PS-341 was well tolerated at 1.04 mg/m(2) on this dose-intensive schedule, although patients need to be monitored for electrolyte abnormalities and late toxicities. Additional studies are indicated to determine whether incorporation of dose/body surface area yields a superior PD model to dosing without normalization. PS-341 showed activity against refractory multiple myeloma and possibly non-Hodgkin's lymphoma in this study, and merits further investigation in these populations.

Overexpression of the MDR1 gene, which encodes a multidrug efflux pump of the major facilitator superfamily, is a frequent cause of resistance to the antimycotic agent fluconazole and other metabolic inhibitors in clinical Candida albicans strains. Constitutive MDR1 overexpression in such strains is caused by mutations in as yet unknown trans-regulatory factors. In order to identify the cis-acting sequences in the MDR1 regulatory region that mediate constitutive MDR1 upregulation, we performed a promoter deletion analysis in the genetic background of an MDR1-overexpressing clinical C. albicans isolate. We found that several different regions in the MDR1 promoter can mediate MDR1 overexpression in this isolate. In contrast, deletion of one of these regions abolished benomyl-induced MDR1 expression in a C. albicans laboratory strain. These results suggest that multiple transcription factors control expression of the MDR1 efflux pump in C. albicans and that the mutation(s) that causes constitutive MDR1 overexpression and drug resistance in clinical C. albicans isolates affects the activities of several of these transcription factors.The yeast Candida albicans is a member of the microflora on mucosal surfaces of the gastrointestinal and urogenitary tracts in many healthy people, but it can also cause superficial as well as life-threatening systemic infections, especially in immunocompromised patients (21). Oropharyngeal candidiasis, which frequently affects patients infected with the human immunodeficiency virus and AIDS patients, is commonly treated with the antimycotic agent fluconazole, which inhibits the biosynthesis of ergosterol, the major sterol in the fungal cell membrane. C. albicans can develop resistance to fluconazole, especially during long-term treatment of oropharyngeal candidiasis (30). Fluconazole resistance is caused by different molecular mechanisms, including alterations in the sterol biosynthetic pathway; overexpression of the ERG11 gene, which encodes the target enzyme of fluconazole, sterol 14␣-demethylase (Erg11p); mutations in the ERG11 gene that result in a reduced affinity of Erg11p to fluconazole; and overexpression of genes encoding membrane transport proteins which actively transport fluconazole out of the cell. In clinical C. albicans strains, several of these mechanisms are often combined to result in the stepwise development of clinically relevant fluconazole resistance (for a review, see reference 18).Two types of efflux pumps that mediate resistance to fluconazole and structurally unrelated toxic compounds have been identified in C. albicans (6,(23)(24)(25). While CDR1 and CDR2 belong to the ATP-binding cassette (ABC) transporters, MDR1 is a member of the major facilitator superfamily which uses the proton gradient across the cytoplasmic membrane as an energy source for transport. In drug-susceptible C. albicans strains, MDR1 is expressed only at low levels in standard laboratory media, but its expression can be induced by some toxic compounds, like benomyl (10, 13, 27). In contras...

Drosophila Fasciclin I is the prototype of a family of vertebrate and invertebrate proteins that mediate cell adhesion and signaling. The midline fasciclin gene encodes a second Drosophila member of the Fasciclin I family. Midline Fasciclin largely consists of four 150 amino acid repeats characteristic of the Fasciclin I family of proteins. Immunostaining and biochemical analysis using Midline Fasciclin antibodies indicates that it is a membrane‐associated protein, although the sequence does not reveal a transmembrane domain. The gene is expressed in a dynamic fashion during embryogenesis in the blastoderm, central nervous system midline cells, and trachea, suggesting it plays multiple developmental roles. Protein localization studies indicate that Midline Fasciclin is found within cell bodies of midline neurons and glia, and on midline axons. Initial cellular analysis of a midline fasciclin loss‐of‐function mutation reveals only weak defects in axonogenesis. However, embryos mutant for both midline fasciclin and the abelson nonreceptor tyrosine kinase, show more severe defects in axonogenesis that resemble fasciclin I abelson double mutant phenotypes. © 1998 John Wiley & Sons, Inc. J Neurobiol 35: 77–93, 1998