Ferreri Am

RXRγ and PPARγ ligands in combination to inhibit proliferation and invasiveness in colon cancer cells

Nuclear retinoid X receptors (RXRs) and peroxisome proliferator-activated receptors (PPARs are potential candidates as drug target for cancer prevention and treatment. We investigated if the rexinoid 6-OH-11-O-hydroxyphenantrene (IIF) potentiates the antitumoral properties of PPARgamma ligands as ciglitazone and pioglitazone, on two colon cancer cell lines: HCA-7 and HCT-116. Drugs inhibited cell growth and induced apoptosis synergistically. The combination resulted in a decrease of cyclooxigenase-2, metalloproteinases-2 and -9 expression level and activity while PPARgamma, RXRgamma and tissue inhibitors of metalloproteinase-1 and -2 expression were increased. Finally, IIF potentiated PPAR transcriptional activity by enhancement of peroxisome proliferator response elements transactivation.

Cytoplasmic receptors for 17β-estradiol, 5α-dihydrotestosterone and progesterone in normal and abnormal human uterine tissues

Summary Determinations of specific cytoplasmic receptors for 17 β -estradiol (E), 5 α -dihydrotestosterone (DHT) and progesterone (P) in normal and abnormal endometrium are reported. The standardization of methodology with particular emphasis on specificity trials is outlined. Receptors were present in all but one case, a moderately differentiated endometrial adenocarcinoma. Generally speaking, steroid and peptide hormone plasma content in patients with malignant conditions were at the lower limit values of normal, except for follicle-stimulating hormone which had values significantly higher than normal. The question of E competition with DHT in binding DHT-receptor and the therapeutic implications of P-receptor estimation are discussed.

Simple and Dendritic Cyclam Derivatives. Photophysical Properties, Effect of Protonation and Zn2+ Coordination, Preliminary Screening as Inhibitors of Tumour Cell Growth

We have synthesized two novel dendrimers (BG1 and BG2) consisting of a 1,4,8,11-tetraazacyclotetradecane (cyclam, 1) core with appended four dimethoxybenzene and eight benzyl units (BG1) and twelve dimethoxybenzene and sixteen benzyl units (BG2). The absorption and luminescence spectra of these compounds and the changes taking place upon protonation and Zn2+ coordination of their cyclam core have been investigated in acetonitrile-dichloromethane 1:1 v/v solution. For comparison purposes, the absorption and luminescence spectra of 1,4,8,11-tetrabenzyl-cyclam (2), and dendrons BD1 and BD2, model compounds of the branches of BG1 and BG2 respectively, have also been studied. BD1, BD2, BG1, and BG2 exhibit the absorption and emission spectra of their 1,3-dimethoxybenzene unit, but in the two dendrimers the emission intensity is quenched by the cyclam amine groups and increases upon protonation and metal coordination. In order to test if these cyclam derivatives have an antitumour effect, we have studied their action on proliferation in the human neuroblastoma TS12 cell line. Screening experiments have shown that cell proliferation was (i) strongly reduced by the tetrabenzyl substituted cyclam 2, and (ii) unaffected by cyclam and the benzo dendrimers BG1 and BG2. Antitumour screening experiments have also been performed on the tetranaphthyl substituted cyclam 3 and the naphtho-dendrimer NG2, whose photophysical properties have been previously studied. Cell proliferation came out to be moderately reduced by 3, whereas dendrimer NG2 had no effect, similar to dendrimers BG1 and BG2.

Induction of diphtheria toxin-resistant mutants in human cells by halogenated compounds

SummaryThe mutagenic power of 1,2-dichloroethane, 1,2-dibromoethane, 1,2-diiodoethane was tested in the human cell line, EUE. In our mutagenic system, based on selection against diphtheria toxin, the halogenated compounds, 1,2-dichloroethane and 1,2-dibromoethane revealed a strong mutagenic effect, whereas 1,2-diiodoethane was not mutagenic at a concentration allowing survival of 41%.

Toxic, DNA-damaging and mutagenic activity of epichlorohydrin on human cells cultured in vitro.

Epichlorohydrin (ECHH) highly inhibited the tritiated thymidine uptake by human lymphocytes cultured in vitro, although the corresponding cell viability was unaffected. Furthermore, it elicited unscheduled DNA synthesis, acting as a DNA-damaging agent after its metabolic activation. ECHH also showed a clear toxic and mutagenic activity toward a human epithelial-like cell line, causing a decrease in cell viability and an increase in mutants resistant to 0.05 Lf/ml of diphtheria toxin.

The effect of urethan on the synthesis of nucleic acids in the cells of regenerating rat liver.

By administration of urethane (1 mg/g body weight) at the beginning of the S phase i. e. 19 hr after partial hepatectomy the initial rise in DNA synthesis was reversibly inhibited. An inhibitory effect on the total, the soluble, the mitochondral and the microsomal RNA was demonstrated up to 36 hr after hepatectomy. Nach partieller Hepatektomie und Gabe von 1 mg/g Körpergewicht Urethan zum Beginn der S-Phase, d. h. 19 Std nach dem Eingriff, wurde der beginnende Anstieg der DNA-Synthese reversibel gehemmt. Ein Hemmeffekt auf die gesamte, die lösliche, die mitochondriale und die mikrosomale RNA wurde bis 36 Std nach Hepatektomie beobachtet.

Effect of antioxidants on mutagenesis induced by Dmba in human cells

The effect of vitamin A palmitate (VAP), vitamin A acetate (VAA), 2,3-tert-butyl-4-hydroxyanisole, and 2,6-di-tert-butyl-p-cresol (BHT) on mutagenesis induced by 7,12-dime-thylbenz[a]anthracene (DMBA) was examined in a human epithelial-like cell line. Cultures were exposed to DMBA with or without the antioxidant compound, and mutation frequencies were determined by selection against diphtheria toxin. A clear inhibition of mutagenesis was observed particularly with VAA and BHT.

Compared effects of N-hydroxyurethan, urethan and hydroxyurea on DNA synthesis. In vivo and in vitro studies

The effect of N-hydroxyurethan (HUR) on DNA synthesis has been tested both in vivo on various tissues and in vitro on concanavalin A (ConA)-stimulated rat thymocytes and compared with the action of urethan and hydroxyurea. HUR suppresses scheduled DNA synthesis, except that of non-stimulated spleen cells in vitro. The inhibition is efficient and rapid and takes place immediately if the drug is administered at the peak of the S-phase. UR inhibits DNA synthesis in vitro only at much higher doses and with different time course. It is effective or slightly effective if it is administered at the peak of the S-phase. A conversion of urethan into HUR the latter depressing DNA synthesis could partly explain the differences observed. No toxicity was found after treatment with drugs at the concentrations employed. Finally, the relationships between drug doses and cell responses have been particularly observed in vivo.

Metabolism of complex carbohydrates of rabbit skin during treatment with 7,12-dimethylbenz(a)anthracence

The metabolism of mucopolysaccharides (MPS) and glycoproteins in the rabbit skin was studied after painting with 7,12-Dimethylbenz(a)anthracene (DMBA). The synthesis and turnover of MPS increased progressively in the early phases of treatment and remained at high values for the duration of the treatment. Sialic acid-containing glycoproteins of fractions soluble and insoluble in saline had variations similar to those of MPS. The data are related to the role attributed to the dermal changes during skin carcinogenesis. Nach Pinselung mit 7,12-Dimethylbenz[a]anthrazen (DMBA) wurde der Stoffwechsel von Mukopolysacchariden (MPS) und Glykoproteinen in Kaninchenhaut untersucht. Die Synthese und der Turnover von MPS wurde in den frühen Phasen der Behandlung zunehmend erhöht und blieb bei hohen Werten während der Dauer der Behandlung. Sialinsäure enthaltende Glykoproteine aus in Kochsalzlösung löslichen und unlöslichen Fraktionen zeigten ähnliche Unterschiede wie die MPS. Die Ergebnisse stehen in Beziehung zu der Rolle, die dermalen Änderungen während der Hautcarcinogenese zugeschrieben wird.