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M C Mathieu

Publications and source records attributed to M C Mathieu.

34 records · Page 2Linked to original sources
PubMed1995

Primary proliferative T cell response to wild-type p53 protein in patients with breast cancer.

Mutations in the p53 tumor suppressor gene are the most frequent genetic alterations found in human tumors. There are mainly point mutations that lead to single amino acid substitutions. The mutated proteins have a longer half-life than wild-type p53 and accumulate in the nucleus of tumor cells. Anti-p53 antibodies have been found in sera of patients with several types of cancers including breast cancer. This report describes a T cell immune response in three patients with breast tumors who had mutated p53 gene and accumulated p53 protein. All showed a humoral response to p53 protein and the T cells of these patients recognized the wild-type p53 protein and proliferated in response to it. The data reported here are relevant to the immune processes leading to autoimmunity and have a bearing on anti-p53 vaccine development in tumor immunology.

Antibodies↗
PubMed1995

p53 mediated tumor cell response to chemotherapeutic DNA damage: a preliminary study in matched pairs of breast cancer biopsies.

Wild type p53 plays a crucial role in maintaining genomic stability in both normal and tumor cells in vitro. When DNA damage occurs, p53 acts as a cell cycle checkpoint and induces a cellular response that aims at restoring genomic integrity. p53 may either allow the repair of damaged DNA by inducing a transient G1 arrest or may eliminate the damaged cells by triggering apoptosis. Mutant p53 fails to mediate any of these effects. From this, a p53 status-dependent response to therapy might be expected when tumors are treated with DNA-damaging genotoxic agents: Although wild type p53-harboring tumors have an intact checkpoint that might allow them to restore genomic integrity back to a pre-exposure level, mutant p53 tumors have a corrupted checkpoint that could lead to an accelerated loss of genomic stability. Until now, no studies have been described that examine such a p53-mediated effect in vivo. The authors tested this response model in vivo comparing 32 matched biopsy pairs from patients with breast cancer before and after rigorously standardized polychemotherapy. Four of the five drugs specifically induce a wild type p53-mediated checkpoint response. Tumor tissue from matched pairs of untreated and treated biopsies of the same patient were analyzed for treatment-associated changes of p53 protein expression by immunocytochemistry and, in a few available specimens, of p53 genotype changes by polymerase chain reaction-based DNA analysis. Treatment-associated changes of the p53 immunophenotype, which the authors speculate to reflect clonal selection, occurred in 39% (12 of 31) of the specimens. One specimen was not informative. Most tumors undergoing clonal selection originally harbored mutant p53 (nine of 12), and only three of 12 tumors were wild type. This study shows that exposure to genotoxic agents is commonly associated with a change in p53 immunophenotype. Although the limited material in this cohort prevented direct analysis of genetic instability, these results suggest that tumors with altered p53 may be genomically less stable and, therefore, may be more likely to undergo treatment-induced clonal changes than wild type tumors. This study also shows that the rigorous matched sample approach, although difficult to obtain, is an important tool that allows the in vivo assessment of the tumor response to genotoxic therapy in a controlled fashion.

Adult↗
PubMed1994

[Anatomopathological problems of mastopathies at risk].

As breast cancer screening programmes gain momentum, there is a parallel increase in histological problems mainly related to the identification of an increasing number of "borderline" breast lesions. The results of recent studies are often inconsistent, and bear witness to the lack of a consensus regarding the interpretation of both ductal and lobular epithelial hyperplasia. The authors insist on the need for an adequate number of samples and an irreproachable histologic technique which is indispensible if the morphologic subtleties, currently the only valid factors permitting the diagnosis, are to be appraised. The role of the pathologist is therefore crucial in the management of specimens which are entrusted to him and in helping the clinician to tailor treatment to fit each individual patient.

Breast↗
PubMed1993

Main drug-metabolizing enzyme systems in human breast tumors and peritumoral tissues.

In an attempt to better understand breast tumors sensitivity or resistance to anticancer drugs, the main drug-metabolizing enzyme systems were evaluated in both breast tumors and their corresponding peritumoral tissues in 12 patients. The following enzymes were assayed by Western blot: cytochromes P-450 (1A1/A2, 2B1/B2, 2C8-10, 2E1, 3A4); glutathione S-transferases (GST-alpha, -mu, and -pi); and epoxide hydrolase. The activity of the following enzymes or cofactor were determined by spectrophotometric or fluorometric assays: GST; total glutathione; UDP-glucuronosyltransferase; beta-glucuronidase; sulfotransferase; and sulfatase. Results showed the absence of all probed cytochromes P-450 in both tumoral and peritumoral tissues. GST activity was significantly (P < 0.05) higher in tumors (mean +/- SD, 399 +/- 362 nmol/min/mg) than in corresponding peritumoral tissues (86 +/- 67). The GST isoenzymes GST-mu and GST-pi (determined by immunoblotting) were also higher in tumors than in corresponding peritumoral tissues (3- and 5-fold, respectively). Both GST-mu and GST-pi levels were significantly correlated with GST activity. GST-alpha was not detected in either tumoral or peritumoral tissues. Glutathione levels in tumors (22 +/- 23 nmol/mg protein) were not statistically different from peritumoral tissues (11 +/- 12). Epoxide hydrolase was expressed at similar levels in tumors and peritumoral tissues. The glucuronide-forming enzyme UDP-glucuronosyltransferase was 5-fold lower in tumors (0.1 +/- 0.2 nmol/h/mg) than in peritumoral tissues (0.5 +/- 1), whereas the opposite was observed for the hydrolytic enzyme beta-glucuronidase, which was 6-fold higher in tumors (736 +/- 1392 nmol/h/mg) compared to peritumoral tissues (125 +/- 75). No difference was noted between tumoral and peritumoral tissues for sulfotransferase (1 +/- 2 nmol/h/mg), but the corresponding hydrolytic enzyme (sulfatase) was 2-fold higher in tumoral tissues (14 +/- 15 nmol/h/mg) than in peritumoral tissues (6 +/- 2). In conclusion, several differences were observed between human breast tumors and peritumoral tissues for many conjugating enzymes (GST-mu, GST-pi, and UDP-glucuronosyltransferase) and hydrolytic enzymes (sulfatase and beta-glucuronidase). These noteworthy differences between tumoral and peritumoral tissues with regard to their main drug-metabolizing enzymes could play a role in the relative drug sensitivity or insensitivity of human breast cancer tissues to chemotherapeutic agents and could be potential targets for chemotherapeutic interventions.

Adult↗
PubMed1993

Visualization of the plasmin receptor on sections of human mammary carcinoma cells.

In previous studies we observed the presence of an antigen reacting with anti-plasminogen serum on tumor cells found in sections of human colorectal and mammary carcinomas, using immunofluorescence. This antigen could be plasminogen, or plasmin or both. These results led us to surmise that carcinoma cells, and not normal epithelial cells, had a receptor for plasmin and plasminogen. We demonstrated the existence of such a receptor on cells of established tumor cell lines of colonic and mammary origin. We observed that binding of plasmin(ogen) to its receptor was inhibited by lysin and its analogs. We undertook to characterize the plasmin receptor on sections of human mammary carcinomas (18 series of sections, originating from 15 infiltrating ductal carcinomas). In our immunofluorescence studies, we observed that the fluorescence induced by anti-plasminogen serum was suppressed by pre-treatment of the sections with tranexamic acid, a lysin analog. Furthermore, when parallel sections were incubated with tranexamic acid, then with solutions of plasminogen, tumor cells were made fluorescent again. Another important finding was the strong increase of labelling observed when sections were incubated with plasminogen or plasmin before reaction with anti-plasminogen serum. This labelling disappeared when tranexamic was added to plasminogen. As a whole, these results confirm the existence of plasmin receptors on tumor cells in mammary carcinoma sections. They also show that these receptors are not saturated in vivo and may bind, in vitro, additional amounts of ligand.

Breast Neoplasms↗
PubMed1992

Intratumor treatment of C3H mouse mammary carcinoma with 5-fluorouracil adsorbed on activated charcoal particles.

A dosage form comprising 5-fluorouracil (5-FU, 25 mg/ml) adsorbed on a suspension of micronized charcoal (100 mg/ml) 2-5 microns in diameter, adsorbing 5-FU in aqueous solution was studied for intratumor treatment of mammary carcinoma in animal experiments. An in vitro desorption method is described to determine the amount of 5-FU adsorbed on activated charcoal particles which would be released once the drug concentration decreased around the charcoal. In vivo results indicate that an intratumor injection of 5-FU adsorbed on activated charcoal particles is a highly effective method for achieving tumor regression without increasing toxicity.

Adenocarcinoma↗
PubMed1992

Prognostic significance of S-phase fraction in good-risk, node-negative breast cancer patients.

PURPOSE: Formalin-fixed, paraffin-embedded tissues from axillary node-negative breast cancer patients were analyzed by flow cytometry to determine the prognostic significance of DNA ploidy and S-phase fraction (SPF). PATIENTS AND METHODS: All patients were registered on a good-risk control arm of an intergroup clinical trial. They had small- to intermediate-sized (less than 3 cm), estrogen receptor (ER)-positive tumors and received no adjuvant therapy after modified radical mastectomy or total mastectomy with low axillary-node sampling. The median follow-up was 4.8 years. RESULTS: Assessable ploidy results were obtained from 92% of the 298 specimens studied (51% diploid, 49% aneuploid), and SPFs were assessable for 83% of the tumors. SPFs for diploid tumors ranged from 0.7% to 11.9% (median, 3.6%), compared with a range of 1.2% to 26.7% (median, 7.6%) for aneuploid tumors (P less than .0001). No significant differences in disease-free or overall survival were observed between patients with diploid and aneuploid tumors. Using different SPF cutoffs by ploidy status (4.4% for diploid, 7.0% for aneuploid), patients with low SPFs had significantly longer disease-free survival rates than patients with high SPFs (P = .0008). The actuarial 5-year relapse rates were 15% and 32% for patients with low (n = 142) and high SPFs (n = 105), respectively. Similar relationships between SPF and clinical outcome were observed for patients with diploid tumors (P = .053) and for patients with aneuploid tumors (P = .0012). CONCLUSION: S-phase fraction provides additional prognostic information for predicting disease-free survival for axillary node-negative breast cancer patients with small, ER-positive tumors.

Actuarial Analysis↗
PubMed1990

Immunohistochemical staining of bone marrow biopsies for detection of occult metastasis in breast cancer.

Immunohistochemical (IHC) techniques should allow for a greater detection of bone marrow micrometastasis in patients with breast carcinoma. We studied a series of bone marrow (BM) biopsies negative by conventional histologic techniques from 93 patients with breast carcinoma. Prior to this study, twelve BM biopsies, positive by conventional histology, were stained with a panel of monoclonal antibodies (MoAb), directed either against cytokeratin (KL1, AE1-AE3, CAM5-2) or epithelial membrane antigen (EMA, HMFG2). KL1 appeared to be the most sensitive of the markers used in the detection of metastases and is available commercially. It therefore was the only MoAb used with the series of 93 BM biopsies negative by conventional examination. Within this series, among 45 patients clinically suspected of having bone marrow metastasis but with BM biopsies negative by conventional staining, one case showing myelofibrosis stained positive with KL1 demonstrating isolated tumor cells. For the 48 patients without suspicion of bone marrow metastasis at initial diagnosis for breast carcinoma, KL1 revealed no marrow metastasis. Single bone marrow biopsy techniques whether stained by conventional or IHC methods do not appear to be useful tests to detect occult bone marrow metastasis, especially at initial diagnosis of clinically Mo breast carcinoma patients.

Antibodies, Monoclonal↗
PubMed1989

Structure and expression of c-erbB-2 and EGF receptor genes in inflammatory and non-inflammatory breast cancer: prognostic significance.

C-erbB-2 and epidermal growth factor receptor (EGFR) genes were independently shown to be associated with breast cancer progression. In this report, we have analyzed the structure and expression of these 2 genes in the same tumor specimens of a large series of breast cancers. Two clinical types of tumor were studied: inflammatory (IBC) and non-inflammatory breast cancers (NBC) obtained from 221 untreated patients at different clinical stages. Amplification and over-expression of the c-erbB-2 proto-oncogene were observed in 27% and 47% of tumors, respectively, and were strongly associated with breast cancers of the most unfavorable prognosis, namely IBC and NBC with multiple positive axillary nodes. EGFR gene was neither amplified nor rearranged. A restriction fragment length polymorphism (RFLP) for HindIII endonuclease was observed. EGFR transcripts were detected in 46% of tumors and observed more frequently in IBC than in NBC (p less than 0.02). In NBC the presence of EGFR transcripts increased linearly with lymph-node involvement and was associated with estrogen-receptor-negative tumors (p = 0.01). Analysis of both genes from the same tumor samples indicated that genes are associated with cancer aggressiveness. Furthermore, in NBC these 2 genes were independently activated, in contrast to IBC in which activated genes were negatively correlated, suggesting that c-erbB-2 and EGFR genes play different roles in NBC and IBC.

Breast Neoplasms↗
PubMed1986

[Immunohistologic marking of epithelial antigens in sarcomatoid carcinomas of the upper aerodigestive tracts].

The immunoperoxidase localization of epithelial antigen (keratin, epithelial membrane antigen) was identified in 18 cases of sarcomatoid carcinomas localized in the upper aero-digestive tract. These tumors are an association of a differentiated squamous cell carcinomatous component and of spindle, or pleomorphic cells component. The anti-keratin monoclonal antibody KL1 stained the sarcomatoid component in 4 cases. A continuous staining between differentiated squamous cells and spindle cells in observed in two cases. The identification of cytokeratin is better with KL1 than with the polyclonal anti-keratin antiserum KT. The monoclonal antibody HMFG2 is not retained. These results suggest the dedifferentiation of epithelial cells in sarcomatoid component. They confirm the heterogeneity of these tumors, which has been previously found in ultrastructural studies. These immunostaining are helpful in recognizing sarcomatoid carcinoma, when they are only represented by the sarcomatoid component.

Aged↗
PubMed1985

[Prostatic carcinoma: immunoperoxidase study with antisera against prostatic acid phosphatase and the prostate-specific antigen].

An immunoperoxidase study in 19 patients with cancer of prostate, using antiserums directed against prostatic acid phosphatase (PAP) and prostate specific antigen (PSA), allowed classification of tumors as strongly, moderately and poorly differentiated, and undifferentiated forms. Tests were conducted on specimens fixed and embedded in paraffin wax. Evaluation of degree of positivity for cells most marked by PAP and by PSA failed to establish its correlation with tumoral differentiation. Results, in fact, showed that poorly differentiated or undifferentiated forms of prostatic carcinoma contained cells with enhanced positive reactions when compared with strongly differentiated forms. Morphologically strongly differentiated forms showed weaker positivity than observed in normal prostate, this positivity being relatively homogeneous throughout the zone of proliferation, and cells varied little in their degree of positivity. Characteristic findings in less well differentiated forms were several strongly positive cells, with marked differences in positivity between cells and frequent alternating positive and negative zones. These findings may be of particular interest for diagnostic interpretation of strongly or poorly differentiated forms.

Acid Phosphatase↗
PubMed1983

[Fc receptors and immunomodulating effects of immunoglobulins. In vitro study].

Immunomodulating effect of immunoglobulins (Ig) preparations can be investigated by the mean of in vitro models of human B lymphocyte polyclonal activation. Such models concern the final differentiation of mature B lymphocytes into plasma cells. Several stages can be identified, each of them being controlled by distinct regulatory mechanisms: cell proliferation as estimated by tritiated thymidine incorporation, maturation into Ig containing cells, then into Ig secreting cells, and quantification of secreted Ig. In addition to the quantitative control of each stage (potentiation or suppression) a qualitative regulation of the production of each Ig class (IgM, IgG, IgA) can be studied. Depending on experimental protocols, several regulatory mechanisms have been described: 1) polyclonal activation induced by Fc fragments or aggregated Ig acting on monocytes, 2) suppression by aggregated IgG which induce prostaglandin PGE2 release from monocytes, 3) suppression by aggregated IgG interacting with T cell Fc receptors. The latter mechanism selectively decreases the number of IgG containing cells and that of IgG secreting cells, does not change IgG nor IgM containing cell numbers. A comparable suppressive effect can be achieved by Fc receptors purified by affinity chromatography on IgG sorbents. The possible relevance of these various regulatory mechanisms to the in vivo effect of Ig treatment deserves further investigations.

Antibody Formation↗