Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0220723 (PCA)
 4,687 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

MKT-077, a delocalized lipophilic cation, selectively targets cancer cells. MKT-077 has been reported to inhibit the growth of several tumor types and has undergone phase I clinical testing. We have examined the effect of MKT-077, alone and in combination with the antidiarrheal drug loperamide. Ten human cancer cell lines, four prostate (PC3, DU145, LNCaP, MDA-PCA-2B), two breast (MCF-7 and MDA-MB-231) and four colon (LoVo, Colo320DM, SW1116 and LS174t) were tested in vitro. Cells were grown to confluency prior to treatment. Loperamide potentiated the antiproliferative effect of MKT-077 in all ten cell lines, in a dose-dependent manner. The sensitivity of MDA-PCA-2B cells, the two breast and four colon cancer cell lines to MKT-077 was relatively low (>2.5 microg/ml MKT-077 required to inhibit growth by 95%). In these cell lines, 0.5-5 microg/ml (1-10 microM) loperamide caused a marked increase in the response to MKT-077. Loperamide is known to activate micro-opioid receptors at nanomolar concentrations and block voltage-gated calcium channels at micromolar doses. We found that calcium channel-blockers diltiazem and nifedipine (10-20 microg/ml), as well as tamoxifen (1.5-2.5 microg/ml) can also potentiate the growth-inhibitory effects of MKT-077. These synergistic interactions could be exploited for therapeutic benefit.
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PMID:Potentiation of the antiproliferative activity of MKT-077 by loperamide, diltiazem and tamoxifen. 1453 37

AML patients may suffer from a disseminated coagulopathy, which can aggravate a pre-existing bleeding tendency due to thrombocytopenia and platelet dysfunction. The cellular and molecular mechanisms underlying this coagulopathy, however, are not completely understood. Indeed, the broad and increasing therapeutic use of cytotoxic drugs and growth factors is likely to contribute to the complexity of hemostatic abnormalities encountered in this hematologic malignancy. The nature of coagulation activation in AML was therefore investigated in vitro using the human leukemic cell line, HL60. Tissue factor (TF) was almost entirely located on the cell surface and bound factor VIIa, but only 15-25% of this TF was primarily functionally active. Treatment with increasing concentrations of daunorubicin or cytosine-beta-D-arabinofuranoside, two cytotoxic drugs commonly used in AML therapy, induced apoptosis and secondary necrosis of HL60 cells and resulted in marked decryption of TF PCA independent of de novo protein synthesis. This PCA-modulating effect was concomitant with and functionally dependent on the exposure of phosphatidylserine on the outer membrane leaflet. Similar observations were made in analogous ex vivo studies on patient-derived myeloblasts. Incubation of HL60 cells with GM-CSF, a cytokine expressed in the bone marrow microenvironment and used as an adjunct to AML treatment, evoked a cellular response, which included both enhanced TF production and release of VEGF-A and uPA into the culture medium. We conclude that both decryption of pre-formed TF PCA by chemotherapeutic drugs and de novo induction of TF by cytokines such as GM-CSF can regulate the pro-coagulant phenotype of HL60 cells in vitro.
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PMID:An in vitro study on the mechanisms of coagulation activation in acute myelogenous leukemia (AML): role of tissue factor regulation by cytotoxic drugs and GM-CSF. 1554 44

Dietary restriction (DR)-induced changes in the serum metabolome may be biomarkers for physiological status (e.g., relative risk of developing age-related diseases such as cancer). Megavariate analysis (unsupervised hierarchical cluster analysis [HCA]; principal components analysis [PCA]) of serum metabolites reproducibly distinguish DR from ad libitum fed rats. Component-based approaches (i.e., PCA) consistently perform as well as or better than distance-based metrics (i.e., HCA). We therefore tested the following: (A) Do identified subsets of serum metabolites contain sufficient information to construct mathematical models of class membership (i.e., expert systems)? (B) Do component-based metrics out-perform distance-based metrics? Testing was conducted using KNN (k-nearest neighbors, supervised HCA) and SIMCA (soft independent modeling of class analogy, supervised PCA). Models were built with single cohorts, combined cohorts or mixed samples from previously studied cohorts as training sets. Both algorithms over-fit models based on single cohort training sets. KNN models had >85% accuracy within training/test sets, but were unstable (i.e., values of k could not be accurately set in advance). SIMCA models had 100% accuracy within all training sets, 89 % accuracy in test sets, did not appear to over-fit mixed cohort training sets, and did not require post-hoc modeling adjustments. These data indicate that (i) previously defined metabolites are robust enough to construct classification models (expert systems) with SIMCA that can predict unknowns by dietary category; (ii) component-based analyses outperformed distance-based metrics; (iii) use of over-fitting controls is essential; and (iv) subtle inter-cohort variability may be a critical issue for high data density biomarker studies that lack state markers.
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PMID:Development of biomarkers based on diet-dependent metabolic serotypes: practical issues in development of expert system-based classification models in metabolomic studies. 1566 13

In prostate cancer, biomarkers may provide additional value above standard clinical and pathology parameters to predict outcome after specific therapy. The purpose of this study is to evaluate an 80 kDa fragment of the cell adhesion molecule e-cadherin as a serum biomarker. A broad spectrum of prostate cancer serum samples, representing different stages of prostate cancer disease, including benign prostatic hyperplasia (BPH), localised (Loc PCA) and metastatic prostate cancer (Met PCA), was examined for the cleaved product. There is a significant difference in the expression level of the 80 kDa fragment in the serum of healthy individuals vs patients with BPH and between BPH vs Loc PCA and Met PCA (P<0.001). Highest expression levels are observed in advanced metastatic disease. In the cohort of Loc PCA cases, there was no association between the 80 kDa serum concentration and clinical parameters. Interestingly, patients with an 80 kDa level of >7.9 microg l(-1) at the time of diagnosis have a 55-fold higher risk of biochemical failure after surgery compared to those with lower levels. This is the first report of the application of an 80 kDa fragment of e-cadherin as a serum biomarker in a broad spectrum of prostate cancer cases. At an optimised cutoff, high expression at the time of diagnosis is associated with a significantly increased risk of biochemical failure, potentially supporting its use for a tailored follow-up protocol for those patients.
Br J Cancer 2005 Jun 06
PMID:Assessment of a fragment of e-cadherin as a serum biomarker with predictive value for prostate cancer. 1587 Jul 7

Protein kinase Pim-1 has been implicated in the development of hematopoietic and prostatic malignancies. Here, we present the evidence that two isoforms, the 44 and 33 kDa Pim-1, are expressed in all human prostate cancer cell lines examined. The subcellular localization of human 44 kDa Pim-1 is primarily on the plasma membrane, while the 33 kDa isoform is present in both the cytosol and nucleus in PCA cells. The 44 kDa Pim-1 contains the proline-rich motif at the N-terminus and directly binds to the SH3 domain of tyrosine kinase Etk. Such interaction leads to the activation of Etk kinase activity possibly by competing with the tumor suppressor p53. This is corroborated by the fact that overexpression of the 44 kDa Pim-1 in prostate cancer cells confers the resistance to chemotherapeutic drugs. Our results suggest that these two isoforms of Pim-1 kinase may regulate distinct substrates and the 44 kDa Pim-1 may play a more prominent role in drug resistance in prostate cancer cells.
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PMID:The 44 kDa Pim-1 kinase directly interacts with tyrosine kinase Etk/BMX and protects human prostate cancer cells from apoptosis induced by chemotherapeutic drugs. 1618 5

In recent studies, we have identified several highly potent all-trans-retinoic acid (ATRA) metabolism blocking agents (RAMBAs). On the basis of previous effects of liarozole (a first-generation RAMBA) on the catabolism of ATRA and on growth of rat Dunning R3227G prostate tumours, we assessed the effects of our novel RAMBAs on human prostate tumour (PCA) cell lines. We examined three different PCA cell lines to determine their capacity to induce P450-mediated oxidation of ATRA. Among the three different cell lines, enhanced catabolism was detected in LNCaP, whereas it was not found in PC-3 and DU-145. This catabolism was strongly inhibited by our RAMBAs, the most potent being VN/14-1, VN/50-1, VN/66-1, and VN/69-1 with IC50 values of 6.5, 90.0, 62.5, and 90.0 nM, respectively. The RAMBAs inhibited the growth of LNCaP cells with IC50 values in the microM-range. In LNCaP cell proliferation assays, VN/14-1, VN/50-1, VN/66-1, and VN/69-1 also enhanced by 47-, 60-, 70-, and 65-fold, respectively, the ATRA-mediated antiproliferative activity. We then examined the molecular mechanism underlying the growth inhibitory properties of ATRA alone and in combination with RAMBAs. The mechanism appeared to involve the induction of differentiation, cell-cycle arrest, and induction of apoptosis (TUNEL), involving increase in Bad expression and decrease in Bcl-2 expression. Treatment of LNCaP tumours growing in SCID mice with VN/66-1 and VN/69-1 resulted in modest but statistically significant tumour growth inhibition of 44 and 47%, respectively, while treatment with VN/14-1 was unexpectedly ineffective. These results suggest that some of our novel RAMBAs may be useful agents for the treatment of prostate cancer.
Br J Cancer 2006 Feb 27
PMID:Inhibitory effects of retinoic acid metabolism blocking agents (RAMBAs) on the growth of human prostate cancer cells and LNCaP prostate tumour xenografts in SCID mice. 1644 97

In order to diagnosis colon early cancer with laser-induced 5-ALA-PpIX fluorescence spectra, a multivariate statistical method to distinguish these fluorescence spectra acquired in vivo was developed. 343 spectra were collected from 8 normal SD rats, and 20 1,2-DMH-induced SD colon cancer models, and 12 second generation rats of induced rats. 150 min after trail intravenous injections of 5-ALA at a dose of 25 mg x kg(-1) BW, fluorescence spectra excited with 370 nm Ti-laser were collected in vivo. All spectra were divided into a calibration group and a prediction group. After preprocessing, 4 principal components were extracted with PCA. And then, discrimination models were built by stepwise multivariate logistic regression (SMLR) on calibration group. 3 pathological styles were combined each other, and then 3 SMLR models were derived. Normal tissues were classified from early cancers and advanced cancers with sensitivity of 100% and 98.4%, and specificity of 96% and 100%, and accuracy of 98% and 99.2% on prediction group, respectively. The multivariate statistical discrimination method of PCA and SMLR together can effectively distinguish normal tissues from early cancers and advanced cancers with high sensitivity and specificity by means of systemic 5-ALA at low dose. Laser induced fluorescence 5-ALA-based technique is promising for the detection of colonic early cancer.
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PMID:[Study of a multivariate statistical 5-ALA-based discrimination method for fluorescence spectra of colonic tissue of SD rats]. 1654 99

A fundamental obstacle in systemic therapy for cancer patients is the specific targeting of therapy directly to solid tumors. A strain of the domestic bacterium Bifidobacterium longum, which is non-pathogenic and anaerobic, showed selective localization to and proliferation within solid tumors after systemic application. Here, we propose a novel approach to cancer gene therapy in which anaerobic and non-pathogenic bacteria of the genus B. longum are used to achieve tumor-specific gene delivery and enzyme-prodrug therapy. We constructed a plasmid, pBLES100-S-eCD, which included eCD. Transfected B. longum produced CD in hypoxic tumors and achieved tumor site-specific conversion of 5-FC to 5-FU. Furthermore, we demonstrated antitumor efficacy in rat bearing autochthonous mammary tumors injected with the transfected B. longum directly or intravenously. This method was confirmed to be effective for enzyme-prodrug therapy not only by intratumoral injection but also by systemic administration. To estimate the toxicity of this bacterial vector, the systemic immunogenicity was evaluated by ASA reaction and the anaphylactic activity of IgG was evaluated by PCA reaction in guinea pigs. In the ASA reaction, no anaphylaxis symptoms were observed in any immunized guinea pigs injected with transfected B. longum. In the PCA reaction, B. longum/S-eCD specific-PCA-induced antibody was not detected. Thus, we proposed that anaerobic bacteria of the genus B. longum were an attractive and safe tumor-targeting vector and transfected B. longum was a potential anticancer agent that could effectively and specifically treat solid tumors.
Cancer Sci 2006 Jul
PMID:Genetically engineered Bifidobacterium longum for tumor-targeting enzyme-prodrug therapy of autochthonous mammary tumors in rats. 1682 6

PSA-only recurrence after definitive RP or RT for PCA is an increasingly com-mon scenario. The very definition of advanced prostate cancer is changing. Multimodal therapy improves cancer-specific outcomes especially in men with high-risk disease. After RP, a detectable serum PSA has been considered suggestive of PCA recurrence. After RT, the ASTRO definition of BCR has been widely used to define BCR. Both of these definitions of BCR are subject to dispute. The kinetics of a rising PSA (PSA doubling time) appears to be the best surrogate marker for disease risk, clinical progression, and ultimately cancer-specific death. Therapeutic options include salvage RT after primary RP or systemic HT through surgical/chemical castration, antiandrogens, or nontraditional HT. Re-cent studies suggest that early HT can provide modest survival benefits, but at both an economic cost and decreased quality of life. The diminished side effects of an oral antiandrogen are appealing, and may be as efficacious as castration therapies in low-volume disease. More clinical trials are needed to determine the best treatments, alone and in combination. The potential opportunities for novel therapeutic agents with low associated morbidity are great.
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PMID:Management of the patient with a rising PSA alone. 1686 Nov 21

The goal of this study was to determine whether patterns of expression profiles of p73 isoforms and of p53 mutational status are useful combinatorial biomarkers for predicting outcome in a gynecological cancer cohort. This is the first such study using matched tumor/normal tissue pairs from each patient. The median follow-up was over two years. The expression of all 5 N-terminal isoforms (TAp73, DeltaNp73, DeltaN'p73, Ex2p73 and Ex2/3p73) was measured by real-time RT-PCR and p53 status was analyzed by immunohistochemistry. TAp73, DeltaNp73 and DeltaN'p73 were significantly upregulated in tumors. Surprisingly, their range of overexpression was age-dependent, with the highest differences delta (tumor-normal) in the youngest age group. Correction of this age effect was important in further survival correlations. We used all 6 variables (five p73 isoform levels plus p53 status) as input into a principal component analysis with Varimax rotation (VrPCA) to filter out noise from non-disease related individual variability of p73 levels. Rationally selected and individually weighted principal components from each patient were then used to train a support vector machine (SVM) algorithm to predict clinical outcome. This SVM algorithm was able to predict correct outcome in 30 of the 35 patients. We use here a mathematical tool for pattern recognition that has been commonly used in e.g. microarray data mining and apply it for the first time in a prognostic model. We find that PCA/SVM is able to test a clinical hypothesis with robust statistics and show that p73 expression profiles and p53 status are useful prognostic biomarkers that differentiate patients with good vs. poor prognosis with gynecological cancers.
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PMID:Patterns of p73 N-terminal isoform expression and p53 status have prognostic value in gynecological cancers. 1696 85


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