMI had more frequently postmenopausal replacement therapy than the other categories (P=0.0004). Surgical operative time, mean length of hospitalization in days were not significantly different among the 4 groups. In the obese group there were significantly higher peroperative blood loss (P=0.01), more wound abces (P=0.05), more eventration (P=0.02) and more reinterventions for complications (P=0.03). Patients had the same protocols of treatment (surgery and adjuvant treatment) and histological characteristics were the same between groups but obese patients had much less positive lymph nodes (P=0.03). There were no statistically significant difference in overall 5-years survival between groups (P=0.54) DISCUSSION AND CONCLUSIONS: Our study demonstrate a survival equivalency for obese and non-obese women even though obese women showed less positive lymph nodes.

[Reliability of imaging modalities for preoperative assessment of patients with endometrial carcinoma]. / Pertinence de l'imagerie dans l'évaluation préopératoire des patientes avec cancer endométrial.

OBJECTIVES: To investigate the value of transvaginal sonography, computed tomography and magnetic resonance imaging for the preoperative staging of endometrial cancer. PATIENTS AND METHODS: The patient group consisted of consecutive women undergoing surgery for endometrial cancer in our institution between January 2000, and September 2012. Clinical data included comorbidities, BMI (kg/m(2)), preoperative imaging findings, surgical procedures, surgical International Federation of Gynecology and Obstetrics stage, histological grade, relevant prognostic factors. The pathological data from surgical staging were compared with the preoperative imaging results. RESULTS: Two hundred and forty-four patients with the final diagnosis of endometrial cancer were enrolled. Hundred and ninety-six had preoperative transvaginal ultrasonography, 56 preoperative computed tomography and 158 preoperative MRI assessment. In our analysis, MRI had better sensitivity and specificity for all imaging criteria but lymph node assessment where MRI and CT-scan are equivalent (MRI: Se=45.45 %, Sp=79.52 %; CT: Se=50 %, Sp=80 %). DISCUSSION AND CONCLUSION: In patients with endometrial cancer, preoperative MRI may not accurately diagnose absence of myometrial invasion. This data should be kept in mind before planning the operative treatment modality and particularly before choosing patients for conservative endometrial carcinoma treatment.

[The impact of therapeutic management on survival of elderly women with endometrial cancer]. / Impact de la prise en charge thérapeutique sur la survie chez les femmes très âgées avec cancer de l'endomètre.

OBJECTIVES: We aimed to determine whether patients characteristics, clinicopathologic features and survival rates were worse in elderly women with endometrial cancer. PATIENTS AND METHODS: The study cohort consisted of consecutive women undergoing surgery for endometrial cancer in our institution from January 2000 to October 2011. Patients were divided by age into two groups: patients aged 65 to 79 and those aged 80 or older. Clinical data included comorbidities, BMI (kg/m(2)), surgical procedures, surgical International Federation of Gynecology and Obstetrics (FIGO) stage, histological grade, relevant prognostic factors, occurrence of perioperative complications, adjuvant therapies, overall survival and long term disease specific mortality. RESULTS: As expected, elderly women had more major comorbidities and were less likely to undergo optimal surgery, FIGO stages, histological grades. The 5-year disease specific survival was significantly poorer for the older group compared to younger women 64.5% 95%CI [54.3-73.8] vs 83.49% 95%CI [74.7-90.2] P = 0.008. Cancer-specific mortality was also higher in the elderly: 100% vs 41.17% (P = 0.005). DISCUSSION AND CONCLUSION: Oldest patients with newly diagnosed endometrial cancer were found to have worse overall survival and higher cancer-specific mortality than younger patients because of less aggressive care. Clinical efforts must be managed toward the oldest patients with an early stage of endometrial cancer to maximize the therapeutic ratio, in particular surgical.

[The use of pattern recognition for analysing the possible relation between molecular structure of polycyclic hydrocarbons and their carcinogenicity]. / Utilisation de la "reconnaissance de formes" pour analyser le lien éventuel entre la structure moléculaire des hydrocarbures polybenzéniques et leur pouvoir cancérogène.

Pattern recognition has been used for investigating the part played by the molecular structure of polycyclic hydrocarbons in their carcinogenic action. A series of molecules has been considered, whose physicochemical properties are known to be closely related to the number and location of their aromatic rings. From a pattern recognition program and two learning subsets (carcinogenic and non carcinogenic molecules), it has been shown that (i) the shape of the molecule is correlated with its carcinogenic power; (ii) an index of carcinogenicity can be estimated for any molecule in the considered set.

Comparison of the in vitro metabolisms and mutagenicities of dibenzo[a,c]anthracene, dibenzo[a,h]anthracene and dibenzo[a,j]anthracene: influence of norharman.

The comparison of the behaviour of three dibenzoanthracene (DBA) isomers, dibenzo[a,c]anthracene (DB[a,c]A), dibenzo[a,h]anthracene (DB[a,h]A) and dibenzo[a,j]anthracene (DB[a,j]A), polycyclic aromatic hydrocarbons (PAHs), whose carcinogenicity varies from very potent to apparently inactive, has been carried out. Influence of norharman (NH; 9H-pyrido[3,4-b]indol) was investigated for mutagenicity (reversion of histidine prototrophy) on Salmonella typhimurium TA 100, using 3-methylcholanthrene (3-MC)-induced rat liver microsomes or S9 (post-mitochondrial fractions). A correlation with its influence, on the in vitro metabolism of radiolabelled molecules by the same enzymatic systems, was carried out. NH enhances the mutagenicities of DB[a,c]A and DB[a,h]A which are very well known mutagenic and carcinogenic PAHs. Contrary to its two isomers, the mutagenic potency of DB[a,j]A, which is considered as a weak mutagen and not a carcinogen, is strongly inhibited by NH. The balance sheets of the in vitro metabolism by microsomal enzymes, where the conjugation is excluded, were reported with or without NH. In the presence of the latter, the amounts of remaining DBAs slightly decreased while the metabolites covalently bound to microsomal proteins strongly decreased and the amount of hydrophobic metabolites highly increased. At the same time, the HPLC elution profiles of the metabolism pathways of the three DBAs are found to be modified in a similar way by NH: some of the metabolites are highly enhanced, and for all three DBAs, a tetraol, not detectable in the absence of NH, emerges. The results are discussed with regard to possible effects of NH.

Reactivity with DNA of three pyrenofuran analogues of benzo(a)pyrene and benzo(e)pyrene.

Three pyrenofurans, the pyreno[1,2-b]furan (FP1), the pyreno[2,1-b] furan (FP2) and the pyreno[4,5-b]furan (FP3) have been synthesized as analogues of the mutagenic and carcinogenic benzo(a)pyrene (FP1 and FP2) and of its non-carcinogenic isomer benzo(e)pyrene (FP3). For each of the pyrenofurans, the reactivity with DNA has been tested in presence of liver microsomes of rats induced with 3-methylcholanthrene. Fluorescence spectroscopy showed that only FP2 and FP3 which possess a "bay region" react with DNA. In both cases, metabolites bound to DNA have a fluorescence emission comparable to that of the "bay region" dihydrodiols obtained after the "in vitro" metabolism of initial molecules. FP2 is shown to react similarly to benzo(a)pyrene whereas the reactivity of FP3 is different from that of benzo(e)pyrene, in spite of their structural similarities. This is probably due to reasons of three-dimensional space configuration. The peculiar reactivity of FP3 is predicted by calculations of the bond order values.

[Study by fluorescence of DNA treated by 7-methyl-benzo (a) anthracene in the presence of a microsomal oxidation system]. / Etude par fluorescence d'ADN traite par le méthyl 7 benzo(a) anthracène en présence d'un système microsomal d'oxydation

When calf thymus DNA is treated with 7 methyl benzo(a)anthracene is presence of NADPH requiring microsomal hydroxylating system, the fluorescent signal observed on DNA after purification of the macromolecule shows the presence of 2 kinds of the hydrocarbon metabolites. One would countain probably a conjugated system analogous to the parent hydrocarbon ones, the other corresponds to a reduced conjugated system.

Metabolic activation of benz(a)anthracene: fluorescence spectral evidence indicates the involvement of a non-'bay-region' diol-epoxide.

The fluorescence spectral properties of the principal hydrocarbon-nucleoside adducts present in hydrolysates of DNA that had been isolated from hamster embryo cells or from mouse skin treated with benz(a)anthracene have been examined using photon-counting spectrophotofluorimetry and compared with the spectral properties of the products formed when different diol-epoxides derived from benz(a)anthracene react with nucleic acid in solution. The adducts were separated by chromatography on LH20 Sephadex columns and purified by high pressure liquid chromatography. The spectra obtained are phenanthrene-like and not anthracene-like, a result that is consistent with metabolic activation occurring, through the formation of a vicinal diol-epoxide, in the 8,9,10,11-ring, rather than in the 1,2,3,4-ring of this hydrocarbon.