Cancer detection and prevention最新文献

We studied the effects of inhibition of cytochrome P-450 by proadifen (SKF525A) on the processes induced in myeloid leukemia HL-60 cells by all-trans-retinoic acid (ATRA). The parameters reflecting cell proliferation, differentiation, and apoptosis were detected by flow cytometry as the principal method at selected time intervals (24-96 hours). Changes in the expression of Bcl-2 protein were detected by Western blotting. The majority of experiments were designed as a factorial combination of the treatment and assessed for significance of the interactions. Proadifen was demonstrated synergistically (1) to potentiate the antiproliferative and differentiation effects of ATRA, and (2) to increase cell viability and prevent ATRA-induced apoptosis. Moreover, proadifen weakened ATRA-induced downregulation of the Bcl-2 protein. Our results may be of practical importance because cytochrome P-450 inhibitors are used clinically in treating cancer patients. Assuming that effects on the leukemic cells in vivo would be similar, this type of combined therapy could help to achieve better results even with lower doses of ATRA.

The combination of a noninvasive, quantitative immunoassay, NMP22, with voided urinary cytology prior to cystoscopy was evaluated in patients with urothelial transitional cell carcinoma. Fifty-six patients with a history of transitional cell carcinoma were evaluated. Voided urine was obtained for NMP22 and cytology prior to cystoscopy. One hundred and twenty-three NMP22 assays, 124 cytologies, and 124 cystoscopies were performed. The type of anesthesia used for cystoscopic evaluation was determined by the NMP22 value in 30 patients. Cystoscopy results were considered positive on biopsy-confirmed malignancy. The reference value used for NMP22 was 10.0 U/ml. NMP22, cytology, and the combination of NMP22 and cytology were compared to cystoscopy and to pathologic grading and staging. Thirty-four recurrent transitional cell carcinoma episodes occurred; 22 were low-grade (I-II), and 12 were high-grade (III-IV). Twenty-seven were stage Ta; four were T1; and three were T3b or 4. Within this group, NMP22 detected low- and high-grade tumors equally, as compared to cytology, which was sensitive only to high-grade tumors. Nineteen patients were NMP22-negative and underwent cystoscopy under topical anesthesia; 17 were tumor-free. Eleven patients were NMP22-positive and had anesthesia, and all had visible lesions, which were subjected to biopsy and were resected. Six lesions were tumors, five were inflammatory. Overall sensitivity of combined NMP22 and cytology was 70%; specificity was 72%; positive predictive value was 54%; and negative predictive value was 77%. An accurate assessment of the risk of a bladder cancer can be obtained with NMP22, cytology, and cystoscopy in patients with a history of bladder cancer. NMP22 values can be used to determine the level of anesthesia for cystoscopy in patients with a history of bladder cancer.

Antioxidants are often added to culture media as cytoprotective agents. We examined the effects of antioxidants on the results and interpretation of the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay for cell viability. Without cells, the thiol-containing antioxidant compounds beta-mercaptoethanol, dithiothreitol, pyrrolidine-dithiocarbamate, and N-acetyl-L-cysteine (acetylcysteine) reduced MTT tetrazolium salts to a blue formazan product in a dose-dependent manner. Addition of the compounds L-ascorbic acid and (+)-alpha-tocopherol acid succinate had different effects. In contrast, addition of the antioxidants N-acetyl-5-methoxytryptamine and (-)-2-oxo-4-thiazolidine carboxylic acid, which do not contain reactive thiol groups, did not result in the development of blue formazan product. These results showed that antioxidants, and potentially other chemotherapeutic compounds that contain free thiol groups or other reducing equivalents, readily reduce MTT to produce the blue formazan, irrespective of the viability of the cells present. This undescribed reaction can, therefore, significantly influence the results and interpretation of cell-viability experiments.

Because in experimental hepatocarcinogenesis apoptosis increases from normal to preneoplastic to carcinoma tissue, proapoptotic factors, such as activin-A, may represent useful markers for hepatocellular carcinoma (HCC). In this study, serum activin-A was measured in 99 cirrhotic patients, of whom 55 had HCC. Activin-A concentrations were higher in HCC patients (median, 2.33 ng/ml; range, 0.41-8.12) than in patients with nonmalignant cirrhosis (1.28 ng/ml; range, 0.35-6.25) (P < .05). All 12 patients with activin-A greater than 3 ng/ml and serum alpha-fetoprotein greater than 30 ng/ml had HCC, in comparison to 32 of 41 patients who had only one and to 11 of 46 patients who had both markers below these cutoffs (P < .0001). No correlation was found between activin-A and alpha-fetoprotein in the two groups, whereas in patients with HCC, activin-A was strictly correlated with serum aspartate aminotransferase (P < .001). Activin-A mRNA for inhibin betaA subunit was expressed both in tumor and nontumor liver tissues in a case of HCC superimposed on cirrhosis and was not expressed in a case of HCC without cirrhosis. In conclusion, cirrhotic patients with HCC have high serum activin-A, to the production of which both the cirrhotic liver and the liver tumor are likely to contribute.

Multiple genomic alterations are involved in the development of most human cancers. They include alterations in oncogenes, tumor suppressor genes, DNA mismatch repair and excision repair genes. Genetic testing for susceptibility has been a part of the management of patients with well-defined but uncommon hereditary cancers in which certain susceptible gene mutations are determined in the germ line. However, a molecular diagnostic approach to sporadic cancers, which comprise the vast majority of malignant tumors in human beings, is still under development. One of the best characterized tumor-related genes is K-ras, which somatically mutates in several types of sporadic human cancers. Since mutations of this gene occur exclusively in three hot spots (codons 12, 13 and 61), and are frequently detected and well characterized in colorectal, pancreas and lung cancers, molecular diagnosis and susceptibility (risk) assessment targeting K-ras mutations are being developed. For this purpose, sample collection methods that reflect the state of the entire affected organ are important. Clinical samples used for molecular diagnosis and risk assessment include stool and lavage fluid, pancreatic and duodenal juices, and sputum and lavage fluids for colorectal, pancreas and lung cancers, respectively. The reported incidence of K-ras mutations detected in these samples ranges from 7% to 80% for colorectal cancers, 25% to 87% for pancreatic cancers, and 25% to 48% for lung cancers. Incidence of mutations clearly depends on the sensitivity of the method for detecting the mutant K-ras allele, as well as the nature and the quality of the clinical samples. Various methods including plaque hybridization, dot blot hybridization, combined PCR and RFLP or SSCP, and sensitive PCR have been used, and they exhibited high specificity (75 to 100%) in detecting mutations. Molecular analysis is demonstrating promise in assessing susceptibility to, or risk of developing, sporadic cancers.

Skin self-examination (SSE) is promoted widely so that individuals will become familiar with their skin and be better able to identify suspicious changes earlier. However, individuals can also become familiar with their skin other than through purposeful SSE. In this article, we develop a measure of skin familiarity based on the density of spots on 14 different areas of the body. A factor analysis of the 14 body-area scores revealed that they could be grouped into four broad body regions (shoulders and back, front of legs, back of legs, and feet). Each total body score and body-region score has high internal consistency (Cronbach's alpha coefficients ranging from 0.79 to 0.93). Moreover, the scores correlate as expected with skin self-examination behaviors and other personal characteristics, indicating high construct validity. We consider the advantages that skin familiarity measures offer over the exclusive use of SSE measures in the assessment of early detection activities and discuss the direction of future research in this area.

Pfaffia paniculata (Brazilian ginseng) administered subcutaneously and intraperitoneally inhibits growth of allogeneic cancer cells in mice. The goal of this study was to determine whether oral administration of P. paniculata inhibits development of spontaneous leukemia. Four-week-old female AKR/J mice were given oral doses of powdered roots from P. paniculata three times weekly for 8 weeks; controls received phosphate-buffered saline. Enlargement of thymic lymphoma in the mice treated with P. paniculata was significantly suppressed, as compared with controls (128 +/- 67.3 mg versus 219.9 +/- 84.2 mg, respectively; P < .01); proliferation of endogenous recombinant murine leukemia viruses (MuLV) in the thymus was markedly inhibited after the first oral treatment as compared with untreated controls (final age, 28 weeks; P < .05). In normal 3-week-old female AKR/J mice, mortality from thymic lymphoma was delayed markedly after injection into the thymus of cell-free extract of thymus from the experimental female 28-week-old AKR/J mice that received the oral P. paniculata preparation. These results suggest that the agent's suppressive effects on spontaneously occurring leukemia caused by endogenous recombinant MuLV in female AKR/J mice may depend on enhancement of nonspecific immune or cellular immune systems (or both) by the P. paniculata preparation.

The aim of this study was to analyze possible changes in the total phospholipid distribution in murine mammary adenocarcinomas induced in transgenic mice by the tissue-specific expression of the neu oncogene, as compared with normal tissues. To understand whether the altered phospholipid profile might be specifically tissue-related to the oncogene expression, phospholipid composition also has been analyzed in liver, kidney, lung, and spleen. The data indicate that only tumor mammary tissues show a drastic increase of the total phospholipid content (P < 0.0001) associated with a significant increment of phosphatidylethanolamine, phosphatidylcholine, and sphingomyelin (P < 0.05). Moreover, gas-chromatography analysis of total phospholipid-derived fatty acids shows a decrease in the percentage content of linoleic acid in tumor tissues, suggesting an altered metabolism of this fatty acid related to the enhanced epithelial proliferation. We conclude that neu transgenic mice provide a good model to clarify the involvement of phospholipids in neu-induced neoplastic transformation and to study in vivo the metabolic pathways related to the intracellular signaling.

Lipid peroxidation produces several toxic carbonyls, including biologically active aldehydes. In previous studies, we demonstrated that 4-hydroxynonenal (HNE), one of the major products of lipoperoxidation, inhibited growth and c-myc expression in K562 and HL-60 human leukemic cells. In this study, we compared the HNE effects with those of 4-hydroxyoctenal (HOE), 4-hydroxyundecenal (HUE; different lengths of the lipophilic tail), and the analogous aldehydes 2-trans-nonanal (lacking the OH group) and nonenal (lacking the OH group and the trans CC double bond), on HL-60 cell proliferation and c-myc expression. HUE and HOE inhibited growth and c-myc expression in a dose-dependent fashion, with an effectiveness comparable with that of HNE, whereas 2-nonenal and nonanal did not affect these parameters. Our results showed that different aldehydes produced from lipid peroxidation may contribute to growth inhibition by c-myc downregulation and that the molecular features involved seem to be the hydroxy group and the trans CC double bond.

This study was designed to analyze the cytochrome P450 isoenzyme mRNA expression pattern of transitional cell carcinomas of the bladder (N = 19) and normal urothelium (N = 10). In addition, biopsies from normal urothelium (N = 32) taken at the time of transurethral resection of bladder cancer in eight patients from surrounding histologically normal urothelium also were characterized concerning their specific cytochrome P450 mRNA expression pattern. A total of 13 of 19 of the analyzed tumor specimens (68%) revealed expression of cytochrome P450 1B1. Cytochrome P450 4B1 and 1A1 mRNA expression were detected in 79% (15 of 19) and 53% (10 of 19) of the tumor specimens, with no correlation between tumor stage and grade of the neoplasm. Biopsies from macroscopically and histologically normal urothelium from tumor-invaded bladders also showed expression of cytochrome P450 1B1 in 75% (24 of 32), 4B1 in 62.5% (20 of 32), and 1A1 in 50% (16 of 32). Furthermore, a 75% homology concerning cytochrome P450 1B1 and 4B1 mRNA expression was observed between the bladder tumor and the biopsies from this bladder. The polymerase chain reaction analysis of normal urothelium from normal bladders that do not harbor a neoplasm revealed CYP450 mRNA expression for CYP450 1A1 in 6 of 10; 1B1 in 5 of 10; 4B1 in 6 of 10; 2D6 in 2 of 10; and 2E1 in 2 of 10. According to our data, CYP450 1B1 mRNA expression is not tumor-specific. The present findings are the first to compare CYP450 expression in bladder cancer with biopsies from the same tumor-bearing bladder, and they indicate that, from the enzymatic point of view, bladder cancer also is a panurothelial field disease present in even normal urothelium.