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E Reed

Publications and source records attributed to E Reed.

At least 181 records · Page 10Linked to original sources
PubMed1992

Population and family studies of HLA-DR4 by use of oligonucleotide typing.

Using PCR and DR4 group-specific primers and SSO's we have examined DRB1*04 nucleotide polymorphisms in a population of 123 DR4-positive individuals (86 NAC, 27 Hispanics and 10 African Americans) from New York carrying a total of 134 DR4 haplotypes. We found that the distribution of DRB1*04 alleles on DR4 haplotypes differs in these three ethnic groups. In this relatively small population, certain alleles such as DRB1*0406 and 0411 were encountered only in Hispanics, while others such as DRB1*0403, 0408 and 0409 were found only in NAC (North American Caucasians). Such differences may be important in studies of HLA-DR4 and disease associations. Evidence from MLC and PLT studies of an HLA-B/DR crossover family, which was informative for the segregation of HLA-DRB1*0406 and DRB1*0407, supports the concept that subtypes of HLA-DR4 and/or associated HLA-DP alleles elicit T-cell alloreactivity, and may thus play a role in transplantation.

Amino Acid Sequence↗
PubMed1992

Polymorphism of HLA in the Romanian population.

We have investigated the HLA-class I and class II polymorphism in a population of 83 Romanians using conventional serology together with PCR amplification and oligonucleotide typing of HLA-class II genes. Romanians show a higher frequency of HLA-A11, B13, B18, B37, B39, B51 and DR2 than other European populations. HLA-DRB1*1501 and 1601 account for the high frequency of the serologic specificity DR2. In Romanians, HLA-DR2 is in linkage disequilibrium with HLA-B18 and HLA-Bw52 rather than with HLA-B7 as in the case in other Europeans. Unexpected HLA-DR2 haplotypes include HLA-DRB1*1502, DQA1*0102, DQB1*0601; HLA-DRB1*1602, DQA1*0102, DQB1*0502. Other unusual haplotypes include HLA-DRB1*0405, DQA1*03, DQB1*0302; HLA-DRB1*1305, DQA1*0103, DQB1*0603; and HLA-DRB1*1405, DQA1*0101, DQB1*05032. Analysis of the genetic distance between Romanians and other Europeans who have been studied serologically are consistent with the hypothesis that Romanians descend from Roman ancestors who colonized Dacia between the 1st century B.C. and 1st century A.D.

Base Sequence↗
PubMed1992

Increased gene-specific repair of cisplatin interstrand cross-links in cisplatin-resistant human ovarian cancer cell lines.

We have studied several aspects of DNA damage formation and repair in human ovarian cancer cell lines which have become resistant to cisplatin through continued exposure to the anticancer drug. The resistant cell lines A2780/cp70 and 2008/c13*5.25 were compared with their respective parental cell lines, A2780 and 2008. Cells in culture were treated with cisplatin, and the two main DNA lesions formed, intrastrand adducts and interstrand cross-links, were quantitated before and after repair incubation. This quantitation was done for total genomic lesions and at the level of individual genes. In the overall genome, the initial frequency of both cisplatin lesions assayed was higher in the parental than in the derivative resistant cell lines. Nonetheless, the total genomic repair of each of these lesions was not increased in the resistant cells. These differences in initial lesion frequency between parental and resistant cell lines were not observed at the gene level. Resistant and parental cells had similar initial frequencies of intrastrand adducts and interstrand cross-links in the dihydrofolate reductase (DHFR) gene and in several other genes after cisplatin treatment of the cells. There was no increase in the repair efficiency of intrastrand adducts in the DHFR gene in resistant cell lines compared with the parental partners. However, a marked and consistent repair difference between parental and resistant cells was observed for the gene-specific repair of cisplatin interstrand cross-links. DNA interstrand cross-links were removed from three genes, the DHFR, multidrug resistance (MDR1), and delta-globin genes, much more efficiently in the resistant cell lines than in the parental cell lines. Our findings suggest that acquired cellular resistance to cisplatin may be associated with increased gene-specific DNA repair efficiency of a specific lesion, the interstrand cross-link.

Blotting, Southern↗
PubMed1992

Dose-intensive induction therapy with cyclophosphamide, cisplatin, and consolidative abdominal radiation in advanced-stage epithelial ovarian cancer.

PURPOSE: The primary goal of this trial was to evaluate the clinical activity of a high-dose cisplatin-based induction regimen for women with advanced-stage ovarian cancer. A secondary goal was to assess the use of whole-abdominal radiation as consolidative therapy in the subset of women left with less than 5 mm residual disease after completion of chemotherapy. PATIENTS AND METHODS: Fifty consecutive patients with newly diagnosed, advanced-stage ovarian cancer received cisplatin 40 mg/m2/d and cyclophosphamide 200 mg/m2/d intravenously (IV) for 5 days, every 4 to 6 weeks. After three to four cycles of chemotherapy, patients who still had residual disease less than 5 mm in greatest diameter at second-look surgery were given whole-abdominal radiotherapy. RESULTS: The overall response rate in 49 patients assessable for response was 61.3% (24.5% pathologic complete responses [pCRs], 32.7% pathologic partial responses [pPRs], and 4.1% clinical partial responses [cPRs]). Median survival for all patients was 23.4 months, and actuarial 4-year survival was 33.7% (95% confidence interval [CI], 21.8% to 48.1%). Multivariate analysis showed stage III and serous histology as independent favorable prognostic factors for survival. Median survival for stage III patients was 36.5 months, with an actuarial 4-year survival of 41.6% (95% CI, 25.5% to 59.6%). Median survival for stage IV patients was 12.0 months, with actuarial 4-year survival of 22.9% (95% CI, 9.5% to 45.5%). The major acute toxicities encountered were myelosuppression and peripheral neuropathy. Patients who received consolidative radiotherapy were at increased risk of developing late-onset enteropathy. CONCLUSIONS: This regimen is active against advanced-stage ovarian cancer, but the associated toxicity is severe. Consolidative whole-abdominal radiation did not appear to prolong survival in the subset of women left with less than 5 mm residual disease after chemotherapy.

Adolescent↗
PubMed1992

Phase I study of taxol and granulocyte colony-stimulating factor in patients with refractory ovarian cancer.

PURPOSE: To increase the taxol dose beyond the current standard dose intensity of 175 mg/m2 per 21 days in patients with refractory ovarian cancer. PATIENTS AND METHODS: Fifteen patients who had platinum-refractory or recurrent advanced-stage ovarian cancer were treated with taxol in a phase I trial and were given granulocyte-colony stimulating factor (G-CSF). Taxol was administered at doses of 170, 200, 250, and 300 mg/m2 every 3 weeks. G-CSF was given as a daily subcutaneous injection that started 24 hours after the completion of the taxol infusion. RESULTS: Four patients required either taxol dose reduction or delay. The dose-limiting toxicity (DLT) was peripheral neuropathy, and it occurred at 300 mg/m2. This toxicity was manifested clinically as a stocking-and-glove sensory disturbance that primarily affected proprioception, and was associated with objective changes on nerve conduction studies in affected individuals. Mucositis was rarely observed. Substantial myelosuppression was observed, but was not dose-limiting. Five of 14 assessable patients experienced an objective response to therapy, with another five individuals who experienced a 30% to 45% reduction in tumor mass. CONCLUSION: Taxol can be safely administered in doses up to 250 mg/m2 with G-CSF support, which may make it possible to study taxol dose intensification.

Adult↗
PubMed1992

Cisplatin-DNA damage and repair in peripheral blood leukocytes in vivo and in vitro.

We have extended our studies on the relationship between cisplatin/carboplatin-induced DNA damage in readily accessible tissue(s) and clinical response to therapy. Such an approach may assist in the study of cancer drug resistance and in establishing parameters for assessing human populations for sensitivity to DNA damaging agents in the environment. Platinum-DNA adduct levels were measured by atomic absorbance spectrometry. DNA repair capacity was assessed in human T-lymphocytes by the ability to repair cisplatin lesions in cellular DNA or in transfected plasmid DNA. In a "blinded" study of 21 patients receiving combination cisplatin/carboplatin drug therapy, there was a direct relationship between DNA damage in leukocytes and disease response (summary two-sided p = 0.00011). The cohort of patients had 15 different tumor types, suggesting that blood tissue and tumor tissue of an individual may process platinum-DNA damage similarly regardless of the tissue of origin of the tumor. In leukocytes in vivo, persistence and accumulation were prominent features of the cisplatin-DNA adduct profile. Functional DNA repair capacity has been studied in eight human leukocyte cell lines in vitro (three, T-cells; three, B-cells; one, monocytic; one, promyelocytic), using a host cell reactivation assay with cisplatin-damaged pRSVcat. In the three T cell lines studied, host cell reactivation efficiency was directly related to the cells' abilities to repair cisplatin-damaged cellular DNA (correlation coefficient = 0.993).(ABSTRACT TRUNCATED AT 250 WORDS)

Carboplatin↗
PubMed1992

Cisplatin.

Explore the source record for details and available documents.

Animals↗
PubMed1992

Effect of anti-HLA and anti-idiotypic antibodies on the long-term survival of heart and kidney allografts.

Long-term survival of heart and kidney allografts is threatened by the development of chronic rejection. Analysis of the relationship between reversible acute rejection episodes and actuarial survival at 5 years showed an inverse correlation suggesting that early cellular events may trigger antibody-mediated chronic rejection. In both heart and kidney allograft recipients producing anti-HLA antibodies we found a significant decrease in the 5-year graft survival rate. However, there was heterogeneity among anti-HLA antibody producers with respect to the development of anti-idiotypic antibodies. The actuarial 5-year graft survival was significantly higher in patients with Ab2 compared to patients without.

Actuarial Analysis↗
PubMed1992

Effect of recipient gender and race on heart and kidney allograft survival.

Study of long-term survival of heart allografts shows that AA males and females have lower graft survival rates than those observed in NAC recipients. Primary kidney allografts in AA males, but not females, also display lower 5-year survival rates compared to those observed in the corresponding populations of NAC. Comparison of graft survival in the overall population of male and female recipients of kidney allografts shows that females have higher graft survival rates, probably as a result of better HLA matching. The level of alloantibody activity in posttransplantation sera is similar in the two populations, suggesting that factors other than HLA mismatching may contribute to the higher degree of graft failure in AA recipients.

Actuarial Analysis↗
PubMed1991

Biosynthesis and partial amino acid sequence of the human NDA4 antigen. An activation antigen common to B and T cell lineages.

NDA4, a cell surface protein of molecular mass 46 kDa common to activated peripheral blood B and T cells, plays a unique role in the control of B and T cell maturation. NDA4 inhibits B and T cell activation, as mitogen-stimulated B and T cell blastogenic responses are decreased in the presence of mAb NDA4, the antibody recognizing NDA4. After mitogen-activation, however, the regulatory function of NDA4 changes. Addition of mAb NDA4 to cultures of Staphylococcus aureus Cowan strain A-activated B cells or alloreactive T cell clones stimulates their proliferation. NDA4 epitopes are conserved across primate species lines and are present on transformed cells of neuroectodermal origin. NDA4 is synthesized as a molecular mass 50 kDa precursor and is processed to a mature 46 kDa form within 30 min. The NDA4 Ag also exists as soluble forms of 40 and 42 kDa. The membrane and soluble forms of NDA4 have been purified to homogeneity and sequenced by N-terminal Edman degradation.

Amino Acid Sequence↗
PubMed1991

In vitro studies of the effect of MAb NDA 4 linked to toxin on the proliferation of a human EBV-transformed lymphoblastoid B cell line and of gibbon MLA leukemia cell line.

The rejection of allografts is mediated by cytolytic T cells and antibody-secreting B cells. Selective ablation of these activated cells from peripheral blood lymphocytes may offer a a method of controlling allograft rejection. An immunotoxin was prepared from the monoclonal antibody (mAb) NDA 4, which recognizes a differentiation antigen (NDA 4) common to activated B and T cells. MAb NDA 4 was conjugated to the ribosome-inhibiting protein gelonin via a cleavable disulfide bond provided by a crosslinking reagent. The purified immunotoxin was evaluated for in vitro cytotoxicity on NDA 4 positive T and B cell lines. Conjugation of mAb NDA 4 to gelonin increased the in vitro cytotoxicity by a concentration factor of 1000, compared to gelonin alone. The specificity and saturability of mAb NDA 4 binding, as well as the number of antigenic sites per cell on resting versus activated T lymphocytes, were also evaluated. Resting T cells expressed 400-800 sites per cell. PHA-activated T cells and the MLA T cell leukemia expressed 10,000 to 80,000 sites per cell. Peripheral blood mononuclear cells obtained from allografted baboons in quiescence or undergoing rejection were compared for NDA 4 expression by flow cytometry. Lymphocytes obtained from baboons rejecting a heart allograft expressed NDA 4, whereas transplant recipients in quiescence showed no detectable NDA 4. These results suggest that mAb NDA 4-derived immunotoxins may be valuable for the selective depletion of activated lymphocytes while sparing the resting population.

Animals↗
PubMed1991

Gene-specific formation and repair of cisplatin intrastrand adducts and interstrand cross-links in Chinese hamster ovary cells.

We have used three methods to study the formation and repair of intrastrand adducts and interstrand cross-links in the DNA of Chinese hamster ovary cells induced by the anticancer drug cis-diamminedichloroplatinum II (cisplatin). Using atomic absorption spectroscopy, we found that 21% of the total genomic cisplatin adducts were removed at 8 h and 42% at 24 h. We used ABC excinuclease digestion, coupled with out previously reported methodology to quantify DNA in specific genomic regions. These adducts were removed faster in the transcribed dihydrofolate reductase and c-myc genes compared to a noncoding fragment, a region containing the little or nontranscribed c-fos oncogene, and to the overall genome. Interstrand cross-links in specific sequences were quantified by Southern hybridization of denatured-renatured DNA separated on a neutral gel. We found that cross-links were removed more efficiently from the gene regions than intrastrand adducts and, at high levels of cross-linking, removal was similar from transcribed and from nontranscribed regions.

Animals↗
PubMed1991

The alloantibody response of pregnant women and its suppression by soluble HLA antigens and anti-idiotypic antibodies.

The aim of this study was to investigate the time course of maternal allosensitization to fetal HLA antigens during normal human pregnancy and to explore mechanisms of suppression of anti-HLA alloantibodies. We found that the mother produces antibodies against some but not all of the mismatched HLA antigens of the fetus as early as the 8th week of pregnancy. These antibodies (Ab1), however, are often complexed with soluble HLA alloantigens and become detectable when immune complexes are dissociated. Soluble HLA antigens of fetal origin are present in the maternal circulation throughout the entire pregnancy beginning at 8 weeks. In some women the production of anti-anti-HLA antibodies (Ab2) became evident as early as the first trimester, while in others Ab2 was documented during the second or third trimester. Analysis of antibody specificity showed that some healthy primipara develop antibodies reactive with self HLA antigens. Although the allo- and autoantibody responses appear to be modulated by soluble HLA antigens, cyclic variations in the level of alloantibodies, as well as the mother's selective response to some, but not all, paternal HLA antigens, are best explained by the development of anti-idiotypic antibodies.

Antibodies, Anti-Idiotypic↗
PubMed1991

Platinum-DNA damage in leukocyte DNA of patients receiving carboplatin and cisplatin chemotherapy, measured by atomic absorption spectrometry.

Previous studies have shown that platinum-DNA adduct level in leukocyte DNA (measured by antibody methodology) is directly related to disease response in ovarian cancer and testicular cancer. To determine if this principle could be more broadly applied, platinum-DNA damage was studied in a blinded fashion in leukocyte DNA of 21 cancer patients who received carboplatin (day 1) and cisplatin (day 3) in a phase 1 clinical trial. Fifteen different tumor types were included in this cohort. Using atomic absorption spectrometry with Zeeman background correction, DNA-bound platinum was measured during cycles 1 (C1) and 2 (C2) of therapy for most patients. For each of two cycles of therapy, most patients developed measurable levels of adduct after carboplatin, and in most patients adduct levels increased further after cisplatin, often in a supra-additive fashion. Total mg dose levels varied by less than 2-fold, whereas individual patients differed by as much as 10(3) in their adduct measurements after C1 and after C2, and by 29-fold after the very first carboplatin dose. All patients had refractory disease at the initiation of therapy, and 19 patients were evaluable for disease response. Adduct determinations were made 24 h after the first dose of platinum therapy in 17 of these individuals. Mean adduct levels after the first dose of carboplatin were higher in six responders (50 fmol/micrograms DNA +/- 26) than in 11 non-responders (14 fmol/micrograms DNA +/- 10); Wilcoxon two sample test two-sided P = 0.0071. The six responders were patients with pleural mesothelioma (2), breast cancer, buccal mucosa cancer, esophageal cancer and ovarian cancer. Adduct levels were consistently higher in the group of responders on each day that adduct was measured, with a summary two-sided P value of 0.00011. We conclude that analysis of platinum-DNA adduct formation may help determine whether pharmacogenetics are important in cancer drug resistance; and may help to determine the relationship between DNA damage in the peripheral blood compartment and internal organ response to in vivo exposures to DNA-damaging agents.

Carboplatin↗
PubMed1991

Dose-escalation study of carboplatin (day 1) and cisplatin (day 3): tolerance and relation to leukocyte and buccal cell platinum--DNA adducts.

Carboplatin and cisplatin have similar antitumor activities but different toxicities. Combining these two analogs may be expected to balance the toxicities and allow higher doses of platinum compounds to be administered with tolerable toxicity. To test this concept, a Phase I trial of carboplatin in combination with cisplatin was performed. Thirty-three eligible patients received carboplatin doses ranging from 200-480 mg/m2 on day 1 and cisplatin doses ranging from 50-100 mg/m2 on day 3 of the 28 day cycle. A 2-day interval ensured no interference in renal excretion of carboplatin by cisplatin. Myelosuppression was the dose limiting toxicity. With the usual full dose of carboplatin, 480 mg/m2, patients tolerated 50 mg/m2 of cisplatin, without apparent additional toxicity. At 100 mg/m2 of cisplatin, non-hematologic as well as hematologic toxicities frequently precluded administration of more than 300 mg/m2 of carboplatin. Platinum-DNA adduct quantitation was done in leukocytes and buccal cells during cycle 1 in most patients. The adduct-specific immunosignal in buccal cells was always increased after carboplatin and in all but one after cisplatin. The level of adducts in buccal cells increased with increasing doses of carboplatin and cisplatin. In leukocytes, measurable levels of adducts were formed after carboplatin with further contribution made by cisplatin but not obviously in a dose dependent fashion. We conclude from the toxicities observed, that combinations of carboplatin with cisplatin may have advantages over either drug alone in certain clinical situations; and that further study of platinum-DNA adducts may shed light on platinum dose-response relationships.

Adult↗
PubMed1991

Immunomodulation of kidney and heart transplants by anti-idiotypic antibodies.

To explore the possibility that circulating HLA antigens from the graft and anti-anti-HLA (anti-idiotypic) antibodies influence the long-term survival of renal and cardiac allografts, analysis of 330 renal allograft recipients and 174 recipients of cardiac allografts was conducted. Anti-donor-HLA antibodies (Ab1) present before or after transplantation are associated with graft failure, whereas irrelevant anti-HLA antibodies had no impact on actuarial graft survival. Ab1 may be uncovered by dissociation of immune complexes and depletion of soluble antigens with monoclonal antibody-coated magnetic beads. Of the 421 sera tested from 65 heart recipients, 97 showed Ab1 before depletion and 178 after depletion; similar rise in positive sera was seen in 39 renal transplant recipients. Three distinct patterns of appearance of Ab1 and Ab2 (anti-Ab1 antibody) were recognized. Patients with cyclic variations of Ab1 in association with Ab2 had 100% graft survival, whereas patients with cyclic variations of Ab1 but no detectable Ab2 had 2-year graft survival of 36% for kidneys and 71% for hearts. Presence of Ab1 in all sera after transplantation led to 47% and 56% 2-year renal and heart allograft survival, respectively.

Actuarial Analysis↗