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E Reed

Publications and source records attributed to E Reed.

At least 109 records · Page 6Linked to original sources

Plasma protein binding of phenylacetate and phenylbutyrate, two novel antineoplastic agents.

Phenylacetate and phenylbutyrate, two novel inducers of tumor cytostasis and differentiation, are currently in clinical trials for the treatment of cancer in adults. The purpose of our study was to evaluate the plasma protein-binding characteristics of phenylacetate and phenylbutyrate in the plasma of normal volunteers and that of patients with cancer. Drug plasma protein-binding analysis was examined using three separate devices: a micropartition system and two equilibrium dialysis systems, all of which exhibited similar results. Phenylacetate and phenylbutyrate concentrations were determined by high-performance liquid chromatography. Both drugs exhibited concentration-dependent binding. Our results showed sodium phenylacetate to have a higher free fraction than sodium phenylbutyrate at corresponding concentrations (> 0.442 +/- 0.008 and > 0.188 +/- 0.001, respectively). Plasma pH did not greatly affect protein binding of either drug. As albumin concentration decreased, an increase in free fraction of both drugs was observed, however alpha 1-acid glyco-protein showed no change in free fraction as its concentration increased. Patients with cancer with lower levels of albumin showed an increase in free fraction with both phenylacetate and phenylbutyrate. When phenylacetate and phenylbutyrate were added together in plasma, the free fraction of phenylacetate increased, whereas the phenylbutyrate free fraction slightly decreased. We conclude that phenylacetate and phenylbutyrate have high free fractions that change with varying albumin levels and when both phenylacetate and phenylbutyrate are present together in plasma.

Adult↗

Lack of correlation between prostate-specific antigen and the presence of measurable soft tissue metastases in hormone-refractory prostate cancer.

Appropriate staging procedures for patients with hormone-refractory prostate cancer are poorly defined. In particular, there are no studies correlating prostate-specific antigen (PSA) with more traditional methods of staging. We have evaluated the abdominal/pelvic CT scan, bone scan, and PSA results following initial diagnosis of hormone-refractory prostate cancer in 177 consecutive patients (median age = 63.1 years, range 45-80). Thirty-four patients (19.2%) had measurable lesions (> or = 2 cm) on CT scan compatible with metastatic disease. Of the patients with measurable lesions, 29/34 (85.3%) had retroperitoneal and/or pelvic adenopathy; 5 patients (14.7%) had measurable lesions in the liver. Other sites of metastatic disease were detected in less than 1% of the patients receiving scans. All patients had bone scan abnormalities compatible with metastatic disease. Results of these imaging studies were then compared to PSA serum concentration (Abbott IMx). The mean PSA concentration was not different in those patients with soft tissue disease as compared to those without soft tissue involvement and there was no correlation between PSA concentration and the presence or absence of measurable soft tissue disease. In contrast to previously published studies in hormone-naïve prostate cancer patients, these studies in hormone-refractory patients indicate that the detection of metastatic disease by standard radiological procedures cannot be predicted by measurement of serum PSA.

Abdominal Neoplasms↗

Closing Remarks.

About twenty years ago, the leaders of the National Cancer Institute (NCI) decided to start a new branch in the Clinical Oncology Program of the Division of Cancer Treatment. That new entity was named the Clinical Pharmacology Branch (CPB), and its first leader was a brilliant, young, promising investigator named Bruce A. Chabner. Chabner was educated at Yale and Harvard, and appeared to have an extraordinary grasp of novel concepts that were being developed in the emerging area of cancer chemotherapy. What the NCI leaders did not fully appreciate at the time was that they had just given birth to one of the most extraordinary careers in academic medicine. From the early seventies through the early eighties, Bruce Chabner developed a strong laboratory program that was based on scientific discovery and on the development of new talent. The CPB focused on new drug development, elucidation of drug mechanism(s) of action, and the development of new ways to use drugs that were already available. Concurrent with this laboratory effort was active participation in the development of clinical treatment regimens for Hodgkin's disease, non-Hodgkin's lymphoma, and other malignancies. Individuals who trained under Chabner are now cancer center directors, department heads, laboratory chiefs, and hold many other high-profile positions. From 1981 to 1995 Bruce Chabner was Director of the Division of Cancer Treatment (DCT) of the NCI. In that capacity he was Scientific Director of the Intramural Program within DCT, and he had oversight responsibility for the direction of extramural studies that were funded through the NCI, which were focused on the development of new treatments for human malignant disease. The NCI has five divisions for which the NCI Director has ultimate responsibility. While working with one NCI Director from 1981 to 1988, and with another from 1988 to 1995, and during the transition year of 1988, Bruce Chabner provided stability for the DCT while many changes were occurring throughout the five divisions of the NCI. How does one assess the impact of a career on a discipline such as cancer treatment? It's not easy! Each of the articles contributed to this tribute were written by a person who trained directly with Bruce Chabner, or was otherwise directly impacted by Bruce's guidance. As can be seen from the list of contributors to these Proceedings, each individual has made major contributions to the area of cancer treatment in his or her own right. However, Bruce's contribution to cancer treatment goes far beyond the individuals he trained. The many thousands of human lives who have benefited from his efforts cannot be accurately estimated, because his contributions have been so wide-ranging, as indicated below. Being "Scientific Director" is similar in a number of ways to being a football quarterback. One of those ways is that when things go well the quarterback may get a little too much credit, and when things go not-so-well the quarterback may get too much blame. However, it is the quarterback who "calls the plays." With that in mind, a partial list of the accomplishments of the Intramural Program of the DCT while Bruce Chabner was "quarterback" includes the following: * The first human retroviruses, HTLV-1 and HTLV-2, were discovered and shown to be directly linked to the development of specific human malignancies. * Adoptive immunotherapy for human cancer was developed, offering exciting new additions to the anticancer armamentarium. * Paclitaxel (Taxol®) was developed, and shown to be the most important new anticancer agent in the past two decades. * The human genes responsible for the development of several specific malignancies were discovered, such as those for kidney cancer. * Development of blood tests to detect HIV-tainted blood. * Treatment strategies for pediatric AIDS were developed. * The AIDS Drug Development Program within the NIH was established. * New drugs for the treatment of AIDS and AIDS-related conditions were developed. * The only three drugs to date that have been specifically approved for the treatment of AIDS-AZT, DDI, and DDC-were developed under the guidance of the DCT, with Bruce Chabner as Scientific Director. * The first clinical trials conducted with each of these agents-AZT, DDI, and DDC-were performed in the Intramural Program of the DCT. * Concurrently, many of the exciting findings reported by the National Surgical Adjuvant Breast and Bowel Project over the past 10 years (as well as other cooperative groups) were a direct result of the strong support shown by Bruce Chabner during his tenure as Director of the Division of Cancer Treatment. Further, the list above does not include his personal labortory and clinical accomplishments, some of which are: * Development of the principles of use of important antimetabolites, such as methotrexate. * Elucidation of biochemical pathways affected, and the mechanisms of action, of antifols and other antimetabolites. * The conduct of seminal studies in the clinical staging of non-Hodgkin's lymphomas, using laparoscopy as a primary tool. * Important contributions to the development of multiagent regimens in the clinical treatment of lymphomas, and of Hodgkin's disease. * Developed and is editor of the textbook which is considered to be the primary reference source for anticancer chemotherapeutic agents [1]. With all of these accomplishments, his career is long from over. Having just become the Medical Director of the Cancer Center at the Massachusetts General Hospital, Bruce Chabner is uniquely poised to have an even more far-reaching impact on a discipline in which he has played such a strong seminal role. This author was never a postdoctoral fellow in Bruce Chabner's laboratory. However, more than any other single person, he has played a central role in my professional development. I know of many others for whom the same statement would be true. It is a pleasure for me to witness the launching of the second phase of an already tremendous career. From Advances in Cancer Treatment: The Chabner Symposium. Stem Cells 1996;14:64-65.

Journal Article↗

Cisplatin.

Explore the source record for details and available documents.

Animals↗

Paclitaxel dose intensity.

Paclitaxel is effective in the treatment of cancer of the ovary and cancer of the breast, as well as other malignancies. We have analyzed available phase II data in these two diseases, to assess the possibility that paclitaxel dose intensity may be important in the induction of disease response. When analyzed by the methods developed by Hrynuik and Levin, available data suggest that the relationship between objective disease response and paclitaxel dose intensity in recurrent cancer of the ovary is strongly statistically significant with a two-sided p value of 0.022. Available data suggest that the relationship in breast cancer is even stronger, with a two-sided p value of 0.004. In both diseases, optimal results have been observed at the dose schedule of 250 mg/m2/21 days, given as a 24 hour IV infusion. We have also performed an analysis comparing the only two prospective randomized studies that examined the potential role of dose intensity for this drug in cancer of the ovary. At 135 mg/m2/21 days, the objective response rate was 13.2%; and at 250 mg/m2/21 days, the objective response rate was 35.9%. The response rate seen at the intermediate dose of 175 were intermediate to 135 and 250; and linear regression analysis shows a correlation coefficient for these data of 0.946. Since flexible cytokine support may be essential in maintaining paclitaxel dose intensity, we have also discussed this approach as well as the paclitaxel dosing strategy that is associated with optimal clinical results in recurrent cancer of the ovary.

Antineoplastic Agents, Phytogenic↗

Phase I study of lovastatin, an inhibitor of the mevalonate pathway, in patients with cancer.

Lovastatin, an inhibitor of the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase (the major regulatory enzyme of the mevalonate pathway of cholesterol synthesis), displays antitumor activity in experimental models. We therefore conducted a Phase I trial to characterize the tolerability of lovastatin administered at progressively higher doses to cancer patients. From January 1992 to July 1994, 88 patients with solid tumors (median age, 57 +/- 14 years) were treated p.o. with 7-day courses of lovastatin given monthly at doses ranging from 2 to 45 mg/kg/day. The inhibitory effects of lovastatin were monitored through serum concentrations of cholesterol and ubiquinone, two end products of the mevalonate pathway. Concentrations of lovastatin and its active metabolites were also determined, by bioassay, in the serum of selected patients. Cyclical treatment with lovastatin markedly inhibited the mevalonate pathway, evidenced by reductions in both cholesterol and ubiquinone concentrations, by up to 43 and 49% of pretreatment values, respectively. The effect was transient, however, and its magnitude appeared to be dose independent. Drug concentrations reached up to 3.9 micrometer and were in the range associated with antiproliferative activity in vitro. Myopathy was the dose-limiting toxicity. Other toxicities included nausea, diarrhea, and fatigue. Treatment with ubiquinone was associated with reversal of lovastatin-induced myopathy, and its prophylactic administration prevented the development of this toxicity in a cohort of 56 patients. One minor response was documented in a patient with recurrent high-grade glioma. Lovastatin given p.o. at a dose of 25 mg/kg daily for 7 consecutive days is well tolerated. The occurrence of myopathy, the dose-limiting toxicity, can be prevented by ubiquinone supplementation. To improve on the transient inhibitory activity of this dosing regimen on the mevalonate pathway, alternative schedules based on uninterrupted administration of lovastatin should also be studied.

Adult↗

A phase I study of the somatostatin analogue somatuline in patients with metastatic hormone-refractory prostate cancer.

BACKGROUND: Somatuline, a somatostatin analogue, has proven to be effective in several animal models of prostate cancer. Preliminary clinical studies also have suggested antitumor activity in patients with prostate cancer. The authors conducted a dose-escalation trial of 25 patients with metastatic hormone-refractory prostate cancer. METHODS: Dosages of 4, 7, 10, 13, 18, and 24 mg/day were administered by continuous intravenous infusion for at least 28 days. RESULTS: Plasma levels of insulin-like growth factor-I (IGF-I), but not those of IGF-II, declined modestly during therapy. Toxicities included grade I diarrhea, bloating, infection, nausea, and flatus. The gastrointestinal side effects were typically self-limiting and occurred during the initial portion of treatment cycles. In addition, three patients experienced grade II catheter-related infections. No clinical response was noted by either radiographic or tumor marker criteria. The maximally tolerated dose of somatuline was not determined. CONCLUSION: A continuous intravenous infusion of 24 mg/day of somatuline is well tolerated and could be evaluated in other types of cancer or possibly in less advanced prostate cancer, but no clinical activity was noted at this dose in patients with advanced metastatic hormone-refractory prostate cancer.

Aged↗

Malignant and nonmalignant brain tissues differ in their messenger RNA expression patterns for ERCC1 and ERCC2.

Perturbation of the DNA repair process appears to be responsible for the occurrence of a number of human diseases, which are usually associated with a propensity to develop internal malignancies and/or disorders of the central nervous system. We have been interested in the possibility that a subtle abnormality in DNA repair competency might be associated with the transformation of nonmalignant cells to the malignant state. To study this question, we assayed malignant and nonmalignant brain tissues from 19 individuals for mRNA expression levels of the human DNA repair genes ERCC1, ERCC2, and XPAC and for differential splicing of the ERCC1 transcript. We separately compared expression levels of these genes in the following situations: concordance of expression within malignant tissues; concordance of expression within nonmalignant tissues; concordance between malignant and nonmalignant tissues within individuals of the cohort; and concordance of gene expression between two nonmalignant tissue sites within a single individual. Linear regression analyses of mRNA values obtained suggested orderly concordance of these three DNA repair genes in nonmalignant tissues within the patient cohort and an excellent concordance of these genes between two separate biopsy sites from the same individual. In contrast, malignant tissues showed disruption of concordance between the full-length ERCC1 transcript and ERCC2, which have excision and helicase functions, respectively. Furthermore, within the same individuals, malignant tissues were discordant with nonmalignant tissues for ERCC1 and ERCC2, although concordance for XPAC was preserved. These data suggest that one molecular characteristic of human malignancy may be the disruption of the normal relationship between the excision and the helicase functions of the nucleotide excision repair pathway.

Brain↗

Effect of cadmium on human ovarian cancer cells with acquired cisplatin resistance.

Cadmium (Cd) dichloride is a compound that has teratogenic, mutagenic, and carcinogenic properties. Recent reports have suggested the possibility that this compound may also have tumor suppressive properties in some settings. For these reasons, we have studied the subcellular pharmacological profile of elemental cadmium in human ovarian cancer cells, when administered as cadmium dichloride. The cell lines A2780 and A2780/CP70 were used, which are well characterized with respect to their cellular response to platinum-based compounds. Cd was measured in all experiments with the use of atomic absorbance spectrometry with Zeeman background correction. In both cell lines, there were direct relationships between; drug dose and cellular accumulation of drug; cellular accumulation of drug and DNA damage levels; and DNA damage levels and cytotoxicity. These cell lines differed in that the cisplatin-resistant A2780/CP70 cell line, was also comparatively resistant to cadmium dichloride. This enhanced cellular resistance appeared to be mediated through decreased drug accumulation, and increased cellular tolerance to higher levels of DNA damage. Total genomic DNA repair and cytosolic inactivation of drug appeared not to differ substantively between these two cell lines.

Cadmium↗

Family-environment risk factors for attention-deficit hyperactivity disorder. A test of Rutter's indicators of adversity.

BACKGROUND: This study investigated whether family-environment risk factors are associated with attention-deficit hyperactivity disorder (ADHD). Compelling work by Rutter and coworkers revealed that it was the aggregate of adversity factors (severe marital discord, low social class, large family size, paternal criminality, maternal mental disorder, and foster care placement) rather than the presence of any single factor that led to impaired development. Based on the work of Rutter, we hypothesized a positive association between indicators of adversity and the diagnosis of ADHD and ADHD-associated impairments. METHODS: We studied 140 ADHD and 120 normal control probands. Subjects were non-Hispanic white boys between the ages of 6 and 17 years. Rutter's indicators of adversity were used to predict ADHD-related psychopathology as well as impaired cognitive and psychosocial functioning. RESULTS: The odds ratio for the diagnosis of ADHD increased as the number of Rutter's adversity index predicted ADHD-related psychopathology (depression, anxiety, and conduct disorder), learning disabilities, cognitive impairment, and psychosocial dysfunction. CONCLUSIONS: A positive association appears to exist between adversity indicators and the risk for ADHD as well as for its associated psychiatric, cognitive, and psychosocial impairments. These findings support the work of Rutter and stress the importance of adverse family-environment variables as risk factors for children with ADHD.

Adolescent↗

Cutaneous manifestations of Taxol therapy.

Taxol is a novel chemotherapeutic agent that has produced substantial responses in early clinical studies [1]. Taxol has excellent activity in a number of malignancies based on recently completed clinical trials, including a 30% response rate in platinum-refractory ovarian cancer patients [2-5]. We are currently conducting trials of dose-intense taxol with granulocyte colony stimulating factor (G-CSF) support in relapsed or refractory ovarian cancer patients. Such dose intensification produces a major response rate in 50% of patients with this disease [6]. Taxol was supplied in 5 ml ampules (6 mg/ml) in polyethoxylated castor oil (Cremophor EL) 50% and dehydrated alcohol and the dose was diluted in either 0.9% sodium chloride or 5% dextrose at concentrations of 0.6 to 1.2 mg/ml. We have noted 3 patients with previously unreported cutaneous manifestations which we believe are taxol related and also report our overall complication rate with the administration of taxol by peripheral intravenous lines.

Antineoplastic Agents, Phytogenic↗

Genomic copy number changes of DNA repair genes ERCC1 and ERCC2 in human gliomas.

Abnormalities of the genomic region of chromosome 19q13.2-13.4 are a common occurrence in brain malignancies and contain a possible tumor suppressor gene involved in gliomas. Since abnormalities of DNA repair are associated with malignancy, we assessed DNA status of the nucleotide excision repair genes located in this area, viz. ERCC1 and ERCC2. Radiodensitometry was used to assess gene copy number in samples obtained from brain tumor specimens from 24 patients. Nine tumors were of lower grade histology (3 pilocytic astrocytomas, 2 gangliogliomas, 4 astrocytomas); 15 tumors were pathologically higher grade (4 anaplastic astrocytomas, 11 glioblastomas). Tumor samples were obtained prior to radiation or chemotherapy. Abnormalities of gene copy number of ERCC1 and ERCC2 were observed in 11/24 specimens (46%). Whereas increased and decreased copy numbers were observed for ERCC1, only decreases in copy number of ERCC2 were seen. Three tumors (all lower grade) showed concurrent allelic loss of ERCC1 and ERCC2. Abnormalities of copy number for these genes were not associated with response to subsequent therapy nor survival. However, allelic loss of ERCC2 was associated with younger age at diagnosis when compared to those specimens which did not show loss. There were no significant differences between lower grade and higher grade tumors with respect to these investigations. Abnormalities in copy number of ERCC1 and ERCC2 are common in glial tumors. Further study of this genomic region is necessary to define the importance of these observations in tumor pathophysiology and treatment.

Adult↗

Impact of adversity on functioning and comorbidity in children with attention-deficit hyperactivity disorder.

OBJECTIVE: Prior research on risk factors for attention-deficit hyperactivity disorder (ADHD) has shown that familial risk factors play a role in the disorder's etiology. This study investigated whether features of the family environment were associated with ADHD. METHOD: One hundred forty children with ADHD and 120 normal control probands were studied. Subjects were Caucasian, non-Hispanic males between the ages of 6 and 17 years. Exposure to parental psychopathology and exposure to parental conflict were used as indicators of adversity, and their impact on ADHD and ADHD-related psychopathology and dysfunction in children was assessed. RESULTS: Increased levels of environmental adversity were found among ADHD compared with control probands. The analyses showed significant associations between the index of parental conflict and several of the measures of psychopathology and psychosocial functioning in the children. In contrast, the index of exposure to parental psychopathology had a much narrower impact, affecting primarily the child's use of leisure time and externalizing symptoms. CONCLUSIONS: A relationship appears to exist between adversity indicators and the risk for ADHD as well as for its associated impairments in multiple domains. These findings confirm previous work and stress the importance of adverse family-environment variables as risk factors for children who have ADHD.

Achievement↗

Volumetric bone mineral density--a potential role in paediatrics.

The use of areal bone mineral density (aBMD) in paediatric populations has aroused some concern, as it fails to take the age-related increase in bone thickness into account. We have developed a measure of true bone density, volumetric bone mineral density (vBMD), which is independent of age and height. In order to examine the relationship between growth parameters, aBMD and vBMD, we studied patients with phenylketonuria (PKU, n = 40), chronic renal failure (CRF, n = 27) and chronic asthma (n = 19). aBMD of the femoral neck and the mid-femoral shaft was measured using dual energy X-ray absorptiometry (DXA), vBMD was calculated on the basis of values of bone mineral content and bone dimension provided by DXA, with the assumption that both sites are cylinders. aBMD and vBMD were then compared with the normal reference, expressed as a standard deviation score (SDS). aBMD and vBMD were normal in the femoral neck region of the PKU group, but aBMD, either standardized for age or for height, was low in the femoral shaft region (p < 0.01). In the CRF group, profound growth retardation was seen (mean height SDS, -3.2) and aBMD and vBMD were both low in the femoral shaft region but not in the femoral neck. In the asthma group, aBMD for age was low at both sites, but vBMD did not differ from that seen in normal individuals. We conclude that the true vBMD provides a different interpretation of bone density compared with aBMD and requires further evaluation in paediatrics because of its age and height independence.

Absorptiometry, Photon↗