In the preceding paper, we demonstrated that, BMD188 cis-1-hydroxy-4-(1-naphthyl)-6-octylpiperidine-2-one, a newly synthesized cyclic hydroxamic acid compound, induces potent apoptotic death of ...prostate cancer cells in vitro. In this project, we studied the in vivo pharmacokinetic behavior and anti-tumor efficacy of this novel compound.
A bioavailability/elimination study was first performed using radiolabeled BMD188 administered to rats through intraperitoneal (i.p.), intravenous (i.v). or oral (p.o.) routes. Based on these pharmacokinetic data as well as pilot experiments on in vivo toxicity, two sets of efficacy studies, with i.p. administered BMD188, were performed in SCID mice or athymic nude mice which had been orthotopically transplanted with Du145 human prostate cancer cells. Tumor growth rate was measured and the final tumor weights and sizes determined. Subsequently, histopathological data were obtained and tumor tissue sections were used for apoptosis (i.e., TUNEL) staining.
The pharmacokinetic studies revealed low (approximately 8%) absorption through the p.o. route and high (approximately 70%) absorption through the i.p. route. The average plasma half life (T1/2) of BMD188 was approximately 50 h. Post-absorption, plasma elimination of radioactivity was similar to that in animals given 3H-188 intravenously. The in vivo efficacy results indicate that i.p. administered BMD188 significantly inhibited the primary growth and local invasion of Du145 prostate cancer cells orthotopically implanted into SCID or athymic nude mice. The tumor-inhibitory effect of BMD188 was due to apoptosis induction in vivo, as revealed by histological analysis as well as TUNEL staining of the tumor tissue sections.
Collectively, the preceding in vitro and the current in vivo studies suggest that BMD188 and its analogs may find clinical applications in the treatment of prostate cancer patients by inducing apoptotic death of prostate cancer cells.
Sodium butyrate induced cell cycle arrest in mammalian cells through an increase in p21Waf1/Cip1, although another study showed that this arrest is related to pRB signaling. We isolated variants of ...HeLa cells adapted to growth in 5 mm butyrate. One of these variants, clone 5.1, constitutively expressed elevated levels of p21Waf1/Cip1when incubated in regular growth medium and in the presence of butyrate. Despite this elevated level of p21Waf1/Cip1, the cells continue to proliferate, albeit at a slower rate than parental HeLa cells. Western blot analyses showed that other cell cycle regulatory proteins were not up-regulated to compensate for the elevated expression of p21Waf1/Cip1. However, cyclin D1 was down-regulated by butyrate in HeLa cells but not in clone 5.1. We conclude that continued expression of cyclin D1 allowed clone 5.1 to grow in the presence of butyrate and elevated levels of p21Waf1/Cip1.
Cathepsin B activity, including that of a plasma membrane-associated cathepsin B, has been linked to tumor malignancy. As cathepsin B at the tumor cell surface has been hypothesized to play a role in ...the focal degradation of basement membrane during the metastatic cascade, we have examined the ability of human tumor cathepsin B to degrade laminin, an adhesive glycoprotein found exclusively in the basement membrane. We report that at pH 6.5 and 7.0 tumor cathepsin B degraded by specific, limited proteolysis both subunits of native laminin. The disappearance of both subunits and the appearance of lower Mr protein bands could be observed by sodium dodecyl sulfate polyacrylamide gel electrophoresis. Accumulation of degradation products was also observed using gel filtration chromatography and a fluorescamine assay. The proteolysis of laminin by tumor cathepsin B could be inhibited by an active site titrant for cysteine proteinases or stefin B, an endogenous low-Mr cysteine proteinase inhibitor.
Urothelial neoplasia is a unique cancer in that is consists of a spectrum of tumors with different biologic behaviors. The most common urothelial neoplasm is the low grade superficial papillary ...carcinoma or papilloma which may recur numerous times but does not result in significant morbidity or mortality. A variant of the superficial papillary carcinoma, which represents approximately 10% of the tumors, is the noninvasive papillary neoplasm which progresses to a less differentiated invasive transitional cell carcinoma (TCC). Considerable effort has been directed at identifying which of the superficial well differentiated papillary tumors will persist, recur, and progress to invasive cancer. Current approaches to identifying such tumors include cytogenetics, molecular biology, and flow cytometric DNA analysis. In the final group of bladder carcinomas, the high grade invasive neoplasms, evidence suggests that these life-threatening tumors arise de novo without identifiable precursors. Unfortunately, 75% to 90% of invasive TCCs are classified in this group, with the remaining minority progressing from preexisting recurrent superficial papillary carcinomas. Obviously the biologic behavior of these aggressive poorly differentiated tumors is life-threatening, and application of traditional diagnostic procedures and new technologies need to be directed at early diagnosis.
Background and Objectives: Sexually transmitted diseases (STDs) comprise the majority of national infectious disease morbidity reported, yet the number of epidemiologists working in state and local ...STD programs is estimated to be small. Even less is known about the training and activities of those epidemiologists. Goals: To determine the number, training, and affiliation of epidemiologists working with STD programs and the level of satisfaction with epidemiologic support available. Study Design: Survey of 65 program managers in state and local health departments. Results: Program managers named 146 people working on epidemiologic activities, and 84 of those people were classified as "epidemiologist" by the criteria we applied. The median number of full-time equivalent (FTE) epidemiologists working in or with STD programs was 0.5; one quarter of all STD program had no epidemiologists. There was a significant association between number of FTE epidemiologist and population, with most programs with more than 0.5 epidemiologists located in areas with at least 1,000,000 population. State Epidemiologists do not provide technical support to most state STD programs. Almost half (45%) of all program managers indicated that they have inadequate epidemiologic support for routine program activities. Conclusions: The current level of epidemiologic support available to most STD programs is inadequate to perform surveillance and data analyses, interpret data to develop program objectives, and perform program evaluation. An essential next step is the delineation of a set of critical, analytic STD field epidemiology functions to define appropriate standards against which epidemiologic capacity can be more precisely measured.
Pooled time series and cross-sectional data are used to investigate the behavior of rice farmers when a modern rice variety was introduced in a region of the Philippines in the 1970s. The data come ...from the Farm Record Keeping project in Iloilo, Philippines, conducted by the International Rice Research Institute Department of Agricultural Economics from the crop years 1975-1976 to 1979-1980. Labor inputs generally were found to enhance mean productivity and reduce production risk. Nitrogen fertilizer was not found to be necessarily risk increasing, as it was risk reducing with modern varieties under favorable conditions. Lower production risk was found to be linked with appropriate combinations of management and inputs, but not necessarily with any one component of the technology. During the first 2 years of modern-variety adoption, the modern varieties were less technically efficient than the traditional varieties. However, 4-5 years after introduction, the modern varieties were more efficient than the traditional-variety plots.
A gene from Bacillus thuringiensis subsp. kurstaki that codes for a Lepidoptera-specific insecticidal toxin (delta-endotoxin) was engineered for expression in Bacillus subtilis. A low-copy-number ...plasmid vector that replicates in Escherichia coli and B. subtilis was consturcted to transform B. subtilis with gene fusions first isolated and characterized in E. coli. Naturally occurring promoter sequences from B. subtilis (43, veg, ctc, and spoVG) were inserted upstream from the plasmid-borne structural gene. In the most prolific case, when the sporulation-specific spoVG promoter was fused to the heterologous toxin gene, the toxin product accumulated during postexponential growth to greater than 25% of the total cell protein. However, the resulting specific activity of the insecticidal toxin product was not commensurate with the abundance of the protein
PDF
