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Biomedical subjects

M E Marshall

Publications and source records attributed to M E Marshall.

At least 37 records · Page 2Linked to original sources
PubMed1990

Treatment of hormone-refractory stage D carcinoma of prostate with coumarin (1,2-benzopyrone) and cimetidine: a pilot study.

The combination of coumarin (1,2-benzopyrone) and cimetidine has been reported to render objective tumor regressions among patients with metastatic renal cell carcinoma and malignant melanoma. Subsequently, a pilot trial was conducted to evaluate this regimen for the treatment of stage D hormone-refractory carcinoma of the prostate. Patients received coumarin 100 mg orally as a single daily dose for 14 days; on day 15 cimetidine 300 mg four times daily was added, and both drugs were continued until progression of disease. Fourteen patients with advanced prostate cancer were treated. Nine patients had evaluable disease only, whereas five patients had both measurable and evaluable disease. All patients had bone metastases. Although there was no objective evidence of tumor regression, three patients (with evaluable disease only) experienced significant improvement in bone pain with decreased analgesic use that persisted until disease progression at 3, 5.5+, and 9 months. Although coumarin caused no symptomatic or organ dysfunction toxicity, one elderly patient experienced reversible mental confusion from cimetidine. Coumarin and cimetidine, at the dose and schedule described, are not effective for the treatment of advanced prostate cancer. However, the results of laboratory investigations suggest that further clinical trials of coumarin, at higher doses, may be warranted for the treatment of this disease.

Aged↗
PubMed1990

Low incidence of asymptomatic brain metastases in patients with renal cell carcinoma.

Brain metastases from renal cell carcinoma are uncommon. The present study was undertaken to determine the value of routine computerized tomographic (CT) scanning of the brain in patients with renal cell carcinoma. A review of 106 patients with renal cell carcinoma who had undergone CT scan of the brain revealed brain metastases in only 13.2 percent. Brain metastases were accompanied by central nervous system (CNS) symptoms in 78.6 percent of patients, with headaches constituting the most common presenting symptom (64.3%). Brain metastases were detected in only 3.3 percent of patients who had no CNS symptoms at the time of evaluation. It is concluded that CT scanning of the brain should be performed routinely only for those patients who report CNS symptoms at the time of evaluation.

Adult↗
PubMed1990

Human recombinant interleukin-2 provokes acute pulmonary vascular endothelial injury in rabbits.

Human recombinant interleukin-2 (rIL-2), with or without lymphokine-activated killer cells, has been shown to mediate tumor regressions in animals and in humans. A well-recognized adverse effect of rIL-2 is the development of a generalized vascular leak syndrome that involves the pulmonary microvasculature. We present a rabbit model for the study of rIL-2 pulmonary toxicity that closely reflects the human situation. Rabbits were treated with rIL-2 (Cetus) by two dose/schedule schemata. Separate control groups received rIL-2 excipient (Cetus) or 5% dextrose in water (D5W). In a short-term model, animals were treated with 10(6) Cetus units of rIL-2 in five bolus injections of 200,000 Cetus units each. In a long-term model, rabbits were treated with 3 (x) 10(6) Cetus units/kg of rIL-2 daily in three divided doses every 8 h for 9-11 doses (a schedule analogous to one used in human trials). Following treatment, animals were killed and examined for evidence of pulmonary toxicity. Among the treatment and control groups, there was no evidence of pulmonary leukostasis as determined by mean alveolar septal wall granulocytes per high power field or mean lung myeloperoxidase activity per gram of tissue. While there were no differences among the three treatment groups with regard to pulmonary edema formation (wet/dry weights), there was a tendency toward statistically significant differences between the rIL-2 and control groups. Pulmonary vascular permeability was assessed using i.v.-administered [125I]rabbit serum albumin (RSA) and expressed as mean bronchoalveolar lavage fluid/plasma [125I]RSA ratios. The rIL-2-treated animals had significantly increased pulmonary extravasation of [125I]RSA compared to controls, but there were no differences between the excipient- and D5W-treated controls. Lungs from rIL-2-treated (but not controls) animals displayed marked ultrastructural changes by electron microscopy in the arteriolar segment to include intracellular and subcellular blebs throughout the arteriole with separation of endothelial cells from basement membrane, interstitial edema, endothelial adhesion, and transmigration of lymphocytes into interstitium. Immunoperoxidase stains using an antirabbit T-cell monoclonal antibody demonstrated significant T-cell infiltration into the pulmonary interstitium of rIL-2-treated animals compared to controls. The long-term treatment model described appears to be highly suited for studies of rIL-2-induced pulmonary toxicity.

Animals↗
PubMed1990

Human recombinant interleukin-2 provokes infiltration of lymphocytes into myocardium and liver in rabbits.

Treatment with human recombinant interleukin-2 (rIL-2) is associated with multiple organ dysfunctions, including hepatic and cardiac toxicities. We present a rabbit model that may be highly suited to investigations of these organ toxicities. Rabbits were treated with rIL-2 at a dose of 3 x 10(6) Cetus units/kg/day in divided doses every 8 h for 9-11 doses. Control animals received either excipient or 5% dextrose in water. Treatment with rIL-2 resulted in hepatic and myocardial infiltration by lymphocytes and mononuclear cells. Monoclonal antibody-staining techniques revealed a high percentage of T lymphocytes. It remains to be shown whether these infiltrates are responsible for the respective organ toxicities or represent merely an epiphenomenon of rIL-2 treatment.

Animals↗
PubMed1989

Treatment of advanced malignant melanoma with coumarin and cimetidine: a pilot study.

Based on previous results demonstrating that coumarin and cimetidine render objective tumor regressions in renal cell carcinoma, we conducted a pilot study to determine whether these drugs possess activity against malignant melanoma. A total of 22 patients with advanced melanoma received 100 mg coumarin p.o. daily for 14 days; on day 15, cimetidine was added at an oral dose of 300 mg four times daily. Both drugs were continued until progression of disease. In all, 12 patients had previously been treated, but all patients had a favorable performance status. No response was observed in 19 patients. Two patients with a low tumor burden achieved a partial response and a third showed a minor response. There was no toxicity from this regimen. Although coumarin and cimetidine at this dose and schedule did not display significant activity in this study population, further studies are warranted to explore higher doses and focus on patients with relatively low tumor burdens.

Adult↗
PubMed1989

Effects of theophylline on human natural killer cells.

Theophylline has been shown previously to inhibit a number of cellular immune functions of granulocytes and T-lymphocytes. In the present report, we demonstrate that theophylline, in a dose-dependent fashion, suppresses human natural killer (NK) cell activity in vitro. To determine if theophylline produces quantitative or qualitative alterations in NK cells in vivo we quantitated peripheral blood NK cells with three monoclonal antibodies and FACS analysis and measured NK cytolytic activity in eight normal volunteers who took theophylline for eight days. No change was noted in the number of cytolytic activity of NK cells over the eight days of monitoring. We conclude that theophylline does not alter NK cells in vivo when given in therapeutic doses.

Adult↗
PubMed1989

Toxicity of coumarin (1,2-benzopyrone) on human peripheral blood mononuclear cells and human and murine bone marrow progenitor stem cells.

Coumarin (1,2-benzopyrone), in combination with cimetidine, has been subjected to separate clinical trials for the treatment of advanced renal cell carcinoma, malignant melanoma, and non-small cell lung cancer. While objective tumor regressions were observed only in renal carcinoma, no symptomatic or organ dysfunction toxicity was observed in any of the trials. The purpose of the present in vitro study was to determine the concentrations of coumarin and 7-hydroxycoumarin (7-HC) that would be toxic to human peripheral blood mononuclear cells (PB-MNC) and human and murine bone marrow (GM) progenitor stem cells. Coumarin was nontoxic for PB-MNC in concentrations up to 100 micrograms/ml. Concentrations of coumarin or 7-HC greater than or equal to 200 micrograms/ml produced significant suppression of human marrow GM stem cell activity. Coumarin greater than or equal to 25 micrograms/ml produced suppression of murine marrow GM stem cell activity. Differences in human and murine marrow sensitivity probably reflect interspecies differences in metabolism of coumarin. Correlations between toxic concentrations in vitro and maximally achievable serum concentration in vivo in humans await the results of further clinical trials.

Animals↗
PubMed1989

Treatment of renal cell carcinoma with daily low-dose alpha-interferon.

While alpha-interferon has yielded objective tumor regressions in patients with metastatic renal cell carcinoma, such therapy is usually associated with significant toxicity often requiring dose modifications and/or cessation of therapy. In the absence of a clearly defined optimal dose and schedule for alpha-interferon, it appears reasonable to seek a means for improving the therapeutic index for this drug. We report the results of a pilot trial in which patients with renal cell carcinoma were treated with a daily low dose of alpha-interferon. Seventeen patients were treated with alpha-interferon (Roferon-A) at a dose of 1 million U subcutaneously daily. There were no exclusionary criteria for this pilot trial. Sixteen patients were evaluable for response and toxicity. Therapy was well-tolerated with no interruption of therapy for toxicity. No patient experienced the "flu-like" syndrome that is associated with higher doses, and there was no episode of granulocytopenia or thrombocytopenia. Four patients achieved a partial response (PR), with one PR persisting at 20 months. Sites of response included lung (two patients), liver (one patient), and bone (one patient). These results indicate that this regimen is well tolerated and can be expected to render objective responses. Formal Phase II trials are warranted in order to define the response rate for this regimen.

Aged↗
PubMed1989

Effects of coumarin (1,2-benzopyrone) and cimetidine on peripheral blood lymphocytes, natural killer cells, and monocytes in patients with advanced malignancies.

The combination of coumarin and cimetidine has yielded objective tumor regressions in patients with metastatic renal cell carcinoma and malignant melanoma. While the mechanism of action of cimetidine appears to be immunomodulatory, coumarin appears to have direct effects on tumor cells as well as immunomodulatory activity. We utilized monoclonal antibody labeling techniques to monitor peripheral blood lymphocyte, natural killer (NK) cell, and monocyte phenotypes in patients treated with coumarin and cimetidine. Patients received coumarin 100 mg orally daily for 14 days; on day 15 cimetidine 300 mg four times daily was added and both drugs were continued until disease progression. Studies were performed pre treatment and at 2, 4, and 8 weeks on therapy. There were no alterations in T-cells, helper/inducer T-cells, cytotoxic/suppressor T-cells, B-cells, Ia + lymphocytes, or NK cells. However, an increase was noted by 2 weeks on therapy in the percentage of monocytes and the percentage of DR+ monocytes. This change in the monocyte population occurred in the presence of coumarin alone, before the institution of cimetidine. While this treatment appears to increase DR expression by monocytes, further studies with larger numbers of patients are needed to determine if this observed change is related to antitumor response.

Adult↗
PubMed1989

Effects of coumarin (1,2-benzopyrone) on lymphocyte, natural killer cell, and monocyte functions in vitro.

We have demonstrated in a pilot study that the combination of coumarin (1,2-benzopyrone) and cimetidine is capable of producing objective antitumor responses in patients with advanced renal cell carcinoma. In a previous study, we used monoclonal antibody labeling techniques to monitor peripheral blood lymphocytes and monocytes in patients with advanced malignancies treated with coumarin and cimetidine. While there was no quantitative alteration in T-lymphocytes, B-lymphocytes, natural killer (NK) cells, or cells bearing Ia antigen, there was an increase in the percentage of CD-14 (M5E2+) monocytes and DR+ monocytes by 2 weeks on therapy that persisted over the 8 weeks of monitoring. Because patients received coumarin for 2 weeks prior to institution of cimetidine, these changes were attributed to coumarin. In this report, we present the results of in vitro studies designed to determine if coumarin alters the functional properties of normal peripheral blood lymphocytes, NK cells, or monocytes. In a standard NK cytolytic assay, coumarin failed to produce any significant alteration in NK activity against K562, ACHN, or Caki-2 cell lines. Coumarin did produce an augmentation of lymphocyte mitogenic response to phytahemagglutinin but not to concanavalin A or pokeweed mitogen. Coumarin produced a modest suppression of superoxide anion and hydrogen peroxide generation by monocytes but not by macrophages. The effect of coumarin on antigen processing of tetanus toxoid by macrophages was examined using normal donor cells. While an augmentation of antigen processing was noted in some normal donors, this was an inconsistent and inconclusive finding. Further studies are required to define the precise effects of coumarin on immune cell populations from both normal subjects and cancer patients.

Antigens↗
PubMed1987

Treatment of metastatic renal cell carcinoma with coumarin (1,2-benzopyrone) and cimetidine: a pilot study.

Forty-five patients with metastatic renal cell carcinoma were treated with coumarin (1,2-benzopyrone) and cimetidine. Patients received coumarin, 100 mg orally daily; cimetidine administration, 300 mg orally four times daily, was initiated on day 15 of therapy, and treatment with both drugs was continued until progression of disease. Three patients are too early to evaluate (on study less than or equal to 2 months with no change in tumor status). Objective responses (greater than or equal to 50% reduction in measurable disease) occurred in 14 of 42 evaluable patients (33.3%) (the 95% confidence interval based on this rate is +/- 14.3%), with three complete responses and 11 partial responses (PR). Complete responses lasted 9.5, 4+, and 9.5+ months. The median duration of response for the PR group was 5 months (range, 4 to 21+ months). Twelve patients experienced stabilization of disease ranging from 4 to 16.5+ months. No response was seen in 16 patients. There was no symptomatic, hematologic, or chemical (organ dysfunction) toxicity among the 45 patients treated. Coumarin and cimetidine appear to be safe and active agents in the treatment of metastatic renal carcinoma. Further studies are required to determine the optimal dose and scheduling of these agents.

Adult↗
PubMed1986

Malignant melanoma in multiple endocrine neoplasia.

Because of its neurocrest APUD origin, malignant melanoma has been postulated to be a component of the multiple endocrine neoplasia (MEN) syndromes; however, such a case has not been previously described. Prior associations of melanocytes with the MEN syndromes have been confined to hyperplasia. This report describes the first case of malignant melanoma occurring in a patient with the MEN IIA syndrome (bilateral pheochromocytomas and medullary thyroid carcinoma). The role of melanocytic hyperplasia and neoplasia within the MEN syndromes is discussed.

Female↗
PubMed1986

Hemopoietic marrow function in chronic neutropenia of blacks: cure of aplastic anemia by allogeneic marrow transplantation from a neutropenic sibling donor.

A black patient with severe aplastic anemia is described who underwent successful bone marrow transplantation from a sibling with chronic neutropenia. During an evaluation to identify a suitable donor, it was found that the majority of family members tested had neutropenia, with no familial history of significant infections or related hospitalizations. In vitro hemopoietic culture studies of marrow from the patient's HLA-MLC-matched siblings showed normal numbers of pluripotential and committed hemopoietic progenitors; in vitro hemopoietic colony formation from the patient was markedly subnormal, consistent with the clinical picture of severe aplastic anemia. Following appropriate conditioning therapy, marrow transplanted from one of these neutropenic sibs produced full hematopoietic reconstitution. Posttransplant marrow culture studies of the patient showed restoration of a normal pattern of in vitro hemopoiesis. The in vitro culture studies and clinical experience in this patient support the concept that chronic neutropenia of blacks is not primarily a marrow progenitor cell disorder but, more likely, a manifestation of a genetically determined alteration in granulocyte kinetics.

Adult↗