Biomedical subjects

E Reed

Publications and source records attributed to E Reed.

At least 163 records · Page 9Linked to original sources

PubMed1993

Definition of an HLA-DPw2-restricted epitope on NS3, recognized by a dengue virus serotype-cross-reactive human CD4+ CD8- cytotoxic T-cell clone.

We previously reported that the clone JK34 was cross-reactive for dengue virus types 1, 2, 3, and 4 and recognized NS3 (I. Kurane, M. A. Brinton, A. L. Samson, and F. A. Ennis, J. Virol. 65:1823-1828, 1991). In the present experiments, we defined the epitope at the amino acid level, with 93 15-mer overlapping peptides which cover the entire NS3. A peptide 4 which contains amino acids 251 to 265 of NS3 sensitized the autologous B lymphoblastoid cell line (LCL) to the lysis by JK34. The smallest peptide recognized by JK34 was a 10-mer peptide which contains amino acids 255 to 264 (EIVDLMCHAT). A monoclonal antibody to HLA-DP inhibited the lysis of epitope peptide-pulsed autologous LCL by JK34. Genotypic typing revealed that the HLA-DP of this donor is DPA1*01, DPB1*0201, which is serologically defined as HLA-DPw2. JK34 lysed peptide 4-pulsed allogeneic LCL which carried HLA-DPw2. These results indicate that HLA-DPw2 is the restriction allele for recognition of this epitope by JK34.

Amino Acid Sequence↗

PubMed1993

High-dose carboplatin and recombinant granulocyte-macrophage colony-stimulating factor in advanced-stage recurrent ovarian cancer.

PURPOSE: We investigated whether carboplatin myelosuppression could be favorably modulated by the administration of recombinant granulocyte-macrophage colony-stimulating factor (rGM-CSF) in patients with advanced-stage ovarian cancer. PATIENTS AND METHODS: Thirty-four patients with advanced-stage recurrent ovarian cancer were treated with high-dose carboplatin (800 mg/m2 per 35-day cycle) and rGM-CSF. rGM-CSF was administered as a daily subcutaneous injection starting 72 hours after the carboplatin dose and continuing until 7 days beyond the WBC nadir. rGM-CSF was administered in a phase I fashion. Seven patients were treated at an rGM-CSF dose of 3 micrograms/kg, 11 at 5 micrograms/kg, 10 at 10 micrograms/kg, and six at 20 micrograms/kg. RESULTS: rGM-CSF-related toxicities that were not dose-related included nonneutropenic fever, rib pain, acute hypersensitivity reaction, and pericarditis. At the rGM-CSF dose of 20 micrograms/kg, debilitating malaise was seen in four of six patients and this was the dose-limiting toxicity. Patient tolerance of the 3-micrograms/kg and 5-micrograms/kg doses was good, but tolerance was limited for the 10-micrograms/kg dose. Febrile neutropenia was seen in four of seven patients at 3 micrograms/kg, two of 11 at 5 micrograms/kg, two of 10 at 10 micrograms/kg, and one of six at 20 micrograms/kg. Cumulative carboplatin myelotoxicity was blunted only in respect to WBC count, and not for platelets or RBCs. Gastrointestinal bleeding was seen in seven patients. The administered dose-intensity of carboplatin averaged 134 mg/m2/wk for the cohort, or 670 mg/m2 per 35-day cycle. There were two clinical complete responses and eleven partial responses, for a response rate of 38%. CONCLUSION: rGM-CSF appears to be effective and tolerable at 5 micrograms/kg/d administered subcutaneously, if given with carboplatin doses up to approximately 600 mg/m2 over 35 days. The use of rGM-CSF with high-dose carboplatin is associated with a substantial response rate in poor-prognosis ovarian cancer patients.

Adult↗

PubMed1993

Platinum drug-DNA interactions in human tissues measured by cisplatin-DNA enzyme-linked immunosorbent assay and atomic absorbance spectroscopy.

Studies of platinum drug-DNA adduct formation in tissues of cancer patients have involved both atomic absorbance spectroscopy (AAS), which measures total DNA-bound platinum, and anti-cisplatin-DNA enzyme-linked immunosorbent assay (ELISA), which detects a fraction of the AAS-measurable adduct. These studies were designed to explore mechanisms of drug-DNA interactions, to make correlations with clinical outcome, and possibly to validate DNA adduct measurements for use in occupational and environmental biomonitoring. The results, determined by both ELISA and AAS, demonstrate that cisplatin and its analog carboplatin bind to DNA in many human organs, including kidney, brain, peripheral nerve, and bone marrow, which are sites for drug toxicity. Platinum was also observed bound to ovarian tumor DNA. The adducts were highly persistent, being measurable in tissues obtained at autopsy up to 15 months after the last administration of platinum chemotherapy. A comparison of blood cell DNA adduct levels, determined by ELISA, and the clinical response of 139 patients with ovarian, testicular, colon, or breast cancer demonstrated a strong correlation between failure to form DNA adducts and failure of therapy. Conversely, patients who formed high levels of DNA adduct were most likely to respond favorably. A similar correlation was not observed for adducts determined by AAS; that is, the average total DNA-bound platinum levels were the same for patients who did not respond to therapy and for patients who had any kind of response. Thus, in this study, human blood cell DNA adducts measured by ELISA correlate with tumor remission, while those measured by AAS do not.

Blood Cells↗

PubMed1993

Are congregate meals meeting clients' needs for "heart healthy" menus?

This is a report of a dietary analysis of meals offered in one large congregate feeding program and clients' consumption patterns as they relate to self-reported dietary restrictions. Most meals exceeded dietary guidelines for kilocalories, cholesterol, and proportion of energy from fat. Of 438 congregate meal clients 60 years of age and older who were surveyed at senior citizen centers and congregate meal sites, 30% reported following a "special diet." The most commonly mentioned dietary modifications were low sodium and/or low fat/low cholesterol. Clients who reported dietary restrictions also reported eating fewer congregate meals per week than did clients who denied dietary restrictions.

Aged↗

PubMed1993

A reassessment of cardiac toxicity associated with Taxol.

Cardiac toxicity was first noted in patients receiving Taxol during continuous cardiac monitoring, which was performed because of the high incidence of serious hypersensitivity reactions noted early in phase I trials. After cardiac events were documented, patients with cardiac disease and those on medications known to alter cardiac conduction were excluded from most trials. The cardiac events reported with Taxol from the initiation of NCI-sponsored clinical trials through August 1992 are summarized. Adverse cardiac events were reviewed in four clinical databases: 1) the Cancer Therapy Evaluation Program's Adverse Drug Reaction database following treatment of more than 3400 patients; 2) all cardiac toxicities in patients on GOG-111 who were randomized to cisplatin plus either Taxol or cyclophosphamide; 3) cardiac toxicity in 198 patients who received 618 courses of Taxol with or without cisplatin during continuous cardiac monitoring; and 4) cardiac toxicities reported for the first 696 patients on NCI TRC-9103 for ovarian cancer. Published reports of studies of taxine's cardiac effects, and of cardiac toxicity associated with yew poisoning, Cremophor EL, and H1 and H2 antagonists, are also reviewed. In patients without significant cardiac risk factors, asymptomatic sinus bradycardia is frequent (approximately 30%). Heart block and conduction abnormalities occur infrequently and are often asymptomatic. The casual relationship of Taxol to atrial and ventricular arrhythmias and cardiac ischemia is less clear because many patients had other conditions known to be associated with cardiac events. Nevertheless, the incidence of serious cardiac events was low. Routine cardiac monitoring is not required for patients without risk factors. There are, however, insufficient data to make treatment recommendations for patients with cardiac disease and those taking medications that alter cardiac conduction. To maximize patient safety and the clinical database, physicians who administer Taxol should continue to be alert to potential cardiac toxicities associated with Taxol.

Animals↗

PubMed1993

Taxol effect on cisplatin sensitivity and cisplatin cellular accumulation in human ovarian cancer cells.

Taxol and cisplatin are the two most effective agents discovered to date for treating advanced-stage cancer of the ovary. Learning how best to combine these agents is the focus of preclinical and clinical studies conducted at a number of institutions. Taxol's effect on cellular sensitivity to cisplatin was studied in paired cisplatin-sensitive A2780 and cisplatin-resistant A2780/CP70 human ovarian cancer cell lines. Cisplatin growth curves were generated under conditions of specific sequencing with Taxol, and IC50s (concentrations at which growth is inhibited to 50% of control) for cisplatin were obtained and compared. Taxol was used at an IC10 dose in all experiments. Taxol treatments were for 24 hours and cisplatin treatments were for 1 hour in all experiments. Dimethyl sulfoxide (DMSO) was the diluent for all Taxol stock solutions. Separately, the effects of Taxol and DMSO on cisplatin cellular accumulation were measured. End points reported include measures of cytotoxicity and Taxol effects on cisplatin cellular accumulation. Using a microculture tetrazolium assay, cisplatin growth curves were obtained under the influence of Taxol, at a Taxol dose of 3 nM for both cell lines. DMSO alone had no effect on tumor cell growth. In A2780 cells, the influence of Taxol on cisplatin cytotoxicity was modest, whereas cisplatin-induced cell kill was augmented 1.5-fold when cisplatin was given immediately after Taxol. In A2780/CP70 cells, Taxol augmented cisplatin-induced cell kill by 30-fold when cisplatin was given immediately after Taxol; 75-fold when cisplatin was given 24 hours after completion of Taxol; and 19-fold when cisplatin was given 48 hours after completion of Taxol.(ABSTRACT TRUNCATED AT 250 WORDS)

Cisplatin↗

PubMed1993

Taxol dose intensification and its clinical implications.

Taxol is the most exciting new anticancer agent developed in the past two decades. Of great interest is its level of activity in ovarian cancer, as well as substantial activity in breast cancer, nonsmall-cell lung cancer, melanoma, and other malignancies. Recent studies suggest that when taxol is administered in a fashion to increase milligram dosage per unit time (mg/m2/week), the response rate in patients with ovarian cancer is markedly increased. This article reviews studies that suggest taxol dose intensity is important in the treatment of patients with ovarian cancer.

Breast Neoplasms↗

PubMed1993

Cisplatin.

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Cisplatin↗

PubMed1993

Demonstration of the anti-viral activity of garlic extract against human cytomegalovirus in vitro.

The in vitro anti-viral activity of garlic extract (GE) on human cytomegalovirus (HCMV) was evaluated by tissue culture, plaque reduction and early antigen assay. A dose dependent inhibitory effect of GE was evident when GE was applied simultaneously with HCMV. But the effect was stronger when the monolayers were pretreated with GE. In addition, the anti-viral effect of GE persisted long in infected cells after its being removed from the culture medium. The strongest anti-viral effect of GE was demonstrated when it was applied continuously. It is therefore recommended that clinical use of GE against HCMV infection should be persistent and the prophylactic use of GE is preferable in immunocompromised patients.

Antiviral Agents↗

PubMed1993

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

Study of anti-HLA antibodies in a population of 238 primary renal and 199 primary heart allograft recipients showed significant association between development of anti-HLA antibodies and that of chronic allograft rejection. The 5-year renal allograft survival was 70% in recipients without antibodies and 53% in recipients who developed anti-HLA alloantibodies during the first year following transplantation. Heart allograft survival at 5 years was 91% in patients without and 78% in patients with antibodies during the first 12 months posttransplantation. Development of antibodies is associated with acute rejection episodes and probably with the release of soluble HLA antigens.

Antibodies, Anti-Idiotypic↗

PubMed1992

ERCC1 and ERCC2 expression in malignant tissues from ovarian cancer patients.

BACKGROUND: ERCC1 and ERCC2 are human DNA repair genes that are associated with in vitro resistance to selected DNA-damaging agents. PURPOSE: Fresh tumor tissues from 26 patients with ovarian cancer were analyzed for the RNA levels of expression of these genes to determine possible clinical relevance. METHODS: Tumor tissues were harvested from patients immediately before they entered a cisplatin- or carboplatin-based treatment protocol. Clinical response was assessed by standard criteria. Gene expression level was assessed by slot blot analysis, using beta-actin as a control. Relative expression levels were determined by comparing each tumor sample with a Chinese hamster ovary cell line that had a stable transfection of the human ERCC1 gene. RESULTS: Patients who were clinically resistant to platinum-based therapy had a 2.6-fold higher expression level of ERCC1 in their tumor tissue than did patients who responded to that therapy (P = .015). Results obtained by slot blot analysis were qualitatively confirmed by polymerase chain reaction analysis. Relative levels of expression of ERCC2 did not differ significantly between responders and nonresponders. CONCLUSION: We conclude that ERCC1 expression levels in human tumor tissue may have a role in clinical resistance to platinum compounds. These data appear to be consistent with the assertion that ERCC1 serves as an excision nuclease, whereas ERCC2 serves as a helicase.

Blotting, Southern↗

PubMed1992

Multiple biological markers in germ cell tumor patients treated with platinum-based chemotherapy.

Blood samples from 36 germ cell tumor patients receiving chemotherapy with either cisplatin or carboplatin in combination with other drugs [etoposide or vinblastine, cyclophosphamide, dactinomycin, and bleomycin (VAB-6)] were analyzed for the presence of 7 different biological markers. The biomarkers included platinum-protein adducts, platinum-DNA adducts, sister chromatid exchange (SCE), micronuclei (MN), and somatic gene mutation at the hypoxanthine phosphoribosyl transferase (HPRT) locus and the glycophorin A (GPA) loci (NO and NN). Patients were asked to donate 9 serial blood samples: a pretreatment sample followed by another drawn 12-24 h after each of four cycles of treatment and a final sample provided 3-6 months after the last cycle. Most individuals gave 7-8 samples; 7 individuals donated all 9. Because of limited amounts of cells in some cases, it was not possible to carry out all 7 assays on every sample. Pt-protein adducts, Pt-DNA adducts, and SCE showed a direct and consistent effect of treatment and were very highly correlated. A significant correlation was also seen between both Pt-protein and Pt-DNA adducts and HPRT mutation. All of the posttreatment samples were significantly elevated compared to the baseline sample. These markers also remained elevated 3-6 months after the end of treatment. By contrast, MN, HPRT mutation, and GPA mutation (both NO and NN variants) showed varying patterns of dose response, probably reflective of the differing biology of these markers scored in lymphocytes (MN and HPRT) and erythrocytes (GPA). MN were significantly elevated in the posttreatment samples drawn at cycles 2 and 3. Although induction of HPRT mutation was only of marginal significance, results here are for the mutant frequency determination assay only. In progress is the potentially more informative analysis of the type of mutations by Southern blot and the sequencing of mutations to look for characteristic mutational spectra. The GPA assay showed a significant increase over baseline in samples drawn after cycles 3 and 4 (NO variants) and after cycles 2, 3, and 4 (NN variants). The level of GPA mutation (both NO and NN variants) was clearly elevated even 3-6 months after the last cycle of chemotherapy. Correlations were seen between HPRT and MN as well as between GPA NO and GPA NN variants. Analysis of biomarkers by treatment group does not reveal a consistent pattern or trend across all cycles.(ABSTRACT TRUNCATED AT 400 WORDS)

Adolescent↗

PubMed1992

Host cell reactivation of cisplatin-damaged plasmid DNA in human non-T leukocyte cell lines.

Host-cell reactivation of cisplatin-damaged pRSVcat was assessed in three B cell lines (SKW 6.4, WIL2-NS, RPMI 1788), the monocytic cell line THP-1, and promyelocytic HL-60 cells. IC50 values following a 3-day exposure of the five leukocyte cell lines to cisplatin ranged from 0.45 to 1.92 microM. Transfer of pRSVcat into all cell lines was effected by electroporation and the resultant CAT activity was measured 24 h later by a rapid single vial CAT assay. CAT activity corresponding to an average of 0.06 units of purified CAT enzyme was expressed by WIL2-NS cells. Very low to no expression of the CAT vector was observed in all other cell lines studied, despite the presence of intracellular levels of 3H-labelled pRSVcat comparable to WIL2-NS. Epstein-Barr virus transformed B cells (SKW 6.4 and RPMI 1788) did not successfully perform host cell reactivation. In WIL2-NS cells, platination of pRSVcat to defined levels of 5-40 platinum molecules per plasmid led to a graded reduction in CAT activity expressed following transfection. Platination levels of 20 and 40 platinum molecules per plasmid did not alter the efficiency of transfer of pRSVcat into these cells by electroporation. Data obtained in this study suggests that EBV transformation may possibly be a negative influence on host cell-reactivation assays for cisplatin-DNA damaged plasmid in non-T human leukocytes.

B-Lymphocytes↗

PubMed1992

Persistence of platinum-ammine-DNA adducts in gonads and kidneys of rats and multiple tissues from cancer patients.

The persistence of platinum-DNA adducts was investigated using normal rats as well as tissues from cancer patients receiving either cisdiamminedichloroplatinum(II) (cisplatin) or diamminecyclobutanedicarboxylatoplatinum(II) (carboplatin) for cancer chemotherapy. These studies used an enzyme-linked immunosorbent assay, established with a rabbit anti-cisplatin-DNA that is specific for intrastrand platinum-DNA adducts. The gonads and kidneys of male and female rats, sites for antitumor activity and toxicity, respectively, were monitored for cisplatin-DNA adduct formation after a single dose of drug and during multiple-dose exposures (once a wk for 3 wk). DNA adducts were measured by enzyme-linked immunosorbent assay 4 h and 2, 4, 7, and 14 days after administering a single i.v. injection of 8 mg/kg of cisplatin. Adduct profiles in renal tissues were similar in both males and females with adduct levels increasing between 4 h and 2 days, decreasing between Days 2 and 7, and stable between Days 7 and 14. In both sexes, levels of kidney DNA adduct measured 7 to 14 days after cisplatin injection comprised about 30% of the highest (Day 2) value. In testes and ovaries, adduct removal was complete by 4 days, and 40 to 50% of adducts present at Day 2 persisted until Days 7 and 14. A study of multiple dosing showed that adducts in renal and testicular DNA from rats given three weekly doses of 5 mg/kg of cisplatin had different accumulation profiles. In the testis there was a 2-fold accumulation of adduct after the third dose, while in the kidney adducts dropped with repeated dosing. In humans, the persistence of platinum-DNA adducts was studied in tissues from eight cancer patients who received their last dose of cisplatin or carboplatin chemotherapy between 1 day and 15 mo before autopsy. The patients had either ovarian cancer, breast cancer, or lymphoma, and the tissues studied included ovarian tumor, bone marrow, kidney, liver, spleen, lymph node, peripheral nerve, and brain. When samples were available from tumor tissues and from bone marrow within the same patient, adduct levels were similar in the two tissues. In addition, adducts were persistent for many months, since half of the individuals received their most recent platinum-drug therapy 7 to 15 mo before death. Overall, these studies demonstrate a widespread distribution and high degree of platinum-DNA adduct persistence in both animal and human tissues subsequent to cisplatin or carboplatin treatment.

Adult↗

PubMed1992

5-Fluorouracil (5-FU) and leucovorin in platinum-refractory advanced stage ovarian carcinoma.

Twenty-nine patients with recurrent advanced stage ovarian cancer were treated with 5-fluorouracil (5-FU) and leucovorin by intravenous bolus on 5 consecutive days, repeated every 3 weeks. Twenty-one of these patients had experienced disease progression while receiving a cisplatin- or carboplatin-based regimen. There were 2 clinical complete responders and 1 partial responder to therapy (10% response rate; 95% confidence interval, 2 to 27%) and 11 individuals who experienced stable disease for periods ranging from 5 to 27 months. Of 204 cycles of therapy administered, 9 cycles were associated with hospitalization. These occurred in the more heavily pretreated members of the cohort. 5-FU and leucovorin appear to have activity in platinum-refractory ovarian cancer and form a well-tolerated regimen in most patients.

Adult↗

PubMed1992

Determinants of cisplatin sensitivity in non-malignant non-drug-selected human T cell lines.

We have studied molecular mechanisms of cisplatin sensitivity and resistance in 3 non-malignant, non-drug-selected human T lymphocyte cell lines. HuT 78, H9, and MOLT-4 cells were assessed for sensitivity to cisplatin, DNA damage levels following defined drug exposures, drug accumulation, and DNA repair efficiency as measured by adduct removal from cellular DNA and by host-cell reactivation of cisplatin-modified plasmid DNA. Based on 3-day continuous drug exposures, the IC50 values for the cell lines were: HuT 78, 0.83 microM; H9, 0.45 microM; and MOLT-4, 0.33 microM. These cells retained this order with respect to DNA repair capability, whether measured by platinum-DNA adduct removal from cellular DNA or by host-cell reactivation assays. DNA repair values measured by these two assays were directly related to one another with a linear correlation coefficient of 0.993. At sublethal cisplatin doses the more resistant cells showed the highest levels of drug uptake. When drug uptake levels were 'corrected' for drug-induced cell kill, there were equal levels of DNA repair efficiency for a given level of drug uptake. Absolute levels of cisplatin-DNA adduct repair increased with increasing drug dose. However, at supralethal doses of drug, efficient DNA repair could be overcome in all 3 cell lines with percentage-adduct-removal dropping from a 60-80% range to a less than 30% range. We conclude that in non-malignant non-drug-selected human T cells, DNA repair appears to be the primary determinant of cisplatin sensitivity/resistance and that enhanced DNA repair may be a biologic compensatory mechanism for cells that cannot prevent cellular uptake of DNA-damaging agents.

Cell Line↗

PubMed1992

Suramin in advanced platinum-resistant ovarian cancer.

10 patients with ovarian cancer, whose disease had progressed while receiving platinum-based therapy, were entered onto a phase II clinical trial of the antiproliferative agent suramin. Suramin was administered in a fashion that is associated with durable objective disease response in patients with hormonally resistant metastatic prostate cancer. No individual had an objective response to therapy in this study, but 3 of 9 evaluable patients (33%) experienced disease stabilisation and subjective clinical improvement for periods ranging from 2 to 5 months. Disease stabilisation was associated with prolonged periods of comparatively high plasma levels of drug, which appeared to be determined primarily by reduced drug clearance. We conclude that suramin has potential activity in platinum-resistant ovarian cancer, and we have initiated a second clinical trial using pharmacological information derived from this study.

Adult↗

PubMed1992

Therapy of patients with metastatic breast cancer with 5-fluorouracil, leucovorin and carboplatin.

Thirty-four women with metastatic breast cancer were treated at the National Cancer Institute of the National Institutes of Health, with a regimen of leucovorin (L), 500 mg/m2 i.v. over 30 min, followed in 1 h by 5-fluorouracil (5-FU), 375 mg/m2 i.v. bolus on days 1-5, and carboplatin (CBDCA), 50-100 mg/m2 i.v. bolus on days 2-4, every 28 days. All patients had received previous combination chemotherapy with at least one regimen (29 patients with 5-FU-containing regimens). CBDCA, 100 mg/m2 on days 2-4, resulted in grade 4 neutropenia in 10 out of 11 patients associated with sepsis in all 10 patients. CBDCA, 75 mg/m2 (seven patients) and 50 mg/m2 (15 patients), resulted in grade 4 neutropenia in six and eight patients, and neutropenic sepsis in five and two cases, respectively. Grade 4 thrombocytopenia occurred in 10, five and two patients receiving 100, 75 and 50 mg/m2 of CBDCA, respectively. Other toxicities included grade 3/4 mucositis in 18 patients and grade 3/4 diarrhea in 10 patients. Twenty nine patients were evaluable for response, with one pathologic complete response (3%), two partial responses (6%), 18 stable disease (53%) and eight (24%) progressive disease. Sites of response included bone, viscera and soft tissue. The median time from entry on study to progression, for responders, was 15 months. When platinum-DNA adduct formation in peripheral white blood cells was analyzed in 27 patients at 24 h after drug administration, a significant correlation between adduct level and CBDCA cumulative dose was found.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗