This report describes the synthesis and preliminary biological characterization of 2 (ANG1007) and 3 (ANG1009), two new chemical entities under development for the treatment of primary and secondary brain cancers. 2 consists of three doxorubicin molecules conjugated to Angiopep-2, a 19-mer peptide that crosses the blood-brain barrier (BBB) by an LRP-1 receptor-mediated transcytosis mechanism. 3 has a similar structure, with the exception that three etoposide moieties are conjugated to Angiopep-2. Both agents killed cancer cell lines in vitro with similar IC(50) values and with apparently similar cytotoxic mechanisms as unconjugated doxorubicin and etoposide. 2 and 3 exhibited dramatically higher BBB influx rate constants than unconjugated doxorubicin and etoposide and pooled within brain parenchymal tissue. Passage through the BBB was similar in Mdr1a (-/-) and wild type mice. These results provide further evidence of the potential of this drug development platform in the isolation of novel therapeutics with increased brain penetration.

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Clusters of travel associated legionnaires' disease warrant urgent attention, and are detected by the French national surveillance system and the European network EWGLINET. Between September 2001 and August 2003, 37 clusters were identified in French tourist accommodation: 27 hotels and 10 campsites. The number of clinical cases per cluster was as follows: 30 clusters of 2 cases (81%), 6 clusters of 3 cases (16%) and one cluster of 4 cases (3%), a total of 82 cases. The local health authorities performed environmental investigations for 36 of the 37 clusters. Among the 36 clusters investigated, water samples were collected for 35. At 16 (46%) sites, Legionella pneumophila was found at a level of more than 103 cfu/litre. In all of the accommodation where risk assessment was found to be inadequate- control measures were implemented immediately. Six hotels were closed immediately following cluster alerts. Comparison of clinical and environmental isolates by pulsed field gel electrophoresis (PFGE) was possible in 3 clusters and identical genomic profiles of the isolates were found in all. During this two year period of surveillance, we found that on many sites there has been a risk of exposure to Legionella. This reinforces the importance of the European surveillance network and the timely notifications of all the cases to EWGLINET.

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