Prognostic value of a novel interferon-inducible 90K tumor antigen.
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Antigens, Neoplasm↗
Biomedical subjects
C Natoli
Publications and source records attributed to C Natoli.
Elevated serum levels of 90K/MAC-2 BP predict unresponsiveness to alpha-interferon therapy in chronic HCV hepatitis patients.
BACKGROUND: The clinical outcome of hepatitis virus infections is though to depend on the complex interplay between the host immune response profile and virus factors. 90K/MAC-2 BP is a novel member of the Scavenger Receptor Cysteine Rich protein superfamily that functions as a molecular alarm signal for the cellular immune system against both cancer cells and virus infections. METHODS: To assess the significance and the potential clinical usefulness of testing for serum levels of 90K/MAC-2 BP in chronic viral hepatitis patients we studied 115 consecutive patients with chronic HCV hepatitis, 28 HBsAg chronic hepatitis patients, 12 asymptomatic HCV carriers and 11 asymptomatic HBV carriers. 103 out of the 115 HCV patients have been treated with recombinant alpha 2a-interferon at the dose of 3 Mega Units (MU) t.i.w. for 6 months followed by 1.5 MU t.i.w. for 6 months, and have been followed up for a further 12 months. Serum levels of 90K/MAC-2 BP were measured by an immunoradiometric assay based on the specific SP-2 monoclonal antibody. RESULTS AND CONCLUSIONS: Serum 90K/MAC-2 BP levels are increased in chronic viral hepatitis patients, being significantly higher in HCV than in HBV patients. In chronic HCV hepatitis, serum 90K/MAC-2 BP levels are related to both the degree of disease severity and duration of infection. Moreover, elevated 90K/MAC-2 BP serum levels are an independent predictor of failure to respond to alpha-interferon treatment in a cohort of community-acquired chronic hepatitis C patients.
Adult↗
A flow cytometric study of early gastric cancer. The detection of high proliferative activity adds important information to the prognosis.
The prognostic value of DNA ploidy and proliferative activity has been rarely investigated in early gastric carcinoma (EGC). In the present study the ploidy pattern and cell cycle related parameters were evaluated in formalin-fixed paraffin-embedded specimens of 71 followed-up EGCs and compared with that of 20 advanced gastric carcinomas (AGC) using flow cytometry. The results showed that ploidy pattern did not affect patient outcome. On the contrary, EGC with a high S-phase had a worse prognosis. No significant differences in proliferative activity were detected between EGC and AGC. Fatal EGC had an S-phase higher than AGC. In conclusion, proliferative activity seems to affect the prognosis of EGC independent of the stage and could contribute to the identification of aggressive types of EGC.
Adult↗
90K (Mac-2 BP) in human milk.
Human 90K, also known as Mac-2 binding protein (Mac-2 BP), is a secreted glycoprotein which is widely expressed, binds to the human macrophage-associated lectin Mac-2, and may have a role in host defence. We have measured the concentrations of 90K in human breast milk from eight healthy mothers delivering mature healthy infants after full-term pregnancy using a specific immunoenzymatic assay. Maximal 90K concentrations were observed on days 2-3 post-partum, and ranged from 13.4 to 79.2 microg/ml. The concentrations of 90K in the milk had no correlation with those in the maternal blood.
Adult↗
Expression of tumor-associated 90K-antigen in human breast cancer: no correlation with prognosis and response to first-line therapy with tamoxifen.
It has been shown that a 90-kDa protein (90K), with an as yet unknown function, is expressed in the majority of human breast-cancer tissues. In addition, the serum level of this 90K antigen is elevated in a certain proportion of breast-cancer patients, and high serum levels are associated with a poor overall survival. It was therefore of interest to determine whether levels of 90K in tumor tissues could be used as a prognostic variable in breast cancer. In the present study, the levels of 90K in primary breast tumor cytosols were studied with respect to the length of relapse-free or overall survival in 547 patients (median follow-up, 81.4 months), and the relationship with response to first-line tamoxifen therapy and the length of progression-free survival in 184 patients with recurrent disease (median follow-up, 59.8 months). 90K levels in tumor cytosols were determined with an immunoradiometric assay. The cytosolic contents of 90K were not significantly correlated with age, menopausal status, tumor size, nodal status or differentiation grade. On the other hand, the levels of 90K were positively correlated with those of cytosolic estrogen receptor, progesterone receptor, urokinase-type plasminogen activator, its inhibitor PAI-I, cathepsin D and PS2. The cytosolic tumor level of 90K was not associated with the rate of relapse or death in primary breast cancer, nor with response to first-line therapy with tamoxifen or the length of progression-free survival in recurrent disease.
Actuarial Analysis↗
A phase I study of recombinant interferon-alpha administered as a seven-day continuous venous infusion at circadian-rhythm modulated rate in patients with cancer.
A Phase I trial of interferon-alpha (IFN-alpha) administered at circadian-rhythm modulated rate was carried out to evaluate maximum tolerated dose (MTD) and toxicity in patients with advanced malignancies. Recombinant IFN-alpha-2b was administered as a 7-day continuous venous infusion with maximum delivery between 6 p.m. and 3 a.m. Entry dose levels were 0.2, 2 and 4 MU/m2/day. The dose was escalated by an amount equal to the starting dose until a maximum of 6 entry dose levels was achieved, with a 1-week rest between each cycle. The maximal daily dose of IFN-alpha administered was 24 MU/m2/day. A programmable-in-time ambulatory pump was used, so that all patients could receive their treatment at home. Eighteen patients were entered in the study and 16 were evaluable for toxicity. Toxicity was mild to moderate except for two patients who developed WHO grade III toxicity. No significant decline in performance status was associated with treatment. Two objective responses were observed in patients with previously treated metastatic renal cell carcinoma. As compared to standard s.c./i.m. administration or continuous nonchronomodulated i.v. infusion of IFN-alpha, this circadian schedule has allowed to deliver high doses of drug with acceptable toxicity.
Aged↗
Pancreatic juice 90K and serum CA 19-9 combined determination can discriminate between pancreatic cancer and chronic pancreatitis.
OBJECTIVES: Differential diagnosis of pancreatic cancer versus chronic pancreatitis may be difficult. The aim of this study is to determine whether a group of tumor-associated antigens could differentiate between the two pathologies. METHODS: CA 19-9, TAG-72, CAR-3, and a newly discovered antigen termed "90K" were determined in the serum and in the pancreatic juice of 19 patients with pancreatic cancer, 20 patients with chronic pancreatitis, and seven controls with lithiasis of extrapancreatic bile ducts. RESULTS: The serum antigen levels of all three markers except 90K were significantly higher in pancreatic cancer than in chronic pancreatitis. High correlations were found between serum CA 19-9 and both TAG-72 and CAR-3. 90K did not correlate with other markers. In pancreatic juice, only 90K values were significantly higher in chronic pancreatitis than in pancreatic cancer, and only 90K and CA 19-9 were significantly correlated. At the stepwise discriminant analysis, serum CA 19-9 and pancreatic juice 90K had independent diagnostic roles. Used in combination, they correctly identified 84.2% of pancreatic cancer and 90% of chronic pancreatitis. CONCLUSIONS: These data suggest that pancreatic juice 90K and serum CA 19-9 can discriminate between chronic pancreatitis and pancreatic cancer. The data further support the complementary use of tumor-associated antigens along with other diagnostic tools.
Antigens, Neoplasm↗
Characterization of the cyclooxygenase activity of human blood prostaglandin endoperoxide synthases.
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Adult↗
Effects of type-I and -II interferons on 90K antigen expression in ovarian carcinoma cells.
Antigen 90K is produced by several tumor-cell lines and by patients with cancer. Its function has not yet been clarified, although recent reports suggest that it plays a role in the tumor-host relationship--for example by stimulation of natural killer and lymphokine-activated killer-cell activity. Previous studies have indicated that 90K expression may be under the influence of interferon-alpha. Here, we provide evidence that both interferon-alpha and -gamma can enhance the secretion of 90K and augment the level of specific mRNA expression in 3 ovarian carcinoma cell lines (OVCAR-3, HTB-77 and SKOV-6). However, interferon-gamma leads to depletion of cellular 90K whereas interferon-alpha increases both secreted and cellular 90K levels. In equimolar concentrations, Interferon-alpha was always superior to interferon-gamma in augmenting 90K protein or mRNA levels. Combinations of TNF with interferon-gamma were highly synergistic both in reducing cell proliferation and in increasing 90K secretion and mRNA expression. This synergism was seen to a lesser extent with interferon-alpha.
Antigens, Neoplasm↗
The secreted tumor-associated antigen 90K is a potent immune stimulator.
Immunization of mice with conditioned media from human breast cancer cells yielded the monoclonal antibody SP-2, which recognized an antigen of approximately 90-95 kDa. This protein, designated 90K, was found to be present in the serum of healthy individuals and at elevated levels in the serum of subpopulations of patients with various types of cancer and AIDS. Here we report the primary structure of the SP-2 antigen and demonstrate its relationship to a family of proteins which carry a scavenger receptor cysteine-rich domain. Northern blot analysis of normal tissues, primary tumors, and tumor-derived cell lines indicates a broad expression spectrum of the 90K gene at widely varying levels. Functional characterization reveals stimulatory effects of 90K on host defense systems, such as natural killer cell and lymphokine-activated killer cell activity, and indicates that its immunostimulatory effects may be mediated through the induction of interleukin-2 and possibly other cytokines.
3T3 Cells↗
Iron status in schizophrenic patients with acute neuroleptic-induced dystonic reactions.
1. Serum iron parameters were measured in a group of schizophrenic patients who had developed acute neuroleptic-induced dystonia (N = 17) and in control patients with no history of extrapyramidal disorders (N = 16). No differences were found between the two groups for iron, ferritin or transferrin levels. 2. Iron status was estimated in 44 schizophrenic patients starting treatment with high-potency neuroleptics before and after 3 weeks of medication. In the 6 patients developing dystonia serum iron levels as well as other iron parameters did not differ from the values observed in the remaining 38 patients either on admission or after neuroleptic treatment. In each group the haematological profile was not modified by neuroleptic medication. 3. These results do not support an association between low serum iron and the occurrence of neuroleptic-induced dystonic reactions.
Acute Disease↗
Relationship between the tumour-associated antigen 90K and cytokines in the circulation of persons infected with human immunodeficiency virus.
A tumour-associated antigen known as 90K has been found in high concentrations in the serum of patients infected with human immunodeficiency virus (HIV) even in the absence of neoplastic complications. In order to investigate the relationship between the production of 90K and soluble inflammatory mediators, we studied serum concentrations of the antigen, tumour necrosis factor-alpha (TNF-alpha), interleukin-I-alpha (IL-I-alpha), interferon-gamma (IFN-gamma), IFN-alpha, neopterin and beta 2-microglobulin (beta 2-m) in patients with non-neoplastic HIV infection at various stages of disease and in control persons. The antigen was detected in all those studied but its concentration was higher in HIV-infected patients compared with controls (P < 0.001), increasing progressively with advancing stages of disease. There was a negative correlation between concentrations of 90K and IL-I-alpha in patients in U.S.A. Centers for Disease Control groups II and III (P < 0.02) and also between that of 90K and both TNF-alpha (P < 0.01) and IL-I-alpha (P < 0.05) in control persons. The results indicate that 90K is not merely a tumour-associated antigen and that its production may be part of immune and inflammatory responses in the absence of neoplasia. The correlation between the concentrations of 90K and of some cytokines in asymptomatic patients and healthy persons suggests that 90K may be part of a network of immune and inflammatory reactants.
Adult↗
Prognostic value of a novel circulating serum 90K antigen in breast cancer.
Monoclonal antibody SP-2 to the tumour-associated antigen 90K was generated by immunisation with conditioned medium of human breast cancer cells. We investigated whether circulating levels of 90K can influence the prognosis of patients with breast cancer. Serum samples were obtained from 425 patients with histologically proven breast cancer with no clinical evidence of disease after surgery (NED) and in 310 patients with metastatic disease. Serum 90K was determined by a new immunoradiometric assay (IRMA). Antigen levels in NED patients were elevated in 18.5% of cases, mean levels being higher than in healthy controls (P = 0.001). Among 375 evaluable patients, the 75-month overall survival for 90K-negative (< or = 11 U ml-1) and 90K-positive (> 11 U ml-1) patients was 78% and 53% respectively (P = 0.004). The prognostic value of 90K appeared to be limited to patients with node-positive disease. Number of metastatic axillary lymph nodes and level of 90K antigen were the only independent variables for predicting overall survival. Patients with metastatic breast cancer had elevated 90K in 51.3% of cases. High 90K levels were significantly associated with the presence of metastases to liver, shorter disease-free interval and younger age. We conclude that an elevated 90K antigen level in serum is a predictor of poor prognosis in breast cancer.
Aged↗
Biochemical and pharmacological characterization of the cyclooxygenase activity of human blood prostaglandin endoperoxide synthases.
The aim of our study was to characterize a model of human prostaglandin endoperoxide synthase-2 (PGHS-2) expression allowing the assessment of pharmacological inhibition in vitro and ex vivo. Heparinized human whole blood samples were incubated with lipopolysaccharide (LPS, 0.1-50 micrograms/ml) for 0 to 24 hr at 37 degrees C. The contribution of platelet PGHS-1 was suppressed by either pretreating the subjects with aspirin (300 mg 48 hr before sampling) or adding aspirin (10 micrograms/ml) in vitro at time 0. PGE2 was measured by radioimmunoassay. LPS induced expression of cyclooxygenase activity in a time- and concentration-dependent fashion. After 24 hr at 10 micrograms/ml LPS, PGE2 production averaged 12.1 +/- 6.2 ng/ml (mean +/- S.D., n = 7). Cyclooxygenase activity increased in parallel with the mass of a monocyte protein doublet analyzed by Western blot using antibodies directed against the carboxyl-terminal portion of human PGHS-2. Dexamethasone (2 microM) inhibited LPS-induced PGE2 production by 96 +/- 4% (mean +/- S.D., n = 3). Four different inhibitors were tested in vitro on the cyclooxygenase activity of LPS-induced monocyte PGH-2 and thrombin-stimulated platelet PGHS-1. IC50 values (microM) for inhibition of PGHS-1 and PGHS-2 were: indomethacin, 0.70 +/- 0.20 vs 0.36 +/- 0.10 (P < .05); S-indobufen, 0.64 +/- 0.22 vs. 14.9 +/- 8 (P < .05), R-indobufen, 38 +/- 18 vs. 230 +/- 68 (P < .01), 6-methoxy-2-naphthyl acetic acid (the active metabolite of nabumetone), 278 +/- 96 vs. 187 +/- 96.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Purification and characterization of a 90 kDa protein released from human tumors and tumor cell lines.
A novel tumor-associated protein, termed 90K, and recognized by mAb SP-2 was purified from serum of breast cancer patients, ovarian cancer ascitic fluid and conditioned medium of human breast cancer cells. In these three sources, native 90K is present as a high molecular weight complex that was dissociated by SDS-PAGE into a major band of approximately 90,000 Da. On the basis of electrophoretic mobility, buoyant density value, amino acid composition, and immunoreactivity, the 90K from the different sources appeared to be identical. NH2-terminal amino acid sequence revealed no homology to known protein.
Amino Acid Sequence↗
DNA and S-phase fraction analysis by flow cytometry in prostate cancer. Clinicopathologic implications.
BACKGROUND: Available prognostic factors for prostate cancer have not been proven consistently useful. The authors evaluated the prognostic value of DNA analysis by flow cytometry (FCM) in prostate cancer. METHODS: Paraffin-embedded tumor specimens taken at tru-cut biopsy or transurethral resection (TURP) from 81 patients with prostate cancer were analyzed for DNA content and S-phase fraction (SPF) by FCM according to the method of Hedley et al (1983). RESULTS: Thirty-five of the 63 (55.5%) evaluable DNA histograms had a diploid pattern, 18 (28.5%) a distinct aneuploid peak, and 10 (16%) a tetraploid pattern. An association was established between DNA ploidy abnormalities and Gleason score (P < 0.04) or presence of metastases at diagnosis (P < 0.0002). At Kaplan-Meier analysis, overall survival was significantly longer (P < 0.0002) in patients with diploid than in those with nondiploid tumors. Among patients with different risk categories, i.e. tumor size, Gleason score, and metastases at presentation, ploidy improved the detection of patients with poorer survival, with the exception of those with T1-T2 tumors. Cox regression analysis showed that ploidy was significantly related to survival. Bivariate models containing ploidy and SPF or Gleason score had a predictive value similar to that including all variables. CONCLUSION: The study data show that DNA ploidy provides additional prognostic information in patients with locally advanced or metastatic prostatic cancer. The role of SPF remains to be established.
Aneuploidy↗
Dynamic test with recombinant interferon-alpha-2b: effect on 90K and other tumour-associated antigens in cancer patients without evidence of disease.
We have previously shown that a short course of recombinant interferon-alpha-2b (rIFN-alpha-2b) (3 million units day for 5 days) for patients with primary gynaecologic malignancies was able to increase the circulating levels of a newly discovered tumour associated antigen, termed 90K. In this study, we have investigated the effects of the same modality of administration of rIFN-alpha-2b in 62 patients with breast and colorectal cancer whose primary tumour was surgically removed 1 month before and who were without evidence of disease (NED) at the time of the study. A significant increase of 90K serum concentration was already observed 24 h after the first r-IFN-alpha-2b injection and persisted throughout the investigational period. The increase was more pronounced in patients with a basal 90K-negative than a 90K-positive assay. Of 54 patients who started the test with a 90K negative assay, 17 (31%) shifted to a positive assay after rIFN-alpha-2b. Twenty-eight of 62 (45%) patients exhibited a 90K value above the mean increment of the whole population. The serum levels of CEA, CA-15-3, CA 19-9, and alpha-fetoprotein measured in the same serum samples were not modified. After 2 years of follow-up, ten patients relapsed. Six of them showed a 90K increase above the mean increment of the whole population. As with ovarian cancer, the increase of 90K following r-IFN-alpha-2b administration might be of importance for the early detection of disease recurrence in clinically NED breast and colon cancer patients.
Antigens, Tumor-Associated, Carbohydrate↗
A 90-kDa protein serum marker for the prediction of progression to AIDS in a cohort of HIV-1+ homosexual men.
Levels of a 90-kDa protein (90K), recently reported as a possible marker of HIV-1 infection, were serially examined in a group of HIV-1-infected (HIV-1+) and uninfected (HIV-1-) subjects drawn from the same cohort of homosexual men. The first phase of the study included 61 HIV-1+ AIDS-free subjects 4 years (+/- 6 months) postseroconversion and 75 contemporaneous unifected subjects. Two years later, a subset of 35 HIV-1+ AIDS-free subjects and 72 HIV-1- controls was examined. Mean 90K levels for HIV-1+ subjects were significantly higher than for contemporaneous HIV-1- subjects both 4 and 6 years postseroconversion (p < 0.0001). A significantly more rapid progression to AIDS was seen in HIV-1+ subjects with high 90K levels both 4 years (p = 0.01) and 6 years (p = 0.003) postseroconversion. Four years postseroconversion, 90K was significantly correlated with CD8 cell percent, interferon, neopterin, and beta 2-microglobulin (p < 0.05). Two years later, significant correlations were seen between 90K levels and CD4 cell percent, CD4 cell number, and beta 2-microglobulin (p < 0.05). Stepwise-stepdown regression modeling using 90K, CD4 cell percent, interferon, and beta 2-microglobulin levels 4 years postseroconversion showed that the predictive value of a trivariate model of 90K-interferon-CD4 percent was better than any univariate or bivariate model. We conclude that the 90K protein may be a useful predictor of progression to AIDS in HIV-1+ patients, particularly in combination with the established markers of CD4 cell percent and interferon.
Acquired Immunodeficiency Syndrome↗