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A good sensitizer for photodynamic therapy (PDT) should be a very selective reagent, which should fastly eliminate from healthy tissues. Furthermore it should have a strong absorption in the red light and good energy transfer properties to molecular oxygen to produce singlet oxygen. All these specifications imply that many second generation photosensitizers (porphyrins, chlorins, bacteriochlorins...) have been modified in order to improve their properties, but however, few have received the approval by regulatory authorities. One way to increase the selectivity of a photosensitizer is coupling it to a vector. Carbohydrate-bound porphyrins were found to be of great interest because of the specific affinity of particular carbohydrates for some tumour cells, the increasing of plasmatic life time and solubility. In this study, we report the synthesis and the photophysical properties (absorption, fluorescence, singlet oxygen formation) of new glycosylated porphyrins. Then, in vitro photocytotoxic properties were evaluated on the human colon adenocarcinoma cell line HT29.

While gonadotropin-releasing hormone (GnRH) or GnRH receptor (GnRHR) have been reported to exist in tissues other than brain and pituitary, there is no report concerning co-expression of GnRH and GnRHR in human breast tissues. To address this question, we have examined whether mRNA for GnRH as well as GnRHR was present in different human breast samples, by employing the reverse transcription-polymerase chain reaction (RT-PCR) protocol followed by Southern blotting of the PCR products. Coexpression of GnRH and GnRHR genes was further confirmed by dot blot hybridization using appropriate [32P]-labeled probes. We thus tested fibrocystic breast (4 cases), invasive ductal carcinomas (6 cases) and 1 adjacent non-neoplastic tissue. GnRHR and GnRH mRNAs were found in all actin-positive samples including malignant as well as nonmalignant tissues. Quantitative determinations of mRNA did not reveal significant differences between malignant and non-malignant breast samples for either GnRH or GnRHR gene expression. Our data show that neither gene was overexpressed in the breast cancer samples compared with normal breast tissue. Since GnRH agonists inhibit breast epithelial cell growth, the presence of GnRHR mRNA suggests that GnRH may specifically affect breast cell growth. Our data thus raise the possibility of an autocrine/paracrine role for GnRH in human mammary gland.

Bilirubin UDPglucuronosyltransferase of rat or human liver microsomes was inhibited, in vitro, by triphenylacetic acid and by structurally related arylcarboxylic acids. This inhibition appeared to be competitive towards bilirubin, and mixed-type towards UDPglucuronic acid. A decrease in the number of phenyl rings or the absence of the carboxyl group in the molecule gave structures which did not affect enzyme activity, showing that both the triphenyl moiety and the carboxyl group were necessary for the inhibition. On the other hand, successive additions of methylene groups in the aliphatic chain progressively increased inhibitory potency. Kappi,bilirubin for triphenylacetic acid was 96 microM compared with 5 microM for 7,7,7-triphenylheptanoic acid. The inhibition of bilirubin UDPglucuronosyltransferase was not due to displacement of bilirubin from albumin. On the basis of these results an attempt was made to delineate the molecular events leading to glucuronidation of bilirubin.

A new family of beta-blocking drugs is described. The originality of the new molecules lies in their functionalized hydrophobic folded structure, the basic part of which contains a benzocyclobutene ring. Excellent beta 2-blocker selectivity has been obtained with some of these compounds. Interestingly, this selectivity was not modified toward beta 1-blocker activity by introduction of the usual beta 1 inducer groups.

The in vitro inhibitory potency of 20 structurally related alkanoic and arylalkanoic acids has been investigated on rat liver UDP-glucuronosyltransferase. These compounds were tested on the microsomal and purified enzyme, and a cloned cDNA expressed in COS 7 cell cultures. Among all the acids tested, 7,7,7-triphenylheptanoic acid was the most powerful inhibitor of bilirubin:UDP-glucuronosyltransferase with a lower effect on 1-naphtol, androsterone and testosterone glucuronidation. The inhibition was competitive towards the microsomal and purified bilirubin:UDP-glucuronosyltransferases with Kiapp values of 12.0 microM and 1.6 microM, respectively. Twenty analogues were examined, and the results showed that their inhibitory potency on bilirubin:UDP-glucuronosyltransferase activity was a function of at least three structural features (a) the presence of a hydrophobic triphenyl moiety; (b) the length of the aliphatic chain and (c) the presence of a carboxylic group. These inhibitors were also tested as possible substrates of UDP-glucuronosyltransferases. The strongest inhibitors were poor substrates of rat liver microsomal UDP-glucuronosyltransferases. However, 7,7,7-triphenylheptanoic acid was actively glucuronidated by purified bilirubin:UDP-glucuronosyltransferase, in contrast to its analogues with decreasing alkyl chain length. In addition, glucuronidation of this molecule was enhanced by clofibrate treatment but could not be detected in Gunn rats, which are deficient in bilirubin:UDP-glucuronosyltransferase, further indicating that the glucuronidation of this compound was catalysed by bilirubin:UDP-glucuronosyltransferase. The results suggest that 7,7,7-triphenylheptanoic acid may be a useful structural probe to investigate the molecular basis of glucuronidation of bilirubin and carboxylic acids.

Farnesylacetone (C18 H30 0) is a male hormone extracted from the androgenic gland of crab, Carcinus maenas. Appropriate enzymatic assays, as well as spectrophotometric studies, indicate that micromolar concentrations of farnesylacetone interact with the electron transport pathway of rat liver mitochondria. By the use of artificial electron donors and electron acceptors, it is shown that farnesylacetone immediately inhibits the electron transfer within complex I (NADH ubiquinone reductase activity) and complex II (succinate ubiquinone reductase activity). It is proposed that farneylacetone could interact with these two complexes of the respiratory chain at the level of the iron-sulfur centers implicated in the dehydrogenase activities. These observations are compared with the results obtained with terpenic molecules which interact with mitochondrial respiration.