Human carbonic anhydrase II (CA II), a zinc metalloenzyme, was screened against 960 structurally diverse, biologically active small molecules. The assay monitored CA II esterase activity against the substrate 4-nitrophenyl acetate in a format allowing high-throughput screening. The assay proved to be robust and reproducible with a hit rate of approximately 2%. Potential hits were further characterized by determining their IC(50) and K(d) values and tested for nonspecific, promiscuous inhibition. Three known sulfonamide CA inhibitors were identified: acetazolamide, methazolamide, and celecoxib. Other hits were also found, including diuretics and antibiotics not previously identified as CA inhibitors, for example, furosemide and halazone. These results confirm that many sulfonamide drugs have CA inhibitory properties but also that not all sulfonamides are CA inhibitors. Thus many, but not all, sulfonamide drugs appear to interact with CA II and may target other CA isozymes. The screen also yielded several novel classes of nonsulfonamide inhibitors, including merbromin, thioxolone, and tannic acid. Although these compounds may function by some nonspecific mechanism (merbromin and tannic acid), at least 1 (thioxolone) appears to represent a genuine CA inhibitor. Thus, this study yielded a number of potentially new classes of CA inhibitors and preliminary experiments to characterize their mechanism of action.

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BackgroundThere is limited evidence on the costs of Endometrial Cancer (EC) by stage of disease. We estimated the long-term secondary care costs of EC according to stage at diagnosis in an English population-based cohort.MethodsWomen participating in UKCTOCS and diagnosed with EC following enrolment (2001–2005) and prior to 31st Dec 2009 were identified to have EC through multiple sources. Survival was calculated through data linkage to death registry. Costs estimates were derived from hospital records accessed from Hospital Episode Statistics (HES) with additional patient level covariates derived from case notes and patient questionnaires. Missing and censored data was imputed using Multiple Imputation. Regression analysis of cost and survival was undertaken.Results491 of 641 women with EC were included. Five year total costs were strongly dependent on stage, ranging from £9,475 (diagnosis at stage IA/IB) to £26,080 (diagnosis at stage III). Stage, grade and BMI were the strongest predictors of costs. The majority of costs for stage I/II EC were incurred in the first six months after diagnosis while for stage III / IV considerable costs accrued after the first six months.ConclusionsIn addition to survival advantages, there are significant cost savings if patients with EC are detected earlier.

Ovarian cancer is often diagnosed at an advanced stage and is associated with poor survival. Screening aims at detection of early stage disease with a view of improving overall survival. Incidence of ovarian cancer is about 1-2% in the low-risk and 10-40% in the high-risk population. Transvaginal ultrasound (TVS) and serum CA125 levels have been used for early detection. Annual screening with TVS and serum CA125 levels (using a cutoff value) has not demonstrated detection of ovarian cancer at an early stage. Multimodal screening (MMS) using sequential CA125 levels (with interpretation of risk using Risk of Ovarian Cancer Algorithm-ROCA) and ultrasound as the second-line test have been shown to have improved sensitivity when compared to annual ultrasound in the detection of ovarian cancer. However, no impact on survival has been demonstrated, and therefore, screening cannot be recommended in the general or high-risk population. There is evidence now to suggest that high-grade serous cancers originate from the fallopian tube where precursor lesions have been identified. Newer screening strategies are likely to shift the focus to detecting these precursor lesions with novel techniques such as exfoliative cytology, circulating tumour DNA and use of microbubbles in ultrasound imaging.