Cancer detection and prevention最新文献

Tumor-infiltrating lymphocytes (TIL) consist of T helper 1 (Th1) and T helper 2 (Th2) cells producing interferon-gamma (IFN-gamma) and interleukin4 (IL-4), respectively. Interleukin-12 (IL-12) induces Th1 and Th2 differentiation. Therefore, IL-12, IFN-gamma, and IL-4 gene expression were evaluated by reverse transcriptase-polymerase chain reaction in carcinomas of the breast (n = 10), lung (n = 17), and larynx (n = 13) to investigate whether TIL activation is IL-12-related. IL-12 and IFN-gamma were codistributed in breast carcinomas, and IL-4 was demonstrated in three instances. IL-12 and IFN-gamma were detected in 15 and 13 lung carcinomas, respectively, and were codistributed in 11 cases; IL-4 was observed in 9 cases and was codistributed with IL-12 and IFN-gamma in 7 instances. IL-12 and IFN-gamma expression was observed in five and nine larynx carcinomas, respectively, and were codistributed in four cases; IL-4 was detected in five instances. These data indicate that breast, lung, and larynx carcinomas are characterized by different patterns of IL-12, IFN-gamma, and IL4 gene expression and suggest that Th1 activation may be induced, at least in part, by the neoplastic microenvironment.

Despite global immune system abnormalities in the autoimmune deficiency syndrome, the incidence of only a few tumor types increases, and the degree of immunosuppression does not seem to be critical in the development of these tumors, indicating that the immune system does not prevent tumor development. Consequently, because tumors do not develop in most individuals, other defense systems may exist. We demonstrated previously that 13 substances in the circulatory system acting synergistically induced apoptosis in vitro and in vivo in different tumor cell lines, but not in normal cells and animals. We investigated another 17 compounds and five ions in the circulatory system to determine their participation in the defense provided by the 13 substances. Three of the 17 substances but no ions had a potentiating effect on the mixture of substances used previously. The new 16-component mixture suppressed in vitro growth of six human and murine tumor cell lines, including multidrug-resistant tumor cells, without cytotoxic effects in two normal cell lines. The selectivity also was demonstrated by investigating the mixture's effect over time on tumor and normal cell growth.

Some effects of recombinant p14, a protein encoded by the tat gene of immunodeficiency virus type 1 (HIV-1), were investigated on T lymphocytic cell cultures. In particular, we detected p14 adsorption to cells, the rate of cell replication, the expression of fibronectin (FN) and its receptor (FNR) and of cell surface CD4 antigen in HIV-1-infected or uninfected MT-4 and H9 cells, treated with p14. Moreover, we evaluated the proportion of apoptotic cells in uninfected and chronically infected H9 cells in the presence of p14 and the modulation of interferon (IFN) production induced by p14 in PBMC of healthy subjects. The results obtained demonstrate that p14 exerts multifunctional activities on HIV-1 infected and uninfected cells. In particular, this protein interacts in a specific manner with cell surface, especially with that of infected cells, and enhances the expression of FN and FNR but not that of the CD4 lymphocyte antigen. Moreover, p14 increases cell replication, IFN production and can exert a slight modulation of apoptosis. We also propose a model to explain a possible role in HIV-1 infection of the effects of exogenous p14.

Pancreatic cancer (pancreatic ductal carcinoma) is one of the most malignant solid tumors with poor prognosis. There is accumulating evidence that cellular reduction/oxidation (redox) status is deeply involved in the growth promotion and drug resistance of cancer cells. We therefore investigated the expression of redox-regulating proteins, such as thioredoxin (TRX) and glutaredoxin (GRX) in surgically resected pancreatic tissues and cis-diamminedichloroplatinum (CDDP)-resistant cells. Plasma levels of TRX were also measured in subjects with pancreatic diseases. Pancreatic ductal carcinoma tissues were immunohistochemically more positive for TRX (24/32 cases) and GRX (29/32 cases) than pancreatic cystadenocarcinoma or normal pancreas tissues. Plasma levels of TRX (mean +/- SD) measured by ELISA were significantly higher in patients with pancreatic ductal carcinoma (54.8 +/- 37.6 ng/ml, n = 60) than in healthy controls (24.4 +/- 12.9 ng/ml, n = 81). CDDP-resistant subclones of HeLa cells, HeLa-CP5 cells, had higher expression of TRX (1.5 fold) and GRX (1.6 fold) compared with parental HeLa cells by immunoblotting. These results indicate the possible association of TRX and GRX with malignant potential of pancreatic ductal carcinoma.

Human herpesvirus 8 (HHV-8) is involved in the pathogenesis of Kaposi's sarcoma, of B-cells lymphomas, and of Castelman's disease. However, the role of this virus is not yet well known. To investigate the relationship between HHV-8 infection and diseases correlated with human immunodeficiency virus (HIV), we studied a cohort of 67 HIV-seropositive subjects, some of them coinfected with HHV-8. An indirect immunofluorescence test was employed to detect the antibodies against this virus. Positive cases were 31 (46.3%); among the 67 patients, 14 were weakly positive, or + (20.9%); 11 were significantly positive, or ++ (16.4%); and 6 were strongly positive, or (8.9%). These last six patients were the most affected by opportunistic infections, and all were affected by neoplastic pathologies. Moreover, the HHV-8 positive subjects showed hematologic and martial alterations more severe than those in the negative subjects. HHV-8 seroprevalence in HIV-seropositive patients of our cohort was higher (46.3%) than in normal population (0-10%). The presence of disseminated Kaposi's sarcoma and other neoplasms associated with high HIV-RNA levels in HHV-8-positive patients, and particularly in those with strong positivity, corroborates the hypothesis that the virus is correlated with the progression of HIV infection and with its related diseases, especially those that are neoplastic. Last, the severe alterations of iron metabolism found in the patients coinfected with HHV-8 and the negative effect of this virus on the lymphocytic populations can contribute to the unfavorable evolution of HIV infection and also might facilitate tumor development.

We conducted a case-control study to analyze the effect of neoadjuvant tamoxifen on steroid receptors and histologic grade and to evaluate the feasibility of phase III studies in operable breast cancer. Between 1987 and 1990, 107 patients without clinical metastases who had had no chemotherapy preoperatively, were treated preoperatively with 20 mg/day of tamoxifen for 3 weeks. Of them, 92 were matched with controls for age at diagnosis, year of diagnosis, presence or absence of lymph node involvement, and preoperative radiotherapy. The percentage of ER1 tumors (P = .03) and the mean and median ER levels (P<.001 for both) were lower in the tamoxifen group than in the control group. In six patients analyzed longitudinally, the mean ER decreased from 52 to 19 fmol/mg protein. The difference in relapse-free survival between the two groups was not significant (mean follow-up 87 months). This study suggests a decrease in ER content in patients treated with neoadjuvant tamoxifen. This change may thus be taken into account when ER determination is performed after tamoxifen therapy is started. Further randomized trials should determine whether patients with operable breast cancer benefit from neoadjuvant tamoxifen treatment.

The cytotoxicity of high-dose methotrexate (MTX), 10 and 100 microM, and 5-fluorouracil (5-FU) combinations is independent of sequence in human MDA-MB-436 breast carcinoma cells. The growth inhibitory effects of 10 and 100 microM MTX are 22.54+/-1.56% and 16.20+/-0.74%, respectively, of the control rate. When the MTX and 5-FU concentrations are 10 microM, antiproliferative effects of MTX 2 hr before 5-FU (MTX/5-FU) and 5-FU 2 h before MTX (5-FU/MTX) are 25.17+/-1.23% and 25.60+/-1.28% of the control rate, respectively. The percentage of control rates for 5-FU alone is 94.89+/-1.35%. The growth rates of MDA-MB-436 cells in 100 microM MTX and 10 microM 5-FU are 15.19+/-0.62% (MTX/5-FU) and 16.53+/-0.85% (5-FU/MTX) of the control rate. The growth of cancer cells in the presence of 5-FU alone is 93.82+/-1.69% of the control rate. A comparison of the cell-killing effects of MTX and the nonpolyglutamable antifolate trimetrexate (TMQ) alone and in combination with 5-FU was performed to indirectly explore the role of polyglutamylation in breast cancer and bone marrow cells. The comparisons were made in equitoxic concentrations (10 microM) of MTX and TMQ and the time of exposure was the same. The inhibitory effects of TMQ, TMQ/5-FU, and 5-FU/TMQ in breast cancer cells were identical, but significantly less than MTX, MTX/5-FU, and 5-FU/MTX. The interaction between TMQ and MTX, TMQ/5-FU and MTX/5-FU, and 5-FU/TMQ and 5-FU/MTX was quantitatively similar in bone marrow. (Significant protection occurred in bone marrow cells exposed to 5-FU/TMQ and 5-FU/MTX.) Because the effects of 5-FU/MTX and 5-FU/TMQ on bone marrow were the same, it is unlikely that polyglutamylation plays a significant role in the protective effects of 5-FU. However, the greater inhibitory effect of MTX or MTX and 5-FU combinations, when compared with TMQ or TMQ and 5-FU, suggests that polyglutamylation of MTX may contribute to the cytotoxicity of this antifolate to breast cancer cells. Hence, these studies suggest that a priming and nontoxic dose of 5-FU before high-dose MTX sustains MTX cytotoxicity in breast cancer and protects against MTX toxicity to bone marrow progenitor cells.

CD44 is a cell surface glycoprotein involved in cell migration and cell docking in target organs via interactions with various ligands, including hyaluronic acid (HA), which is the principal ligand of this receptor. Alternative splicing generates many isoforms of CD44, including standard CD44 (CD44s) and CD44 variants (CD44v). LB T-cell lymphoma, which predominantly expresses CD44s, acquires additional CD44v and HA binding capacity after activation with phorbol ester. The HA9 cell line, isolated from parental LB cells, expresses CD44v and constitutively binds HA. Downregulation of CD44v isoforms of HA9 cells, by CD44v specific antisense inhibited their ability to bind HA, indicating that CD44v, rather than CD44s, is associated with the activation status of this molecule. Using the reverse transcriptase polymerase chain reaction, we found that LB cells after infiltrating spleen and lymph nodes of BALB/c mice, contain an enriched repertoire of CD44v, implying that the metastatic cells acquired the activated form of this receptor.

We investigated the usefulness of serum type IV collagenolytic activities and gelatinase levels as diagnostic markers of metastasis in the animal model of spontaneous lung metastasis by FITC-labeled type IV collagen degradation assay and zymographic analyses. High-metastatic RCT(+) and low-metastatic RCT(-) clones were used in the present study. The mean serum type IV collagenolytic activity in the RCT(+) group started to increase from two weeks after hind limb amputation, and was 0.45 and 1.29 unit/ml at three and four weeks. These values were significantly higher than those in the control group (p < 0.01 at three weeks; p < 0.001 at four weeks). A correlation between the number of lung nodules and serum type IV collagenolytic activities in the RCT(+) group was found (r = 0.89, p < 0.001). Zymographic analyses indicated that 105-kD gelatinolytic activities of the RCT(+) group were higher than those of the RCT(-) group at three and four weeks. Thus, type IV collagenolytic activities and serum gelatinase levels might be valuable markers for the detection of metastasis.

Patients with advanced cancer often develop immunodeficiency which may be associated with granulocytosis. The granulocytes have the potential to deplete cytotoxic T cells, resulting in accelerated tumor growth and metastasis. To study the elimination of excess granulocytes using granulocyte apheresis in patients with elevated granulocyte to lymphocyte ratios, 2 patients with recurrent metastatic tumors, were selected. Granulocyte apheresis was performed by extracorporeal vein-to-vein circulation with the G-1 granulocyte and monocyte/macrophage apheresis column filled with cellulose acetate beads, each 2 mm in diameter to adsorb granulocytes and monocytes/macrophages. The patients received 1 or 2 apheresis of 30 to 50 min duration per week, at a flow rate of 30-50 ml/min, with 15 sessions constituting one therapeutic course. Apheresis markedly reduced tumor size and prolonged patient survival time without causing any serious adverse events. The results of the present study suggest that granulocyte and monocyte/macrophage apheresis may be beneficial in patients with metastasizing tumors.