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Objectives The benefits of liquid-based cytology (LBC) in routine cervical cancer screening are often associated with the availability of instrumented platforms and economic considerations. A low-cost alternative to LBC in low-volume settings remains an unmet need. Methods A multisite evaluation of the BD SurePath (SurePath) LBC Direct to Slide (DTS) method was conducted. The DTS preparations were evaluated across 3 sites. Cytology features for DTS preparation included predetermined thresholds for total cellularity, cell distribution, cellular preservation, and stain quality. Rare event detection was evaluated using SiHa cells spiked into pools from negative cytology specimens. Concordance between Bethesda classification results was evaluated for SurePath LBC and DTS methods using routinely collected SurePath specimens in a split-sample study design. Results The DTS specimens met criteria for total cellularity, cell distribution, cellular preservation, and stain quality in more than 98% of all cases. Rare event detection was observed with an average detection of 5 SiHa cells per 2 mL of specimen. Concordant cervical cytology classifications were observed between SurePath LBC and DTS methods. Conclusions The results demonstrate that the DTS process is suitable for routine cervical cytology evaluation. The procedure is reproducible and detected abnormal cervical cells in concordance with standard SurePath LBC preparation. [ABSTRACT FROM AUTHOR]

Presents a study on the clinical features of patients with autoantibodies to centromere protein CENP-F and the frequency of CENF-P autoantibodies in patients with various diseases. Details on methods and materials used in the study; Results of the study; Conclusions reached.

Background: There are several advantages to combinatorial chemoprevention strategies over monotherapeutic approaches. Both the HMG-CoA reductase inhibitor (HRI) lovastatin (LOV) and the selective apoptotic antineoplastic drug (SAAND) exisulind (EXS) have shown remarkable chemopreventive effects in previous studies, in cell lines and limited studies in rodents. Here, experiments were designed to assess the potential use of these two compounds in combinatorial chemoprevention therapy, using two bio-assays in which inhibition of the carcinogen-induced preneoplastic lesions, aberrant crypt foci (ACF), was used to quantitate efficacy., Materials and Methods: ACF were induced by the carcinogen azoxymethane (AOM) in F344 rats by two sequential weekly i.p. injections at a dose of 15 mg/kg. F344 rats were fed seven experimental diets containing LOV @ 50 parts per million (ppm), EXS @ 100, 250 and 1000 ppm and combination diets containing EXS at 100, 250 and 1000 ppm, each combined with LOV @ 50 ppm. Quantification of ACF number and type (singlet, doublet, triplet and four or more) was performed on whole mounts of rat colons stained with 1.0% methylene blue., Results: During the initiation protocol, administration of LOV @ 50 ppm alone and the combination of LOV @ 50 ppm with EXS @ 1000 ppm significantly decreased the mean number of ACF when compared to the positive control by 49% and 47%, respectively; however EXS @ 250 ppm displayed tumor promoting effects by significantly increasing the mean number of ACF by 64%. The post-initiation protocol administration of EXS @ 100, 250 and 1000 ppm and the combinations of LOV @ 50 ppm with EXS @ 100 and 250 ppm significantly increased the mean number of ACF when compared to the positive control by 44%, 48%, 55%, 49% and 40%, respectively., Conclusion: LOV shows greater promise than EXS in fulfilling the role as a supplemental chemopreventive agent in combinatorial chemopreventive strategies for cancers such as colon cancer. EXS did not augment this activity, failing to enhance chemopreventive therapy in this animal model.

We reported previously a significant increase in survival of nude rats harboring orthotopic A549 human non-small cell lung cancer tumors after treatment with a combination of exisulind (Sulindac Sulfone) and docetaxel (D. C. Chan, Clin. Cancer Res., 8: 904-912, 2002). The purpose of the current study was to determine the biochemical mechanisms responsible for the increased survival by an analysis of the effects of both drugs on A549 orthotopic lung tumors and A549 cells in culture. Orthotopic A549 rat lung tissue sections from drug-treated rats and A549 cell culture responses to exisulind and docetaxel were compared using multiple apoptosis and proliferation analyses [i.e., terminal deoxynucleotidyl transferase-mediated nick end labeling, active caspase 3, the caspase cleavage products cytokeratin 18 and p85 poly(ADP-ribose) polymerase, and Ki-67]. Immunohistochemistry was used to determine cyclic GMP (cGMP) phosphodiesterase (PDE) expression in tumors. The cGMP PDE composition of cultured A549 cells was resolved by DEAE-Trisacryl M chromatography and the pharmacological sensitivity to exisulind, and additional known PDE inhibitors were determined by enzyme activity assays. Exisulind inhibited A549 cell cGMP hydrolysis and induced apoptosis of A549 cells grown in culture. PDE5 and 1 cGMP PDE gene family isoforms identified in cultured cells were highly expressed in orthotopic tumors. The in vivo apoptosis rates within the orthotopic tumors increased 7-8-fold in animals treated with the combination of exisulind and docetaxel. Exisulind increased the in vivo apoptosis rates as a single agent. Docetaxel, but not exisulind, decreased proliferative rates within the tumors. The data indicate that exisulind-induced apoptosis contributed significantly to the increased survival in rats treated with exisulind/docetaxel. The mechanism of exisulind-induced apoptosis involves inhibition of cGMP PDEs, and these results are consistent with a cGMP-regulated apoptosis pathway.

Exisulind (sulindac sulfone) and two potent derivatives, CP248 and CP461, have been shown previously to cause growth inhibition and apoptosis in several types of human carcinoma cell lines. These and related compounds have not been previously studied with respect to glioma cell lines. In the present study, we found that these three compounds caused marked growth inhibition in four rat glioma and eight human glioma cell lines, with IC50 values of 150, 1, and 0.075 microm, respectively. When studied at these concentrations exisulind and CP461 had no significant effect on the cell cycle profile of glioma cells, but CP248 caused marked arrest in mitosis. Detailed studies of CP248 in the 9L rat gliosarcoma cell line indicated that treatment with 0.075 microM CP248 caused abnormalities in the spindle apparatus and activation of the spindle assembly check point. In interphase glioma cells, CP248 stabilized microtubules (MTs) at low concentrations (0.075 microM) and depolymerized MTs at higher concentrations (0.2-0.4 microM). In NIH 3T3 fibroblasts, 0.1 microM CP248 caused extensive MT depolymerization. CP248 also caused MT depolymerization when added to assembled MTs in vitro, which indicated that it can directly affect MTs, perhaps because it shares certain structural similarities with Colcemid. In glioma cells, the effects of CP248 on MTs were independent of the previously reported effects of this compound on activation of protein kinase G. Therefore, CP248 is a novel MT-active agent that may be useful in the treatment of glioblastoma, and possibly other types of cancer, because of its dual effects on protein kinase G and MTs.

Docetaxel, a semisynthetic taxane, improves the survival of stage IIIB and IV non-small cell lung cancer patients. However, the 5-year survival remains poor, and few patients experience a complete remission. In this report, we evaluated the effects of exisulind, a novel proapoptotic agent that is a sulfone metabolite of sulindac, in combination with docetaxel on the growth of the human non-small cell lung cancer cell line A549 in vitro and in vivo. Exisulind is a novel sulindac metabolite in that it does not inhibit cyclooxygenase enzymes and has been shown to induce apoptosis in a variety of human cancers by inhibiting cyclic GMP-dependent phosphodiesterase. Exisulind alone increased the fraction of cells in the G(1) phase of the cell cycle from 46% to 65%, whereas it decreased the fraction of cells in the S phase from 38% to 14%. Docetaxel increased the fraction of cells in the S phase from 17% to 19%, and 10 nM docetaxel increased the G2-M phase by 23%. Docetaxel alone induced apoptosis from 11% to 64% at 12-24 h after incubation. The combination of exisulind with concentrations of docetaxel (in concentrations that alone did not alter cell cycle distribution) reduced the G(1) accumulation induced by exisulind, increased the fraction of cells in G(2)-M (9-17%), and increased apoptosis (5-62%). The IC(50) for in vitro growth inhibition by exisulind alone was approximately 200 microM and 2.5 nM for docetaxel. The in vitro combination of exisulind and docetaxel produced an additive to synergistic growth inhibition. In athymic nude rats with A549 orthotopic lung cancers, both exisulind and docetaxel alone moderately prolonged survival, inhibited tumor growth and metastases, and increased apoptosis compared with control animals treated with a carrier. However, the combination of exisulind with docetaxel significantly prolonged survival (P = < 0.0004), inhibited tumor growth and metastases (P = < 0.0001), and increased apoptosis (P = < 0.001) when compared with control animals. These results provide rationale for conducting clinical trials using the combination of exisulind and docetaxel in patients with advanced lung cancer.