Purpose: Hypoxia is a characteristic of solid tumors and a potentially important therapeutic target. Here, we characterize the mechanism of action and preclinical antitumor activity of a novel hypoxia-activated prodrug, the 3,5-dinitrobenzamide nitrogen mustard PR-104, which has recently entered clinical trials. Experimental Design: Cytotoxicity in vitro was evaluated using 10 human tumor cell lines. SiHa cells were used to characterize metabolism under hypoxia, by liquid chromatography-mass spectrometry, and DNA damage by comet assay and gH2AX formation. Antitumor activity was evaluated in multiple xenograft models (PR-104 F radiation or chemotherapy) by clonogenic assay 18 h after treatment or by tumor growth delay. Results: The phosphate ester ''pre-prodrug'' PR-104 was well tolerated in mice and converted rapidly to the corresponding prodrug PR-104A. The cytotoxicity of PR-104A was increased 10-to 100-fold by hypoxia in vitro. Reduction to the major intracellular metabolite, hydroxylamine PR-104H, resulted in DNA cross-linking selectively under hypoxia. Reaction of PR-104H with chloride ion gave lipophilic cytotoxic metabolites potentially able to provide bystander effects. In tumor excision assays, PR-104 provided greater killing of hypoxic (radioresistant) and aerobic cells in xenografts (HT29, SiHa, and H460) than tirapazamine or conventional mustards at equivalent host toxicity. PR-104 showed single-agent activity in six of eight xenograft models and greater than additive antitumor activity in combination with drugs likely to spare hypoxic cells (gemcitabine with Panc-01pancreatic tumors and docetaxel with 22RV1prostate tumors). Conclusions: PR-104 is a novel hypoxia-activated DNA cross-linking agent with marked activity against human tumor xenografts, both as monotherapy and combined with radiotherapy and chemotherapy.Hypoxia is a uniquely attractive target in oncology for two reasons. The first is that hypoxic cells are obstacles to curative cancer therapy with all major treatment modalities. Hypoxia can compromise outcomes of surgery by increasing tumor metastasis (1 -3). It is also a major cause of radioresistance because oxygen is a radiosensitizer, and multiple clinical studies have documented the importance of hypoxia determining local tumor control in radiotherapy (4 -6). Hypoxia also contributes to chemoresistance through multiple mechanisms (7), including limitations on delivery of blood-borne drugs to hypoxic regions of tumors (8,9). The second reason for targeting hypoxia is that it is a common feature of a wide variety of human tumors and is typically more severe in tumors than in normal tissues, thus providing a basis for tumor selectivity (10,11).Several strategies for exploiting tumor hypoxia are now in preclinical or clinical development (7), with the main focus on prodrugs that are activated by metabolic reduction under hypoxic conditions to form cytotoxins. Early efforts focused on quinone bioreductive drugs, such as porfiromycin (12), and 2-nitroimidazole -linked alkylating a...

To evaluate the impacts of the urban heat island (UHI) effect on precipitation over a complex geographic environment in northern Taiwan, the next-generation mesoscale model, the Weather Research and Forecasting (WRF) model, coupled with the Noah land surface model and urban canopy model (UCM), was used to study this issue. Based on a better land use classification derived from Moderate Resolution Imaging Spectroradiometer (MODIS) satellite data (the MODIS case), it has significantly improved simulation results for the accumulation rainfall pattern as compared with the original U.S. Geological Survey (USGS) 25category land use classification (the USGS case). The precipitation system was found to develop later but stronger in the urban (MODIS) case than in the nonurban (USGS) case. In comparison with the observation by radar, simulation results predicted reasonably well; not only was the rainfall system enhanced downwind of the city over the mountainous area, but it also occurred at the upwind plain area in the MODIS case. The simulation results suggested that the correct land use classification is crucial for urban heat island modeling study. The UHI effect plays an important role in perturbing thermal and dynamic processes; it affects the location of thunderstorms and precipitation over the complex geographic environment in northern Taiwan.

Abstract. Biomass burning in the Indochina Peninsula (Indochina) is one of the important ozone sources in the low troposphere over East Asia in springtime. Moderate Resolution Imaging Spectroradiometer (MODIS) data show that 20 000 or more active fire detections occurred annually in spring only from 2000 to 2007. In our tracer modeling study, we identify a new mechanism transporting the tracer over Indochina that is significantly different from the vertical transport mechanism over the equatorial areas such as Indonesia and Malaysia. Simulation results demonstrate that the leeside troughs over Indochina play a dominant role in the uplift of the tracer below 3 km, and that the strong westerlies prevailing above 3 km transport the tracer. These fundamental mechanisms have a major impact on the air quality downwind from Indochina over East Asia. The climatological importance of such a leeside trough is also discussed.

Das hypoxämische Ziel im Blick: Die Kombination einer Nitro‐Wirkstoffvorstufe mit einem wasserlöslichen Phosphat wandelt Duocarmycin‐Analoga von hoch toxischen DNA‐Alkylierungsmitteln in hoch selektive Tumorwirkstoffe um. Diese Wirkstoffvorstufen (siehe Schema) sind in vivo außergewöhnlich wirksam gegen hypoxämische Tumorzellen – die Zellen, die allgemein als am schlechtesten durch herkömmliche Therapiemethoden erreichbar gelten.