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Biomedical subjects

D F Hayes

Publications and source records attributed to D F Hayes.

At least 91 records · Page 5Linked to original sources
PubMed1990

DF3 antigen, a human epithelial cell mucin, inhibits adhesion of eosinophils to antibody-coated targets.

Although mucins provide lubrication and physical protection for epithelial cell surfaces, other functional roles for these large glycoproteins are unknown. One human mucin, designated DF3 Ag, is detectable on apical surfaces of normal epithelial secretory cells and in normal milk, urine, and plasma. The present studies have examined the effects of DF3 Ag purified from both normal and malignant sources on the antibody-dependent cytotoxicity of Schistosoma mansoni by eosinophils (ADCC-E) and on the adherence of eosinophils to inert antibody-coated targets. DF3 Ag purified from tissue culture supernatant of a human breast carcinoma cell line or from human milk inhibited ADCC-E in a concentration-dependent manner, with half-maximal inhibitory activity at 3 to 10 micrograms/ml. Inhibition of ADCC-E was specific for the DF3 mucin, because no inhibition was observed with two other unrelated, circulating glycoproteins: carcinoembryonic Ag and alpha 1-acid glycoprotein. Inhibition was not a result of direct cytotoxicity of the DF3 Ag for eosinophils, as demonstrated by the lack of detectable effect of the mucin on cellular trypan blue exclusion or PMA-induced H2O2 release. The inhibitory effect was time dependent, requiring the presence of DF3 Ag in the ADCC-E culture for at least 4 h, beginning within the first 2 h of eosinophil-schistosomula interaction. Furthermore, inhibition was not a result of interaction between DF3 Ag and the activating lymphokine. These data suggest that inhibition of ADCC-E by DF3 Ag is a result of interference of adhesion of eosinophils to Ig-coated targets. In this regard, purified DF3 tumor Ag prevents eosinophil adherence to human Ig-conjugated Sepharose 4B beads. Preincubation of the inert Ig-coated targets with DF3 Ag did not inhibit subsequent eosinophil adherence, suggesting that DF3 Ag interacts with a moiety present on the eosinophil. Inhibition of adhesion occurred at 37 degrees C, but was also observed at 4 degrees C. These results suggest that DF3 Ag acts as an immunomodulating agent. Because activated eosinophils can damage surrounding normal tissues as well as infectious organisms, DF3 Ag may serve to protect secretory epithelium from the cytotoxic effects of activated inflammatory cells.

Animals↗
PubMed1990

Adjuvant systemic therapy for patients with node-negative tumors.

Early adjuvant therapy studies, especially adjuvant chemotherapy studies, were performed almost exclusively on patients with histologically involved axillary lymph nodes ("node-positive" patients). These therapies were restricted to this group of patients because the toxicities of adjuvant therapy were believed too great to justify its use in patients with a very good prognosis until its benefits were fully established. However, after it was demonstrated that adjuvant therapy can significantly prolong the disease-free survival of almost all groups of node-positive patients and the overall survival of some patient subsets, adjuvant therapy trials specifically designed for patients without histologically involved lymph nodes ("node-negative" patients) were initiated. Results from some of the largest of these second generation trials were recently published, and the early results from these studies have generated new questions. For example, will the mature results from these studies be nearly identical to the results seen in node-positive patients, or will node-negative patients derive greater benefits from adjuvant therapy? Is it possible that adjuvant therapy will "cure" node-negative patients but not node-positive patients? (Cure is defined here as an effect of therapy that returns a patient to the life expectancy she might have had if she had never been diagnosed with breast cancer). Is it possible that the added years of life from adjuvant therapy or that the number of node-negative patients who benefit are so small that these benefits will be outweighed by delayed toxicities that appear in patients who might have been cured even without adjuvant therapy? At present the available data to answer these questions definitely are either contradictory or nonexistent.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1990

Evaluation of monoclonal antibody DF3 conjugated with ricin as a specific immunotoxin for in vitro purging of human bone marrow.

DF3 is an IgG1 monoclonal antibody (MAb) generated against a Mr 350,000-400,000 glycoprotein expressed by approximately 80% of human breast cancers. We have coupled MAb DF3 to ricin. Purification of the immunotoxin (DF3-IT) was obtained by affinity and size exclusion chromatography. DF3 antigen-positive breast cancer cell lines (ZR-75-1, BT-20, and MCF-7) and DF3 antigen-negative lung cancer cell lines (A549 and CALU6) were tested for cytotoxicity with metabolic labeling and clonogenic assays. The cells were exposed for 3 h to different concentrations of DF3-IT, MAb DF3, ricin, and a combination of unconjugated MAb DF3 and ricin. In the presence of 100 mM lactose, DF3-IT specifically inhibited protein synthesis of lines expressing DF3 antigen on their cell surface. Moreover, clonogenic survival experiments demonstrated that DF3-IT at a concentration of 1 x 10(-9) M specifically kills 2.6-2.8 log of ZR-75-1 and BT-20 cells and 1.6 log of MCF-7 cells. At the same concentration, nonspecific toxicity of DF3-IT resulted in a 30% reduction of bone marrow granulocyte and macrophage colony formation. In bone marrow-purging experiments, tumor cells were mixed with an excess of bone marrow cells and treated with DF3-IT or ricin. Tumor cell clonogenic survival assays demonstrated that the presence of bone marrow cells had no detectable effect on activity or specificity of the DF3-IT. These results thus indicate that MAb DF3 is an effective vehicle to specifically deliver toxins to cancer cells which express DF3 antigen on their surface and that DF3-IT may be useful for in vitro purging of bone marrow.

Antibodies, Anti-Idiotypic↗
PubMed1989

Oligosaccharide differences in the DF3 sialomucin antigen from normal human milk and the BT-20 human breast carcinoma cell line.

The murine monoclonal antibody DF3, prepared against a membrane-enriched fraction of a human breast carcinoma, recognized high molecular weight mucin-like glycoproteins from normal human milk and breast carcinoma cell lines. Although the epitope recognized appeared to be a peptide segment, recognition was altered by neuraminidase, suggesting carbohydrate contributions to antigen recognition. Examination of DF3 antigen isolated from normal human milk and the BT-20 human breast carcinoma cell line showed significant oligosaccharide differences. DF3 antigen from BT-20 cells contained three major oligosaccharides, the peanut agglutinin-binding disaccharide Gal beta 1,3GalNAc, which is the carbohydrate component of the Thomsen-Friedenreich antigen, and its mono-(NeuAc2,3Gal beta 1,3GalNAc and/or Gal beta 1,3(NeuAc alpha 2,6)GalNAc) and disialylated (NeuAc2,3Gal beta 1,3(NeuAc alpha 2,6)GalNAc) derivatives. In contrast, the DF3 antigen from normal human milk contained the tetrasaccharide Gal beta 1,4GlcNASc beta 1,6(Gal beta 1,3)GalNAc as its major neutral oligosaccharide and also sialylated derivatives of the tetrasaccharide, including a monosialo derivative (Gal beta 1,4GlcNac beta 1,6(NeuAc alpha 2,3Gal beta 2,3)GalNAc and/or NeuAc alpha 2,3Gal beta 1,4GlcNAc beta 1,6 (Gal beta 1,3)GalNAc). These results suggest the possibility of carcinoma-associated alterations in O-linked oligosacchardes of cell surface sialomucins and in the activity of the beta 1,6-glucosaminyl transferase involved in mucin biosynthesis.

Antibodies, Monoclonal↗
PubMed1989

Circulating tumor markers in breast cancer.

A list of tumor markers evaluated in breast cancer patients is included as well as their relative value for a patient with metastatic breast cancer. Variations in the levels of circulating markers correlated well with disease course; however, the accuracy of these variations is not total.

Antigens, Neoplasm↗
PubMed1988

Comparison of CA15-3 and carcinoembryonic antigen in monitoring the clinical course of patients with metastatic breast cancer.

Fifty-three women with metastatic breast cancer and serial plasma samples were selected to study the correlation between disease course and variations in circulating CA15-3 and carcinoembryonic antigen (CEA) levels. Forty-nine patients had their first sample drawn at the beginning of therapy, while four patients did not receive any treatment during the period of study. Clinical course was scored as progressive disease (PD), responsive disease (RD), and stable disease on the basis of radiological and physical evaluations. The percentage of variation in antigen level between the initial sample and samples drawn at the time of the clinical evaluation was correlated with clinical course. CA15-3 levels above 22.0 units/ml and CEA levels above 3.0 ng/ml were considered elevated values. Antigen levels that increased greater than or equal to 25% and decreased greater than or equal to 25% from the initial value were considered to correlate with PD and RD, respectively. Variations in antigen levels +/- 25% from the initial value were considered to correlate with stable disease. Significantly more patients had elevated circulating levels of CA15-3 than CEA (96.2 versus 69.8%; P less than 0.01) at some point in the course of disease. Overall, CA15-3 correlated with disease progression, regression, or stability in a higher number of patients than CEA (60.3 versus 39.6%; P = 0.02). CA15-3 increased greater than or equal to 25% more often than CEA in patients with PD (75.0 versus 58.3%) and decreased greater than or equal to 25% more often than CEA in patients with RD (38.1 versus 23.8%). In a logistic regression model, changes in CA15-3 levels correlated significantly with both PD (P = 0.0004) and RD (P = 0.02), while changes in CEA levels did not (PD, P = 0.34; RD, P = 0.92). Furthermore, correlations obtained when using both antigens together failed to improve the results obtained with CA15-3 alone. The present study thus demonstrates that CA15-3 is more useful than CEA in monitoring the clinical course of patients with metastatic breast cancer.

Algorithms↗
PubMed1988

Effect of radioiodination on the binding of monoclonal antibody DF3 to breast carcinoma cells.

The murine monoclonal antibody (MAb) designated DF3 is an IgG1 prepared against a membrane enriched fraction of human breast carcinoma. MAb DF3 reacts with a family of large molecular weight glycoproteins expressed by 78% of breast cancer cells and 95% of epithelial ovarian cancer cells. Binding to the breast cancer cell line, MCF-7, of native MAb DF3 was compared to that of MAb DF3 exposed to different concentrations of Iodogen or Bolton-Hunter reagent. The amount of MAb DF3 required to obtain half-maximal binding (B1/2max) with MCF-7 extract for native MAb DF3 IgG was 180 ng, while the B1/2max for MAb DF3 IgG exposed to 1 and 10 micrograms Iodogen was 580 ng and 1800 mg, respectively. In contrast, the B1/2max for MAb DF3 IgG treated with Bolton-Hunter reagent was not different from that for native MAb DF3 IgG. Similar results were obtained with F(ab')2. Immunoreactive fractions for the 125I-labeled MAb DF3 were 0.13, 0.24 and 0.65 for IgG after exposure to 1 microgram Iodogen, 10 micrograms Iodogen and Bolton-Hunter, respectively. Immunoreactive fractions for F(ab')2 were 0.08, 0.08, and 0.53 for 1 and 10 micrograms Iodogen and Bolton-Hunter reagent, respectively. Association constants (Ka) were significantly higher for MAb DF3 IgG radioiodinated with Bolton-Hunter (3.97 +/- 0.38 x 10(8) M-1) than for IgG exposed to 1 microgram Iodogen (2.78 +/- 0.30 x 10(8) M-1) or 10 micrograms Iodogen (1.03 +/- 0.12 x 10(8) M-1). Similarly, the Ka ratio observed for the F(ab')2 radioiodinated with Bolton-Hunter reagent, 1 or 10 micrograms Iodogen was 22 to 3 to 1.(ABSTRACT TRUNCATED AT 250 WORDS)

Antibodies, Monoclonal↗
PubMed1988

Dose-response in the treatment of breast cancer: a critical review.

In animal tumor models the dose-response curve for cytotoxic agents, especially cyclophosphamide, may be steep, but the slope and shape of this curve depends not only on the drug used but on the schedule of drug administration, the specific tumor type, tumor cell kinetics, and tumor mass. It might be anticipated from these studies that the human tumors most sensitive to dose effects would be leukemia, lymphoma, small-cell carcinoma of the lung, and testicular tumors rather than the low growth fraction, relatively less responsive tumors such as breast cancer. However, the clinical evidence for a steep dose-response curve in any tumor type is limited. For breast cancer such evidence is largely retrospective or derived from uncontrolled trials. The data available from randomized trials makes it seem unlikely that small, or even moderate, reductions in drug dose for nontrivial reasons will compromise the survival of patients with either early or metastatic disease. In spite of promising data from small trials, there is, as yet, inadequate evidence to justify the use of very-high-dose therapy and autologous marrow transplant outside the setting of a well-designed clinical trial. The value of high-dose therapy, intensive dose rate, and cumulative drug dose should each be studied in randomized controlled trials.

Antineoplastic Agents↗
PubMed1988

Genetically determined polymorphism of the circulating human breast cancer-associated DF3 antigen.

The murine monoclonal antibody (MAb) DF3 was prepared against a human breast carcinoma. Previous studies have demonstrated that DF3 antigen levels are elevated in plasma of patients with breast cancer. Furthermore, MAb DF3 reacts with circulating glycoproteins of different molecular weights ranging from approximately 300 to 450 kd. The present study demonstrates that plasma DF3 antigen is comprised of at least four moieties with slow (S), intermediate (I), rapid (R) and very rapid (VR) electrophoretic mobilities. The electrophoretic mobility patterns for circulating DF3 antigen differ among individuals. Moreover, DF3 antigen is detectable in urine, and the electrophoretic mobility of the urinary moieties is similar, but not identical, to that in the plasma. Studies in family members suggest that the electrophoretic heterogeneity of plasma DF3 antigen is determined by codominant expression of multiple alleles at a single locus. This locus may code for the core protein of DF3 antigen. These findings thus identify a genetically determined polymorphism of a circulating tumor-associated glycoprotein.

Antibodies, Monoclonal↗
PubMed1987

Primary radiation therapy for locally advanced breast cancer.

The optimal local-regional treatment for patients with Stage III breast cancer has not been determined. To evaluate the effectiveness of radiation therapy as local treatment for such patients, the results of 192 patients (five with bilateral disease) treated with radiation therapy without mastectomy between July 1, 1968 and December 31, 1981 were reviewed. Excisional biopsy (gross tumor removal) was performed in only 54 of the 197 breasts. Patients typically received 4500 to 5000 cGy in 5 weeks to the breast and draining lymph nodes; a local boost to areas of gross disease was delivered to 157 patients. Multi-agent chemotherapy was given to 53 patients. The median follow-up was 65 months. The actuarial probability of survival for the entire group was 41% at 5 years and 23% at 10 years. The probability of relapse-free survival (RFS) was 30% at 5 years and 19% at 10 years. The addition of multi-agent chemotherapy was associated with a significantly improved 5-year RFS (40% versus 26%, P = 0.02). The 5-year survival rate was 51% for patients who received adjuvant multi-agent chemotherapy and 38% for patients who did not (P = 0.16). The actuarial rate of local-regional tumor control (not censored for distant failure) for all patients was 73% at 5 years and 68% at ten years, and the crude incidence of local-regional control was 78%. Local-regional tumor control was principally influenced by radiation dose. Patients who received 6000 cGy or greater to the primary site had a better 5-year rate of control in the breast than did patients who received less than 6000 cGy (83% versus 70%, P = 0.06). Significant complications were seen in 15 patients (8%); these included moderate or severe arm edema in six patients and brachial plexopathy in four patients. Cosmetic results at last evaluation were excellent or good in 56% of evaluable patients, fair in 25%, and poor in 19%. It is concluded that high-dose radiation therapy without mastectomy is an effective means of controlling local-regional tumor in patients with locally advanced breast cancer.

Actuarial Analysis↗
PubMed1986

The syndrome of inappropriate antidiuretic hormone secretion associated with induction chemotherapy for squamous cell carcinoma of the head and neck.

Two patients with squamous cell carcinoma of the head and neck are reported in whom the syndrome of inappropriate antidiuretic hormone (SIADH) secretion occurred transiently during the rapid cytolytic phase of tumor destruction after chemotherapy with cis-platinum diamminedichloride and bleomycin. Immunoperoxidase staining for ADH of the original biopsy specimens from both patients was negative. Possible mechanisms for and the implications of the production of SIADH in this setting are discussed.

Antineoplastic Agents↗
PubMed1986

Comparison of circulating CA15-3 and carcinoembryonic antigen levels in patients with breast cancer.

An immunoradiometric assay (IRMA) has been used to determine circulating levels of the breast cancer-associated antigen, CA15-3. Of 1,050 normal control subjects, serum from 99 (9.4%) had CA15-3 antigen levels greater than 22 U/mL, while that from 58 (5.5%) and 14 (1.3%) had levels greater than 25 U/mL and 30 U/mL, respectively. In contrast, 115 of 158 patients (73%) with metastatic breast cancer had CA15-3 levels greater than 22 U/mL. Thirteen of 26 patients (50%) with only local metastases, 27 of 34 (79%) of those with only bone metastases, and 20 of 24 (83%) with hepatic metastases had CA15-3 levels greater than 22 U/mL. Furthermore, nine of 31 patients (29%) with primary breast cancer had CA15-3 levels greater than 22 U/mL. CA15-3 and carcinoembryonic antigen (CEA) levels were compared for the same patient population. Significantly more patients with metastatic breast cancer had elevated CA15-3 levels than had elevated CEA levels (P less than .001). Furthermore, the CA15-3 IRMA was more sensitive than the CEA assay in patients with only bone metastases, as well as those with only local metastases. Significantly more patients with primary carcinoma of the breast also had elevated CA15-3 than had elevated CEA levels (P less than .02). CA15-3 levels were greater than 22 U/mL in patients with nonmalignant conditions, including five of 25 patients (20%) with benign breast diseases, and 23 of 52 patients (44%) with benign liver diseases. Furthermore, CA15-3 levels were also greater than 22 U/mL in 24 of 54 patients (44%) with gastrointestinal (GI) malignancies, 12 of 17 patients (71%) with bronchogenic carcinoma, and 29 of 44 patients (66%) with epithelial ovarian carcinoma. Serial CA15-3 levels correlated with clinical disease course. Nineteen of 21 patients (91%) with tumor progression had at least a 25% increase in CA15-3 levels. Conversely, seven of nine patients (78%) with tumor regression had at least a 50% decrease in CA15-3 levels. Among 27 patients with stable disease, 16 (59%) had levels that did not vary by more than +/- 25% of the original CA15-3 levels. These results indicate that the CA15-3 antigen is a sensitive marker for the evaluation and monitoring of patients with breast cancer.

Antibodies, Monoclonal↗
PubMed1986

Reactivity of monoclonal antibody DF3 with a high molecular weight antigen expressed in human ovarian carcinomas.

We have previously described the monoclonal antibody (MAb) DF3, prepared against a human breast carcinoma. MAb DF3 reacts with a high molecular weight glycoprotein detectable in human breast carcinomas and in human milk. Previous studies have demonstrated that DF3 antigen levels are elevated in the plasma of patients with breast and ovarian cancer. The present study has further examined the reactivity of MAb DF3 with human ovarian carcinomas. Immunoperoxidase staining demonstrated reactivity of MAb DF3 with 95% of benign, borderline, and malignant tumors (serous, mucinous, and endometrioid) of the ovary. Furthermore, malignant tumors contained cytoplasmic DF3 antigen while benign tumors expressed the antigen only on apical surfaces. Western blot analyses demonstrated that the MAb DF3 reactive ovarian antigen (DF3-O) was a glycoprotein with a heterogenous molecular weight ranging between 300,000 and 450,000. This antigen was detectable by immunofluorescence on the cell surface of five of six cultured human ovarian carcinoma cell lines. The extent of cell surface reactivity with MAb DF3 was equivalent to or greater than that obtained with MAb OC125, an antibody generated against coelomic epithelium and developmental amnion. Furthermore, uptake of 125I-labeled MAb DF3 by human ovarian carcinoma xenografts in athymic mice was 5.4- and 6.2-fold higher than the respective uptake noted in liver and control tumor (P = 0.031). These findings suggest that DF3-O antigen is similar if not identical to the antigen detected in human breast carcinomas by MAb DF3. Thus, MAb DF3 may be a useful reagent in immunodiagnostic evaluation of patients with ovarian cancer.

Adenocarcinoma↗
PubMed1986

Pharmacokinetics of radiolabeled monoclonal antibody B6.2 in patients with metastatic breast cancer.

Thirteen patients with metastatic breast carcinoma were given injections of 50-1593 micrograms of 131I-monoclonal antibody (MAb) B6.2 immunoglobulin G and F(ab')2 for pharmacokinetic evaluation and radioimmunoimaging. Blood clearance of the 131I-MAb-B6.2 was biphasic. The mean half-times (t 1/2 alpha, t 1/2 beta) for the immunoglobulin G were 3.5 +/- 1.7 and 20.9 +/- 11.0 h, respectively. The t 1/2 alpha for the F(ab')2 was 1.7 +/- 1.3 h, and the t 1/2 beta was 31.0 +/- 5.7 h. The percentage of protein bound 131I for the immunoglobulin G and for the F(ab')2 at 72 h was 73.7 +/- 11.4% and 58.2 +/- 14.5%, respectively. In vitro reactivity of MAb B6.2 with granulocytes isolated from normal subjects and patients was demonstrated by cytofluorometric and radioimmunoassays. MAb B6.2 was shown to bind with normal cross-reacting antigen, a cell surface antigen known to be expressed on normal human granulocytes. Reactivity with normal cross-reacting antigen on granulocytes is consistent with the skeletal images obtained during immunoscintigraphy of all 13 patients. A specific tumor image was observed in one patient. No toxicity was encountered. In spite of extensive preclinical data suggesting that 131I-MAb B6.2 would be a useful agent for radioimmunoimaging, the clinical utility of this reagent is probably limited because of the reactivity with granulocytes.

Adult↗