Management and clinical outcome of rectal cancer in patients ≥ 80 years treated in southern France (PACA region) between 2006 and 2008.

BACKGROUND: Rectal cancer is increasingly prevalent in the elderly patients. Their clinical history and outcome after treatment are poorly described. This retrospective study was undertaken to provide more data and to compare therapeutic strategies to the standard of care for younger patients. PATIENTS AND METHODS: Data were retrospectively provided by gastroenterologists, oncologists, and gerontologists of Provence-Alpes-Côte-d'Azur (PACA). Patients concerned were aged 80 years or older, with a rectal cancer diagnosed between 2006 and 2008, irrespective of stage and (the) treatment of the disease. Overall survival (OS) and relapse-free-survival (RFS) were correlated with patient characteristics and treatment. The adopted therapeutic strategy was then compared to the standard-of-care for younger patients. RESULTS: Median follow-up was 36 months. The 3-year OS was 47.4% for the 160 patients analyzed, and 59.2% for the 117 patients treated with curative intent. The 3-year RFS was 76.6% in the "curative" population. In the multivariate analysis, node status and surgery independently influenced OS, while RFS was influenced by age, N status, and gender. For T0-T2 tumors, patients were treated similar to younger patients with an OS of 83.6% and a RFS of 95.2%, respectively. For T3-T4 tumors, 3-year RFS was 65%, even with a less aggressive strategy. CONCLUSION: Surgical resection after evaluation using Comprehensive Geriatric Assessment (CGA) should be the standard treatment for localized rectal cancer (T0-T2) in elderly patients, as it is in younger patients. For locally advanced lesions (T3-T4), results obtained after a conservative approach suggest that a non-surgical strategy can be used in elderly patients.

PPAR-alpha and PPAR-gamma activators induce cholesterol removal from human macrophage foam cells through stimulation of the ABCA1 pathway.

Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that regulate lipid and glucose metabolism and cellular differentiation. PPAR-alpha and PPAR-gamma are both expressed in human macrophages where they exert anti-inflammatory effects. The activation of PPAR-alpha may promote foam-cell formation by inducing expression of the macrophage scavenger receptor CD36. This prompted us to investigate the influence of different PPAR-activators on cholesterol metabolism and foam-cell formation of human primary and THP-1 macrophages. Here we show that PPAR-alpha and PPAR-gamma activators do not influence acetylated low density lipoprotein-induced foam-cell formation of human macrophages. In contrast, PPAR-alpha and PPAR-gamma activators induce the expression of the gene encoding ABCA1, a transporter that controls apoAI-mediated cholesterol efflux from macrophages. These effects are likely due to enhanced expression of liver-x-receptor alpha, an oxysterol-activated nuclear receptor which induces ABCA1-promoter transcription. Moreover, PPAR-alpha and PPAR-gamma activators increase apoAI-induced cholesterol efflux from normal macrophages. In contrast, PPAR-alpha or PPAR-gamma activation does not influence cholesterol efflux from macrophages isolated from patients with Tangier disease, which is due to a genetic defect in ABCA1. Here we identify a regulatory role for PPAR-alpha and PPAR-gamma in the first steps of the reverse-cholesterol-transport pathway through the activation of ABCA1-mediated cholesterol efflux in human macrophages.

Role of the parasite-derived prostaglandin D2 in the inhibition of epidermal Langerhans cell migration during schistosomiasis infection.

Epidermal Langerhans cells (LCs) play a key role in immune defense mechanisms and in numerous immunological disorders. In this report, we show that percutaneous infection of C57BL/6 mice with the helminth parasite Schistosoma mansoni leads to the activation of LCs but, surprisingly, to their retention in the epidermis. Moreover, using an experimental model of LC migration induced by tumor necrosis factor (TNF)-alpha, we show that parasites transiently impair the departure of LCs from the epidermis and their subsequent accumulation as dendritic cells in the draining lymph nodes. The inhibitory effect is mediated by soluble lipophilic factors released by the parasites and not by host-derived antiinflammatory cytokines, such as interleukin-10. We find that prostaglandin (PG)D2, but not the other major eicosanoids produced by the parasites, specifically impedes the TNF-alpha-triggered migration of LCs through the adenylate cyclase-coupled PGD2 receptor (DP receptor). Moreover, the potent DP receptor antagonist BW A868C restores LC migration in infected mice. Finally, in a model of contact allergen-induced LC migration, we show that activation of the DP receptor not only inhibits LC emigration but also dramatically reduces the contact hypersensitivity responses after challenge. Taken together, we propose that the inhibition of LC migration could represent an additional stratagem for the schistosomes to escape the host immune system and that PGD2 may play a key role in the control of cutaneous immune responses.

Immediate post-mastectomy breast reconstruction followed by radiotherapy: risk factors for complications.

The objective is to prospectively determine the factors responsible for reconstruction failure and capsular contracture in mastectomized breast cancer patients who underwent immediate two-stage breast reconstruction with a tissue expander and implant, followed by radiotherapy. This is a multicenter, prospective, non-randomized study. Between February 1998 and September 2006, we prospectively examined 141 consecutive patients, each of which received an implant after mastectomy, followed by chest wall radiotherapy at 46-50 Gy in 23-25 fractions. Radiotherapy was delivered during immediate post-mastectomy reconstruction. Patients were evaluated by both a radiation oncologist and a surgeon 24-36 months after treatment. The median follow-up duration was 37 months. According to Baker's classification, capsular contracture was grade 0, 1, or 2 in 67.5% of cases; it was grade 3 or 4 in 32.5% of cases. In total, 32 breast reconstruction failures required surgery. In univariate analysis, the following factors were associated with Baker grade 3 and 4 capsular contraction: adjuvant hormone therapy (P = 0.02), the surgeon (P = 0.04), and smoking (P = 0.05). Only one factor was significant in multivariate analysis: the surgeon (P = 0.009). Three factors were associated with immediate post-mastectomy breast reconstruction failure in multiple logistic regression analysis: T3 or T4 tumors (P = 0.0005), smoking (P = 0.001), and pN+ axillary status (P = 0.004). Patients with none, 1, 2, or all 3 factors have a probability of failure equal to 7, 15.7, 48.3, and 100%, respectively (P = 3.6 x 10(-6)). The model accurately predicts 80% of failures. Mastectomy, immediate reconstruction (expander followed by implant), and radiotherapy should be considered when conservative surgery is contraindicated. Three factors may be used to select patients likely to benefit from this technique with a low failure rate.

Classic biphasic pulmonary blastoma: A case report and review of the literature.

Pulmonary blastomas represent about 0.5% of primary pulmonary malignancies. The prognosis is poor. Standard treatment consists of surgical excision. There are no published series on which to judge the efficacy of chemotherapy or radiation therapy. We describe an unusual case of classic biphasic pulmonary blastoma (CBPC), with long-term survival despite numerous and varied cancer-related events and review the literature. Our 71-year-old Caucasian woman presented with history of blood in sputum in 2009. Right lower lobectomy yielded a diagnosis of sarcomatoid carcinoma (pneumoblastoma). Unusually, our patient is still alive 7 years after initial surgery, despite metastatic first relapse after 2 years. Metastatic progression was confirmed histologically on three separate occasions during the disease course. The patient received a combination of cisplatin (or carboplatin) and etoposide on three separate occasions. Molecular biology studies of CBPC are needed to identify effective treatments, and a patient registry should be created.

[Management and clinical outcome in patients over 80 years with rectal cancer treated between 2006 and 2008 in Southern France (PACA region)]. / Prise en charge et devenir des patients de plus de 80ans atteints d'un cancer du rectum, en région Provence-Alpes-Côte-d'Azur de 2006 à 2008.

PURPOSE: Rectal cancer is increasingly prevalent in elderly patients. Their clinical history and outcome after treatment are poorly described. This retrospective study was undertaken to provide more data and to compare therapeutic strategies to the standard of care for younger patients. PATIENTS AND METHODS: Patients concerned were aged 80 years or older, with a rectal cancer diagnosed between 2006 and 2008 and treated in Provence-Alpes-Côte-d'Azur (PACA), irrespective of stage and treatment of the disease. Overall survival and relapse-free-survival were correlated with patients' characteristics and treatment. The adopted therapeutic strategy was then compared to the standard-of-care for younger patients. RESULTS: With a median follow-up of 36 months, among the 160 patients included, the 3-year overall survival and relapse-free survival were 59.2% and 76.6%, respectively for the 117 patients who received a treatment with curative intent. In the multivariate analysis, node status and surgery independently influenced overall survival, while relapse-free survival was influenced by age, N status, and gender. For T0-T2 tumours, patients were treated similarly to younger patients with an overall survival of 83.6% and a relapse-free survival of 95.2%. For T3-T4 tumours, the 3-year relapse-free survival was 65%, even with a less aggressive strategy. CONCLUSION: Surgical resection after evaluation using the Comprehensive Geriatric Assessment (CGA) test should be the standard treatment for localized rectal cancer (T0-T2) in elderly patients, as it is in younger patients. For locally advanced lesions (T3-T4), results obtained after a conservative approach suggest that a non-surgical strategy can be used in elderly patients.

Structure-activity relationships in a series of melatonin analogues with the low-density lipoprotein oxidation model.

Despite an increasing number of publications concerning the antioxidant activity of melatonin, little is known about the structural features responsible for this kind of activity. To understand the role played by the different elements of melatonin structure in its antioxidant activity, we have designed and tested several compounds related to this molecule in the low-density lipoprotein peroxidation model. We present here the results of this study in terms of structure-activity relationships focusing on the influence of the acetamidoethyl side chain, the methoxy group, and the indole heterocycle. In this model, we found that changing the acyl residue generally resulted in more active products. We obtained particularly good results with the nonanoyl derivative which showed a level of activity comparable to that of phenols despite lacking a phenolic function. The presence of a methoxy group in position 5 generally had a beneficial influence on the activity, but when located in position 6, the effects were various. The substitution of a hydroxy for the methoxy group led to phenolic compounds endowed with very high antioxidant activity. Replacing the amide with a ketone function did not affect the activity while replacement with an amine group in some cases resulted in prooxidant compounds. Finally, we compared the efficacy of different aromatic rings. The indole heterocycle proved to be better than benzofurane and naphthalene rings.

Oxidized phospholipids activate PPARalpha in a phospholipase A2-dependent manner.

The peroxisome proliferator-activated receptor alpha (PPARalpha) is a transcription factor belonging to the PPAR subfamily of nuclear receptors. Fatty acids and eicosanoids are natural PPARalpha ligands. Here, we show using transient transfection assays that oxidized (oxLDL) but not native low-density lipoproteins (LDL) dose-dependently activate PPARalpha in endothelial cells without affecting PPARalpha protein expression. Fractioning of oxLDL lipids followed by transactivation experiments demonstrated that the oxidized phospholipid component in oxLDL is responsible for PPARalpha activation. Using specific inhibitors, it is shown that oxLDL-mediated PPARalpha activation requires phospholipase A2 activity and that the oxidized fatty acids 9- and 13-HODE activate PPARalpha directly. Finally, we found that, similar to the synthetic PPARalpha ligand Wy-14643, oxLDL induced expression of the fatty acid transport protein-1 in human primary endothelial cells. Our findings define a novel group of PPARalpha activators and provide a molecular basis for certain effects of these biologically active phospholipids on gene transcription.

Antioxidant properties of di-tert-butylhydroxylated flavonoids.

Epidemiological evidence suggests an inverse relationship between dietary intake of flavonoids and cardiovascular risk. The biological activities of flavonoids are related to their antioxidative effects, but they also can be mutagenic, due to the prooxidant activity of the catechol pattern. To prevent these problems, we synthesized new flavonoids where one or two di-tert-butylhydroxyphenyl (DBHP) groups replaced catechol moiety at position 2 of the benzopyrane heterocycle. Two DBHP moieties can also be arranged in an arylidene structure or one DBHP fixed on a chalcone structure. Position 7 on the flavone and arylidene or position 4 on the chalcone was substituted by H, OCH(3), or OH. New structures were compared with quercetin and BHT in an LDL oxidation system induced by Cu(II) ions. Arylidenes and chalcones had the best activities (ED(50) = 0.86 and 0.21) compared with vitamin E, BHT, and quercetin (ED(50) = 10.0, 7. 4, and 2.3 microM). Activity towards stable free radical 1, 1-diphenyl-2-picryl-hydrazyl (DPPH) was measured by log Z and ECR(50) parameters. Synthesized flavones proved to be poor DPPH radical scavengers, the activity increasing with the number of DBHP units. In contrast, arylidenes and chalcones were stronger DPPH radical scavengers (log Z > 3, 0.3 < ECR(50) < 2.12) than BHT (log Z = 0.75, ECR(50) = 12.56) or quercetin (log Z = 2.76, ECR(50) = 0.43). Unlike quercetin, synthesized compounds neither chelated nor reduced copper, proving that these new flavonoids had no prooxidant activity in vitro.

Peroxisome proliferator-activated receptor (PPAR) agonists decrease lipoprotein lipase secretion and glycated LDL uptake by human macrophages.

Lipoprotein lipase (LPL) acts independently of its function as triglyceride hydrolase by stimulating macrophage binding and uptake of native, oxidized and glycated LDL. Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors expressed in monocyte/macrophages, where they control cholesterol homeostasis. Here we study the role of PPARs in the regulation of LPL expression and activity in human monocytes and macrophages. Incubation of human monocytes or macrophages with PPARalpha or PPARgamma ligands increases LPL mRNA and intracellular protein levels. By contrast, PPAR activators decrease secreted LPL mass and enzyme activity in differentiated macrophages. These actions of PPAR activators are associated with a reduced uptake of glycated LDL and could influence atherosclerosis development associated with diabetes.

Radical surgery and conservative treatment of ductal carcinoma in situ of the breast.

70 cases of strictly intraductal breast carcinoma were treated from January 1975 to December 1987. 34 patients underwent radical modified mastectomy, and 36 patients had local excision (2), lumpectomy (26) or quadrantectomy (8), with a complementary irradiation in 34/36 cases (with boost in 32). The main histological subtype is comedocarcinoma (25/70). One local relapse (3%) is noted in radical surgery group at 55 months. 3 local relapses (9%) are noted in conservative treatment group, respectively at 27, 48 and 52 months. The obvious factor influencing the local recurrence is the inefficient surgical excision. Since breast screening programs may lead to early duct carcinoma in situ identification, our results suggest that appropriate conservative surgery associated to radiation therapy could be an adequate alternative to mastectomy in the treatment of this in situ lesion.

Ductal carcinoma in situ of the male breast. Analysis of 31 cases.

From 1970 to 1992, 31 pure ductal carcinoma in situ (DCIS) of the male breast treated in 19 French Regional Cancer Centres were reviewed. They represent 5% of all breast cancers treated in men in the same period. The median age was 58 years, but 6 patients were younger than 40 years. TNM classification (UICC, 1978) showed 12 T0 (discovered only by bloody nipple discharge), 10 T1, 5 T2 and four unclassified tumours (Tx). 11 patients (35.5%) had clinical gynecomastia, and three (10%) had a family history of breast cancer. 6 patients underwent lumpectomy, and 25 mastectomy. Axillary dissection was performed in 19 cases. 6 cases received postoperative irradiation. 15 out of 31 lesions were of the papillary subtype, pure or associated with a cribriform component. The size of the 12 measured lesions varied from 3 to 45 mm. All lymph nodes sampled were negative. With a median follow-up of 83 months, 4 patients (13%) presented a local relapse (LR), respectively, at 12, 27, 36 and 55 months. 3 of these patients had been initially treated by lumpectomy. In one case LR was still in situ, but already infiltrating in the 3 others. Radical salvage surgery was performed in 3 cases, but one patient developed metastases and died 30 months later. The last patient was treated by multiple local excisions and tamoxifen. One 43-year-old patient developed a contralateral DCIS and three others developed a metachronous cancer. The aetiology and risk factors of male breast cancer remain unknown. Gynecomastia, which implies an imbalance between androgen and oestrogen, may be a predisposing factor. As in women, DCIS in the male breast has a good prognosis. Total mastectomy without axillary dissection is the basic treatment. Frequently, the first symptom is a bloody nipple discharge. The age of occurrence is younger than for infiltrating carcinoma, suggesting that DCIS is the first step in the development of breast cancer.

The transcriptional regulating protein of 132 kDa (TReP-132) differentially influences steroidogenic pathways in human adrenal NCI-H295 cells.

Steroid hormones synthesized from cholesterol in the adrenal gland are important regulators of many physiological processes. It is now well documented that the expression of many genes required for steroid biosynthesis is dependent on the coordinated expression of the nuclear receptor steroidogenic factor-1 (SF-1). However, transcriptional mechanisms underlying the species-specific, developmentally programmed and hormone-dependent modulation of the adrenal steroid pathways remain to be elucidated. Recently, we demonstrated that the transcriptional regulating protein of 132 kDa (TReP-132) acts as a coactivator of SF-1 to regulate human P450scc gene transcription in human adrenal NCI-H295 cells. The present study shows that overexpression of TReP-132 increases the level of active steroids produced in NCI-H295 cells. The conversion of pregnenolone to downstream steroids following TReP-132 expression showed increased levels of glucocorticoids, C(19) steroids and estrogens. Correlating with these data, TReP-132 increases P450c17 activities via the induction of transcript levels and promoter activity of the P450c17 gene, an effect that is enhanced in the presence of cAMP or SF-1. In addition, P450aro activity and mRNA levels are highly induced by TReP-132, whereas 3beta-hydroxysteroid dehydrogenase type II and P450c11aldo transcript levels are only slightly modulated. Taken together, these results demonstrate that TReP-132 is a trans-acting factor of genes involved in adrenal glucocorticoid, C(19) steroid and estrogen production.

Concomitant b.i.d. radiotherapy and chemotherapy with cisplatin and 5-fluorouracil in unresectable squamous-cell carcinoma of the pharynx: clinical and pharmacological data of a French multicenter phase II study.

PURPOSE: The aim of this phase II study conducted on unresectable squamous cell carcinoma (USCC) of the oro- and hypopharynx was to associate twice-a-day (b.i.d.) continuous nonaccelerated radiotherapy with concomitant cisplatin (CP)-5-fluorouracil (5-FU) chemotherapy, both given at full dose. Feasibility, efficacy, survival, and pharmacokinetic-pharmacodynamic relationships were analyzed. METHODS AND MATERIALS: Fifty-four consecutive patients with strictly USCC of oro- and/or hypopharynx received continuous b.i.d. radiotherapy (RT) (2 daily fractions of 1.2 Gy, 5 days a week, with a 6-h minimal interval between fractions). Total RT dose was 80.4 Gy on the oropharynx and 75.6 Gy on the hypopharynx. Three chemotherapy (CT) courses of CP-5-FU were given during RT at 21-day intervals (third not delivered after the end of RT). CP dose was 100 mg/m2 (day 1) and 5-FU was given as 5-day continuous infusion (day 2-day 6: 750 mg/m2/day cycle 1, 750 mg total dose/day cycle 2 and 3). Pharmacokinetics was performed for 5-FU (105 h follow-up) and CP (single sample at 16 h). Special attention was paid to supportive care. RESULTS: Good feasibility of RT was observed (85.2% of patients with total dose > 75 Gy). Five patients received 1 CT cycle, 34: 2 cycles, and 15: 3 cycles. The most frequent and severe acute toxicities were mucositis with grade 3-4 occurring in 28% at cycle 1 and 86% at cycle 2, as well as neutropenia (43% at cycle 2). Locoregional control at 6 months was observed in 66.7% of patients. No late toxicity above grade 2 RTOG was noticed. CP dose and 5-FU AUC(0-105h) were significantly linked to grade 3-4 neutropenia (cycle 2). Cumulative total platinum (Pt) concentration and Karnofsky index were the only independent predictors of locoregional control at 6 months. Finally, total RT dose and total Pt concentration were the only independent predictors of specific survival. CONCLUSION: This protocol showed good locoregional response with an acceptable toxicity profile. Pharmacokinetic survey is probably an effective approach to further reduce toxicity and improve efficacy. A multicentric randomized phase III study, now underway, should confirm these encouraging results.

Synthesis and antitumor properties of an anthraquinone bisubstituted by the copper chelating peptide Gly-Gly-L-His.

A new molecule 4 [(GGH-DAE)2DHQ] associating the 1,4,5,8-tetrahydroxyanthraquinone ring (DHQ) of the antitumor drug mitoxantrone (2), two diaminoethylene chains (DAE), and the metal-chelating peptide Gly-Gly-His (GGH) has been synthesized. Such a molecule presents characteristics able to induce antitumor activity: compound 4 intercalates into DNA as measured by delta Tm, fluorescence quenching, and viscometry; ESR studies demonstrate that several types of Cu complexes are formed depending on pH; and the production of free radicals, as evidenced by spin-trapping, is enhanced by 4. In vitro, in leukemia cells L1210 and mammary cells MCF7, 4 is slightly less cytostatic than mitoxantrone, but substantially less toxic. In vivo, in leukemia P388 on mice, a T/C value of 230 is obtained at 25 mg/kg, higher than the one of mitoxantrone, which is toxic at the same dose.

Breast cancer occurred after treatment for Hodgkin's disease: analysis of 133 cases.

PURPOSE: To assess the clinical and histological characteristics of breast cancer (BC) occurring after Hodgkin's disease (HD) and give possible therapies and prevention methods. MATERIALS AND METHODS: In a retrospective multicentric analysis, 117 women and two men treated for HD subsequently developed 133 BCs. The median age at diagnosis of HD was 24 years. The HD stages were stage I in 25 cases (21%), stage II in 70 cases (59%), stage III in 13 cases (11%), stage IV in six cases (5%) and not specified in five cases (4%). Radiotherapy (RT) was used alone in 74 patients (63%) and combined modalities with chemotherapy (CT) was used in 43 patients (37%). RESULTS: BC occurred after a median interval of 16 years. TNM classification (UICC, 1978) showed 15 T0 (11.3%), 44 T1 (33.1%), 36 T2 (27.1%), nine T3 (6.7%), 15 T4 (11.3%) and 14 Tx (10.5%). Ductal infiltrating carcinoma and ductal carcinoma in situ (DCIS) represented 81.2 and 11.3% of the cases, respectively. Among the infiltrating carcinoma, the axillary involvement rate was 50%. Seventy-four tumours were treated by mastectomy without (67) or with (ten) RT. Forty-four tumours had lumpectomy without (12) or with (32) RT. Another four received RT alone, and one CT alone. Sixteen patients (12%) developed isolated local recurrence. Thirty-nine patients (31.7%) developed metastases and 34 died; 38 are in complete remission whereas five died of intercurrent disease. The 5-year disease-specific survival rate was 65.1%. The 5-year disease-specific survival rates for the pN0, pN1-3 and pN>3 groups were 91, 66 and 15%, respectively (P<0.0001), and 100, 88, and 64% for the TIS, T1 and T2. For the T3 and T4, the survival rates decreased sharply to 32 and 23%, respectively. These secondary BC are of two types: a large number of aggressive tumours with a very unfavourable prognosis (especially in the case of pN>3 and/or T3T4), and many tumours with a 'slow spreading' such as DCIS and microinvasive lesions. These lesions developed especially in patients treated exclusively by RT. CONCLUSIONS: The young women and girls treated for HD should be carefully monitored in the long-term by clinical examination, mammography and ultrasonography. We suggest that a baseline mammography is performed 5-8 years after supradiaphragmatic irradiation (complete mantle or involved field) in patients who were treated before 30 years of age. Subsequent mammographies should be performed every 2 years or each year, depending on the characteristics of the breast tissue (e.g. density) and especially in the case of an association with other BC risk factors. This screening seems of importance due to excellent prognosis in our T(1S)T(1) groups, and the possibility of offering these young women a conservative treatment.

1,25-Dihydroxyvitamin D3 regulates gamma 1 transpeptidase activity in rat brain.

gamma-Glutamyl transpeptidase (gamma-GT), primarily described as a kidney enzyme, is also expressed in several cell types of the central nervous system (CNS). It is involved in the glutathione cycle and in cysteine transport. Here we report that the specific activity of this enzyme is transiently increased in the rat brain, following a treatment with 1,25-dihydroxyvitamin D3 (1,25-D3), the active form of vitamin D. In vitro experiments showed that this positive regulatory effect does not affect endothelial cells of the brain microvessels, but does affect pericytes and parenchymal astrocytes. Changes in the specific activity of gamma-GT were not correlated with any important modification of brain amino acid concentrations. Since gamma-GT is though to participate in the scavenging of reactive oxygen species, these data suggest that 1,25-D3 could be an effector controlling detoxification processes in the brain.

4-Mercaptoimidazoles derived from the naturally occurring antioxidant ovothiols 1. Antioxidant properties.

4-Mercaptoimidazoles derived from the naturally occurring family of antioxidants, the ovothiols, were assayed for their antioxidant properties. These compounds are powerful HOCl scavengers, more potent than the aliphatic thiol N-acetylcysteine. They react slowly with hydrogen peroxide with second order rate constants of 0.13-0.89 M(-1)s(-1). Scavenging of hydroxyl radical occurs at a diffusion-controlled rate (k=2.0-5.0 x 10(10)M(-1)s(-1)) for the most active compounds, which are also able to inhibit copper-induced LDL peroxidation. The combination of radical scavenging and copper chelating properties may explain the inhibitory effects on LDL peroxidation. Two molecules of mercaptoimidazole can chelate a copper ion and form a square planar complex detected by EPR. Compounds bearing an electron-withdrawing group on position 2 of the imidazole ring are the most potent antioxidant molecules in this series.

Drug metabolism in in vitro organotypic and cellular models of mammalian central nervous system: activities of membrane-bound epoxide hydrolase and NADPH-cytochrome P-450 (c) reductase.

The membrane-bound form of epoxide hydrolase and NADPH-cytochrome P-450 (c) reductase are two important enzymes involved in the bioactivation/bioinactivation balance of cerebral tissue. In vivo, the developmental profiles and regional localizations of these two enzymes were investigated in the rat. The regional distribution study showed that they are ubiquitously present among the major brain structures. Both enzyme activities were present in the brain prior to birth, and hence tissue from early developmental stages is suitable to develop in vitro cellular or organotypic models for toxicity studies involving these metabolic pathways. Because various neurotoxicological effects can be dependent on spatio-temporally regulated cell-cell interactions, we aimed to employ organotypic tissue cultures in which the cytoarchitecture was well preserved. In such cultures, the temporal expression profiles of epoxide hydrolase and NADPH cytochrome(c) P-450 reductase reflected the in vivo situation. The technically less demanding pure neuronal and glial cell cultures were also investigated. Detoxification of benzopyrene-4,5-epoxide and superoxide production arising from the reductive metabolism of various drugs were determined in all three systems. The results indicate that though organotypic culture is a good model for the metabolic pathways studied, less complicated single cell cultures can also represent appropriate model systems, providing that the expression of the enzymes involved has been first established in these systems. NADPH-cytochrome P-450 reductase-dependent metabolism is active in both neuronal and glial cells, whereas the detoxification of reactive epoxides occurs mainly in glia.

Electron microscopic observations of the effects of anthraquinone derivatives on plasmid DNA.

Electron microscopy was used to analyse the precipitation of DNA observed when mixed with two tripeptide derivatives of mitoxantrone, with or without a 5,8-dihydroxy group (DHQ-GHK and Q-GHK, respectively) on the anthraquinonic ring. This precipitation was compared to that obtained with the basic drugs, mitoxantrone (DHAQ) and ametantrone (AQ). The effects of these compounds on the supercoiling of form I and the lengthening of form II of pBR322 DNA molecules, respectively, were evaluated. A strong lengthening of the DNA molecules was observed for ametantrone (max: 57%), but only 32% for Q-GHK, both at r (drug/base pari) = 250. With the dihydroxy derivative DHQ-GHK, it was not possible to show more than a 10% increase in length because DNA molecules were not measurable at r greater than 100. Only Q-GHK relaxed supercoiled molecules at the low r values of 10. Complex phenomena of condensation-precipitation were observed with these two tripeptide derivatives. In addition to a strong lengthening of form II DNA molecules, AQ induced specifically the formation of toruses, and DHAQ that of large organized DNA condensation. The variety of the aggregations is described and discussed with regard to the antitumor properties of these derivatives, and the literature concerning the various descriptions of DNA aggregation.