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Biomedical subjects

M J Duffy

Publications and source records attributed to M J Duffy.

At least 73 records · Page 4Linked to original sources
PubMed1992

Evaluation of cytotoxicity of some Mannich bases of various aryl and arylidene ketones and their corresponding arylhydrazones.

Mannich bases were synthesized and converted to the corresponding arylhydrazones. X-ray analysis of a ketone (1a) and a hydrazone (4d) revealed structural features of interest. All of the compounds showed cytotoxicity toward murine lymphocytic leukemia L1210 cells in the 4.9-25.0-microM range. The correlation coefficients generated by plotting the IC50 values (the concentrations of compounds that inhibit the growth of tumors by 50%) of some hydrazones against certain electronic, hydrophobic, and steric constants of the aryl substituents indicated only weak correlations. A few ketones and hydrazones displayed significant cytotoxicity to the WiDr human colon cancer cells, and these derivatives, especially the ketones, may serve as prototypes for future drug development. The KB tumor (a human epidermoid carcinoma of the nasopharynx) was somewhat refractory to selected compounds. In an in vitro assay conducted by the National Cancer Institute and involving approximately 53 tumor cell lines originating from eight neoplastic diseases, 65% of the compounds showed some selectivity toward one or more groups of cancers, principally leukemia, melanoma, and colon cancer. The bioevaluation of the ketones and hydrazones against the L1210, WiDr, and KB tumors, as well as evidence from proton nuclear magnetic resonance studies did not support the suggestion that hydrazones may be prodrugs of the corresponding ketones.

Animals↗
PubMed1992

The role of proteolytic enzymes in cancer invasion and metastasis.

The production of metastasis appears to involve a number of different proteases including the urokinase form of plasminogen activator, cathepsin B, cathepsin D and various metalloproteases. Early data implicating these proteases in metastasis were mostly indirect and based on correlation studies in animal models. More recent work, using specific protease inhibitors and antibodies against proteases to block experimental metastasis, have provided more direct evidence that proteases play a role in cancer spread. In addition, transfection of genes encoding certain proteases increases the metastatic phenotype of the recipient cells. In human tumours, a number of different proteases also correlate with metastatic potential. It is concluded that certain proteases may be new prognostic markers in cancer as well as new targets for anti-metastatic therapy.

Animals↗
PubMed1992

Inhibiting tissue invasion and metastasis as targets for cancer therapy.

Many of the steps involved in cancer spread are potential targets for anti-metastatic treatment. Until recently, research aimed at inhibiting metastasis has concentrated on the proteases, especially on urokinase-type plasminogen activator and collagenase IV. However, recent data suggests that both adhesion proteins and motility factors could also serve as targets for new treatments to prevent cancer invasion and metastasis. Almost all the work to date using anti-metastatic agents has been carried out using either in vitro artificial membranes or with animal models. It is, however, likely that some of the inhibitors of experimental metastasis which are described will be evaluated in clinical trials in the near future.

Amino Acid Sequence↗
PubMed1992

TSH as an index of L-thyroxine replacement and suppression therapy.

When hypothalamic-pituitary function is normal, serum TSH levels measured by ultrasensitive assay yield bioassays of endogenous thyroid action and thus provide an ideal index of thyroid secretion and its relationship to fluctuating endogenous thyroid levels. It is theoretically possible that patients receiving exogenous L-thyroxine for primary hypothyroidism should have suppressed TSH levels if physiological needs are constantly met. To examine this possibility free thyroxine, FT4 and TSH were measured in 90 clinically euthyroid patients receiving treatment with L-thyroxine for primary hypothyroidism. TSH levels were normal in 44, suppressed in 16 and elevated in 30 patients. FT4 levels were normal in 68, elevated in 13 and suppressed in 9 patients. Normal TSH levels were associated with normal FT4 levels in 79.5% of patients, elevated FT4 levels in 13.6% and low FT4 in 6.8%. Suppressed TSH levels were associated with elevated FT4 levels in 37.5% of patients and normal FT4 levels in 62.5%. When FT4 levels were normal, however, TSH levels were normal in only 51.5% and abnormal in 48.5%. We also examined the possibility that FT4 levels may remain within normal range when TSH is suppressed during L-thyroxine treatment for goitre or cancer. FT4 and TSH were measured in 45 patients on L-thyroxine as TSH suppression treatment. TSH was suppressed in 23 patients (51.1%), normal in 20 (44.4%) and elevated in 2 (4.5%). When TSH was suppressed, FT4 was elevated in 30.4% but normal in 69.6% of patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

Enzyme-linked immunosorbent assay of c-erbB-2 oncoprotein in breast cancer.

Amplification or increased expression of the c-erbB-2 gene has previously been reported to be a prognostic marker for breast cancer. Gene amplification is usually measured by Southern blotting, whereas increased protein expression is usually detected by immunocytochemistry. We measured c-erbB-2 protein with an enzyme-linked immunosorbent assay (ELISA). High concentrations of oncoprotein were found in 25 of 161 (16%) primary breast cancers and in 3 of 6 (50%) breast cancer metastases. High concentrations were not found in normal breast tissue or benign breast tumors. In the primary cancers, high concentrations of c-erbB-2 protein were found more frequently (a) in estrogen receptor-negative tumors than in estrogen receptor-positive tumors, (b) in progesterone receptor-negative tumors than in progesterone-positive tumors, and (c) in axillary node-positive cancers than in node-negative cancers. Patients with tumors containing high amounts of the c-erbB-2 protein had a significantly shorter (P less than 0.001) disease-free interval and overall survival rate than did patients with low amounts. We conclude that assay of c-erbB-2 protein by ELISA is simple, rapid, and quantitative and offers important prognostic information in breast cancer.

Biomarkers, Tumor↗
PubMed1992

Cathepsin D concentration in breast cancer cytosols: correlation with disease-free interval and overall survival.

Cathepsin D (CD) is an aspartyl protease implicated in cancer metastasis. In this study of 331 patients, we show that patients with primary breast carcinomas containing high concentrations of CD have a significantly shorter disease-free interval (chi-square = 4.28, P < 0.05) and overall survival (chi-square = 7.7, P < 0.01) than patients with low concentrations. CD as a prognostic marker for overall survival was equally valuable for women younger (chi-square = 4.39, P < 0.05) and older (chi-square = 3.97, P < 0.05) than 50 years. CD was also a significant prognostic marker for overall survival within the estradiol receptor (ER)-positive subgroup of patients (chi-square = 5.79, P < 0.025), but not in the ER-negative subgroup. Patients with tumors containing high concentrations of CD and low concentrations of ER had shorter disease-free intervals (chi-square = 15.1, P < 0.001) and lower overall survival (chi-square = 20.9, P < 0.001) than patients with high concentrations of ER but low concentrations of CD.

Biomarkers, Tumor↗
PubMed1992

Evaluation of some N-acyl analogues of 3,5-bis(arylidene)-4-piperidones for cytotoxic activity.

The synthesis of fourteen N-acyl derivatives of two 3,5-bis(arylidene)-4-piperidones was accomplished and these compounds were evaluated against L1210 leukemia cells in vitro. With one exception, the compounds had IC50 values of less than 10 microM and six of them had IC50 figures in the 0.2-0.6 microM range which were comparable to a reference drug melphalan. Twelve of the sixteen compounds showed specificity for human leukemia cell lines in the NCI in vitro screen. Studies using 1H NMR spectroscopy revealed that solutions of three N-acetylated compounds underwent deamination and possibly other reactions, the deaminated product itself being unstable in the solvent used.

Animals↗
PubMed1991

Urokinase-plasminogen activator in breast cancer: assay by both catalytic and immunoassay.

Urokinase plasminogen activator (uPA) is a serine protease implicated in cancer spread and is thus a potential prognostic marker for human cancers. The aim of this investigation was therefore to compare uPA activity and uPA antigen as prognostic markers in breast cancer. Patients with tumours containing high levels of either uPA activity or antigen, had a significantly worse disease-free interval and survival pattern than patients with low levels. However, uPA antigen was a stronger prognostic marker than uPA activity. It is concluded that uPA should be assayed by immunoassay when using this protease as a prognostic marker in breast cancer.

Biomarkers, Tumor↗
PubMed1991

Cathepsin D concentration in breast cancer cytosols: correlation with biochemical, histological, and clinical findings.

Cathepsin D (CD, EC 3.4.23.5) is a lysosomal protease induced by estrogen in certain estrogen receptor (ER)-positive breast cancer cell lines but produced constitutively by ER-negative cell lines. Our aims in this investigation were to study the distribution of CD in human breast cancers and to relate its concentrations to various biochemical, histological, and clinical characteristics. The concentrations of CD were significantly higher in breast carcinomas than in either normal breast tissues or benign breast tumors. In primary carcinomas, CD concentrations did not correlate with the concentrations of ER or with the estrogen-inducible protease t-PA. However, CD concentrations did correlate weakly but significantly with both UK-PA antigen and UK-PA activity. Also, CD concentrations did not correlate with either tumor stage or axillary node status but did correlate significantly with tumor grade. Patients with cancers containing high concentrations of CD had a significantly shorter overall survival than did patients with low concentrations of the enzyme.

Breast Neoplasms↗
PubMed1990

Urokinase-plasminogen activator, a new and independent prognostic marker in breast cancer.

Urokinase plasminogen activator (UK-PA) is a serine protease implicated in cancer invasion and metastasis. In this investigation, patients with breast cancers containing high levels of UK-PA antigen had significantly higher risk of early disease recurrence and shorter overall survival than did patients with low levels of the protein. In univariate analysis, UK-PA was a more powerful discriminator for disease-free interval than axillary node status, tumor size, or estradiol receptor. For overall survival, UK-PA as a prognostic marker, was of similar magnitude to axillary node status but stronger than that of tumor size or estradiol receptor. In multivariate analysis, for both disease-free interval and survival, UK-PA was an independent risk factor, being independent of tumor size, axillary node status, and estradiol receptor. UK-PA appears to be a new and independent prognostic marker in breast cancer.

Antigens, Neoplasm↗
PubMed1990

The overnight dexamethasone test is a worthwhile screening procedure.

The overnight low-dose dexamethasone test is a convenient screening procedure for Cushing's syndrome. Claims that the test is associated with a high incidence of 'false positives', rendering it of little value particularly in obese and hospital in-patients, have been investigated in the present study. The data from 100 consecutive subjects undergoing overnight low-dose dexamethasone tests to examine for the possibility of Cushing's syndrome, were reviewed. Cushing's syndrome was identified in four patients, normal suppression of cortisol values occurred in 84 patients and 12 patients exhibited false positive results. Differences in body weights, body mass indices or in-patient status did not distinguish between those subjects with normal suppression of plasma cortisol and those subjects who yielded false positive results. These data indicate that the simple overnight dexamethasone test substituted for the more cumbersome traditional 48-h dexamethasone test in 84 of 96 patients who did not have Cushing's syndrome. Thus the overnight test provides a useful screening procedure but a small percentage of patients, approximately 12.5%, will require additional procedures to exclude Cushing's syndrome.

Adolescent↗
PubMed1990

Plasminogen activators and cancer.

Plasminogen activator (PA) is a specific serine protease which catalyses conversion of the inactive plasminogen into the broad-spectrum protease, plasmin. PA exists in two structurally related forms known as tissue-type PA (tPA) and urokinase-type PA (uPA). Conversion of normal cells into a malignant state frequently leads to increased production of uPA. There is increasing evidence that uPA is directly involved in the process of metastasis. High levels of uPA in human breast cancers is a marker for poor prognosis. Finally, uPA may be a target for anti-metastatic agents, either by inhibition of its synthesis, inhibition of its activity or its binding to receptor.

Biomarkers, Tumor↗
PubMed1990

Biochemical markers as prognostic indices in breast cancer.

Traditional prognostic markers in breast cancer include histological variables such as tumor size, grade, and axillary node status. In recent years some new potential prognostic markers of a biochemical nature have been described: estradiol receptors, progesterone receptors, epidermal growth factor receptors, erbB-2 proto-oncogene, and certain proteolytic enzymes. None of these new markers excels axillary node status as a prognostic marker. Biochemical markers can, however, be evaluated with use of minimal surgery and may help distinguish the minority of aggressive axillary-node-negative breast cancers.

Biomarkers, Tumor↗