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Biomedical subjects

E Reed

Publications and source records attributed to E Reed.

At least 199 records · Page 11Linked to original sources
PubMed1991

Soluble HLA antigens, anti-HLA antibodies, and antiidiotypic antibodies in the circulation of renal transplant recipients.

Chronic rejection represents the major threat to long-term survival of organ allografts. It is presumed that this form of rejection is mediated by antibodies against mismatched HLA antigens of the graft. The presence and specificity of anti-HLA-antibodies in posttransplantation sera are, however, difficult to document. We have explored the possibility that anti-HLA antibodies form immune complexes with soluble HLA antigens released from the injured graft and/or that they are blocked by antiidiotypic, anti-anti-HLA-antibodies. Our data demonstrate that the long-term survival of renal allografts is significantly lower in patients who develop anti-HLA-antibodies following transplantation than in patients who do not form antibodies. Following depletion of soluble HLA antigens by magnetic immunoaffinity, we could identify anti-HLA-antibodies in 57% of the sera obtained from patients undergoing chronic rejection of kidney allografts, compared with 41% prior to antigen depletion. In patients tolerating the graft for 4 years or more, the corresponding frequencies of antibody-positive sera was 2% and 5% prior and following depletion of HLA antigens. The presence of HLA antigen/anti-HLA-antibody immune complexes in patients' sera was positively associated with chronic humoral rejection (P less than 0.0001). Patients who tolerated the graft in spite of having developed antibodies against one of its mismatched HLA antigens show specific antiidiotypic (anti-anti-HLA-antibodies). Such antiidiotypic antibodies were not found in sera from patients with chronic rejection (P = 0.005). This indicates that antiidiotypic antibodies may delay the progression of chronic humoral rejection.

Antibodies, Anti-Idiotypic↗
PubMed1991

The role of anti-HLA antibodies in heart transplantation.

The major threat to long-term survival of heart allograft recipients is the development of graft atherosclerosis, which seems to be a manifestation of chronic rejection. To assess the role of anti-HLA antibodies in heart allograft rejection we studied 107 patients and compared the survival of recipients who formed anti-HLA antibodies with the survival of recipients who developed no antibodies. At 4 years the actuarial survival was 90% in the nonproducer group and 38% in antibody-producers (P = 0.038). We further explored the possibility that HLA antigens from the injured graft are released into the circulation and can be found in the serum either free or complexed with anti-HLA antibodies. This hypothesis was confirmed by the finding that the frequency of sera containing soluble HLA antigens from the graft or immune complexes of HLA alloantigens with anti-HLA antibodies was significantly higher in patients who rejected compared with patients with successful heart allografts (P less than 0.05). Following depletion of soluble HLA antigens, anti-HLA antibodies became detectable in 53% and 74% sera obtained during the first and second year posttransplantation, respectively, from patients undergoing chronic rejection. Long-term survivors showed a significantly lower (P less than 0.001) frequency of anti-HLA antibodies in sera depleted of HLA antigens. Lastly, studies of anti-anti-HLA-A2 and A3 antibodies in recipient sera suggest that quiescence is maintained by antiidiotypic antibodies.

Antigen-Antibody Complex↗
PubMed1991

RFLP analysis of HLA-DR5 haplotypes.

The analysis of HLA-DR5 haplotypes unravelled a new DRB3 polymorphism and permitted the identification of various associations between alleles of the DRB1 and DRB3 loci. This new polymorphism consists of a 10.5 kb Taq1 restriction fragment which was encountered in an African-American family (JS). In Caucasoids, the DRw11 allele has been previously observed only in association with the DRw52b allele. RFLP and oligonucleotide typing of HLA-DRw52 alleles associated with DRw11 showed, however, that 4 Caucasoid individuals from our panel carried the DRw52a allele and 1 the DRw52c allele. Similarly, DRw12, which is usually associated with DRw52b, was encountered with DRw52a in 1 Chinese and with DRw52c in an African-American and a Chinese panel member. The study of DRB3 alleles associated with DRw11 and DRw12 indicates that, similar to serology, RFLP studies become particularly informative when individuals of different races and ethnic origins are studied.

Alleles↗
PubMed1991

Acquired cisplatin resistance in human ovarian cancer cells is associated with enhanced repair of cisplatin-DNA lesions and reduced drug accumulation.

Studies were undertaken to investigate acquired resistance to cisplatin in human ovarian cancer cells. The cell lines A2780 and A2780/CP70 were studied to assess their respective characteristics of drug accumulation and efflux, cytosolic inactivation of drug, and DNA repair. All experiments were performed using 1-h drug exposures. The A2780/CP70 cell line was 13-fold more resistant to cisplatin than A2780 cells. When studied at their respective IC50 doses, drug accumulation rates were similar for the two cell lines. However, the resistant cell line was twofold more efficient at effluxing drug, which was associated with reduced total drug accumulation for equivalent micromolar drug exposures. At equivalent levels of total cellular drug accumulation, the two cell lines formed the same levels of cisplatin-DNA damage, suggesting that cytosolic inactivation of drug does not contribute to the differential in resistance between these cell lines. Resistant cells were also twofold more efficient at repairing cisplatin-DNA lesions in cellular DNA and in transfected plasmid DNA. We conclude that in these paired cell lines, alterations in drug uptake/efflux and in DNA repair are the major contributing factors to acquired resistance to cisplatin.

Biological Transport↗
PubMed1991

Alkylating agents and platinum: is clinical resistance simply a tumor cell phenomenon?

Alkylating agents and platinum compounds comprise a large group of drugs that may exhibit marked differences in pharmacologic properties on the subcellular and clinical levels. Studies of the subcellular pharmacology of individual agents in this group suggest that cellular resistance to these drugs as a class may be modulated at three general levels: transmembrane drug accumulation, cytosolic inactivation of drug, and altered DNA repair. Traditionally, one unspoken assumption of cancer chemotherapy has been that in vitro tumor cell resistance equates with clinical resistance. Recent studies of platinum DNA adduct in nonmalignant tissues from cancer patients actively receiving therapy suggest that this assumption should be reassessed. In studies of platinum-DNA adduct from four different groups (using four different methods to assess adduct levels in nonmalignant tissues), the relationship between adduct level and disease response is a direct one; ie, the higher the adduct level, the better the clinical response to therapy. Here the data are reviewed that suggest that clinical resistance to DNA-damaging agents is not simply a tumor cell phenomenon and may represent the pharmacogenetic ability of individuals to protect cellular DNA.

Alkylating Agents↗
PubMed1991

Measures of renal function in patients with cisplatin-related chronic renal disease.

Twenty-seven patients with advanced stage refractory ovarian cancer were studied to determine if chronic stable cisplatin-related renal dysfunction was present. Medical histories were examined to determine the types of therapy previously received as well as the total previous platinum doses received that ranged from 200 to 2,100 mg/m2. Standard assessments of renal function were made prior to administering current chemotherapy or immunotherapy to the patient, which included 24-hour creatinine clearance, serum creatinine, and blood urea nitrogen (BUN). For patients with a 24-hour creatinine clearance of less than 60 mL/minute, serum creatinine was highly variable (range: 0.9 to 2.0 mg/dL) and was not related to the degree of diminution in the 24-hour creatinine clearance value. Conversely, for patients with a serum creatinine of less than 1.5, the 24-hour creatinine clearance values varied by almost three-fold, ranging between 46 and 120 mL/minute. Two patients with serum creatinines of less than 1 had creatinine clearances of less than 50 mL per minute. Similarly, BUN measurements did not correlate with 24-hour creatinine clearance values, and the 24-hour creatinine clearance value was not related to the total cumulative platinum dose. We conclude that patients who receive substantive doses of cisplatin may experience chronic stable cisplatin-related renal dysfunction and that serum creatinine cannot be relied on to assess the degree of renal compromise. In such patients, we recommended that the 24-hour creatinine clearance value should be used when medical management is influenced by renal function.

Adult↗
PubMed1991

Cisplatin.

Explore the source record for details and available documents.

Animals↗
PubMed1990

Enhanced malignant conversion of benign mouse skin tumors by cisplatin.

The chemotherapeutic agent cisplatin, reported to be a complete carcinogen in rodents and a tumor initiator for mouse skin, was tested for activity to enhance the conversion of carcinogen-induced skin papillomas to carcinomas. Initiation of mouse skin by 7,12-dimethylbenz[a]anthracene followed by 12 weeks of promotion by 12-O-tetradecanoylphorbol-13-acetate produced seven to eight papillomas/mouse. Ten weekly injections of 100 micrograms of cisplatin into these papilloma-bearing mice induced a 2.3-fold enhancement of conversion relative to the spontaneous rate of 1.9%. Even a single exposure to cisplatin in tumor-bearing mice increased the carcinoma incidence to the same extent as 10 exposures to urethane, an agent previously shown to enhance malignant conversion. At the dose tested, cisplatin was inactive as a complete carcinogen or a tumor promoter. Cisplatin-DNA adducts, measured in samples from skin, liver, and kidneys, were persistent for at least 4 weeks after the last exposure to cisplatin. Thus cisplatin is a relatively potent inducer of the putative genotoxic changes required for conversion of skin tumors from a benign to a malignant phenotype. The activity of cisplatin in the initiation and malignant conversion stages in this animal model for carcinogenesis suggests that patients given cisplatin-based chemotherapy are at increased risk for the development of treatment-induced second cancers.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1990

Evaluation of platinum-DNA adduct levels relative to known prognostic variables in a cohort of ovarian cancer patients.

Single-agent chemotherapy with cisplatin or carboplatin can induce remissions in approximately 30% of previously treated patients with advanced stage ovarian cancer. Previous studies have shown that the extent of platinum-DNA adduct formation measured in WBC DNA of ovarian cancer patients treated with cisplatin or carboplatin is directly associated with disease response (Reed et al., Proc. Natl. Acad. Sci. USA, 84: 5024-5028, 1987). It has been unclear whether adduct level in WBC DNA is independent of known prognostic variables in this disease, or whether adduct level parallels a known prognostic variable that can be more easily monitored. In a cohort of 24 ovarian cancer patients treated with single-agent cisplatin or carboplatin, we retrospectively assessed the relationship between disease response, platinum-DNA adducts in WBC DNA, and each of eight prognostic variables by both univariate analysis and multivariate analysis. The prognostic variables evaluated included: response to previous treatment, Karnofsky status, total platinum dose prior to current therapy, stage of disease, age, bulk of disease at initiation of therapy, histological type, and histological grade. By univariate analysis, adduct level was strongly associated with disease response (two-sided P = 0.0058), with the next strongest associations with disease response being held by Karnofsky status (P = 0.125), stage of disease (P = 0.189), response to previous treatment (P = 0.352), total previous platinum dose (P = 0.358), and age (P = 0.374). No significant associations were found between adduct level and histological type or histological grade. Further, when patients were stratified by the number of cycles studied (one cycle, two cycles, or three cycles), higher levels of adduct were consistently seen in those patients responding to therapy. We conclude that, in this small cohort of refractory ovarian cancer patients treated with single-agent cisplatin or carboplatin, adduct level in WBC DNA appears to be more closely related to disease response than other previously identified prognostic variables.

Antineoplastic Agents↗
PubMed1990

Host-cell reactivation of cisplatin-damaged pRSVcat in a human lymphoid cell line.

A method has been developed for studying host-cell reactivation of cisplatin-damaged plasmid DNA in human T lymphocytes. Parameters of electroporation were established for transfection of the shuttle vector pRSV cat into H9 cells, and a rapid single-vial assay was used for measurement of chloramphenicol acetyltransferase (CAT) activity in extracts of transfected cells. pRSVcat was modified with cisplatin to defined levels ranging from 5 to 40 platinum molecules per plasmid, and then transfected into H9 cells. Graded reductions in CAT activity were observed with increasing levels of platination of the plasmid. At 40 platinum molecules per plasmid, CAT activity was reduced to levels of the negative controls. The efficiency of electroporation-mediated transfer of plasmid into H9 cells was not reduced by high levels of cisplatin modification. The level of modification effecting a 63% reduction in CAT gene expression (the B0), was found to be 17 cisplatin molecules per plasmid. This assay system offers a rapid and sensitive method for assessing the capability of human lymphoid cells to reactivate cisplatin-damaged plasmid DNA.

Avian Sarcoma Viruses↗