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Biomedical subjects

B G Durie

Publications and source records attributed to B G Durie.

At least 19 recordsLinked to original sources
PubMed1992

Modulation of multidrug-resistant multiple myeloma by cyclosporin. The Leukaemia Group of the EORTC and the HOVON.

Resistance to chemotherapy in refractory multiple myeloma is frequently associated with expression of multidrug resistance (MDR). In resistant cells, intracellular accumulation of doxorubicin and vincristine does not occur because the MDR-1 gene product, a membrane glycoprotein (PgP), is an energy-dependent efflux pump. Cyclosporin is one of several non-cytotoxic drugs that can block the function of PgP. In a prospective study, we assessed the possibility that cyclosporin could be used clinically to modulate MDR. We studied 21 patients with multiple myeloma; disease had progressed during primary chemotherapy in 6 and was resistant to VAD (vincristine, doxorubicin, dexamethasone) in 15. The patients received cyclosporin by continuous infusion during VAD treatment; there were three cyclosporin dosage groups (5, 7.5, 10 mg/kg daily). Serum cyclosporin concentrations adequate for MDR modulation were reached in all patients receiving 7.5 or 10 mg/kg daily. 47% (7) of the VAD-refractory patients and 48% (10) of the whole group responded to VAD. Before treatment, MDR-1 expression was present in 12 patients. After VAD plus cyclosporin, no MDR-1-positive plasma cells were present in 6 of 8 patients tested. The response rate in MDR-1-positive patients was 58% compared with 33% in all our patients. Toxic effects were mild and reversible and did not include nephrotoxic or serious cardiovascular side-effects. 12 months after the start of treatment, survival was 85%, and disease-free survival at a median of 9 months after the response was 65%. Thus, in multiple myeloma clinical resistance to VAD can be circumvented by cyclosporin, which enables the cytotoxic drugs to eliminate resistant myeloma cells.

Adult↗
PubMed1992

An unexpected complication following immunoadsorption with a staphylococcal protein A column.

Extracorporeal immune adsorption with staphylococcal protein A (SPA) columns can remove immune complexes and immunoglobulins in the treatment of a variety of diseases. We present the case of an elderly man with neuropathy associated with monoclonal gammopathy, treated by 3 on-line SPA procedures. At the completion of these treatments his neuropathy relapsed, progressing to near-total paralysis. Return to a baseline clinical status required several months. The reason for this severe relapse is not clear. Possible explanations include SPA activation of T-lymphocytes, with release of gamma interferon and increased antigen recognition, or removal of an antiidiotype control mechanism. We advise caution in the application of immunoadsorption to conditions in which it has not yet been evaluated.

Hereditary Sensory and Motor Neuropathy↗
PubMed1992

Multiple myeloma. New treatment options.

Before proceeding to treatment selection for multiple myeloma, it is important to exclude monoclonal gammopathy of unknown significance or any similar smouldering or indolent type of myeloma not requiring immediate chemotherapy. In patients with active myeloma, pretreatment prognostic classification is important for appropriate balancing of the risks and benefits of particular treatment options. For example, conventional chemotherapy such as melphalan/prednisone may be appropriate for an elderly patient with active stage III myeloma, whereas high dose chemotherapy with or without bone marrow transplantation or cytokine support may be considered for the patient under age 45 with even earlier stage disease. A variety of options are now available for patients with relapsing or resistant disease, particularly using agents with potential for reversal of multi-drug resistance. The use of interferon-alpha as maintenance following initial response to chemotherapy is important for prolongation of remission, duration and potentially survival. A variety of supportive measures are also helpful including the use of epoetin (erythropoietin) to improve refractory anaemia and bisphosphonates for the inhibition of ongoing bone resorption. With the availability of various treatment options, it has become important for patients to be evaluated by a specialist in the field.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1992

Cellular and molecular genetic features of myeloma and related disorders.

The last decade has seen major advances in the acquisition of knowledge concerning both the cellular and molecular genetics of multiple myeloma. Although discrete and specific changes associated with the plasma cell disorders have yet to be identified, a pattern is emerging that one can associate with the plasma cell disorders. This pattern includes the frequent involvement of chromosomes 1 and 14, and in particular presence of the 14q+ abnormality. But in addition there are typically many other numeric and/or structural changes that can, in fact, involve almost any chromosome, but particularly chromosomes 3, 5, 6, and 7, as well as 11, 14, 17, and 18. The presence of one or more unidentified marker chromosomes is also a typical feature. The ongoing challenges include identification of a crucial initial genetic change (if such exists) as well as the factors contributing to the ongoing karyotypic evaluation that results in complex karyotypes in patients with advanced disease. There is no doubt that the complex karyotypic picture contributes to the major heterogeneity of plasma cells that occurs in malignant plasma cell disorders. Karyotypic complexity underlies heterogeneity in cell morphology, surface antigen expression, response to cytokines, and a variety of other functional characteristics. The aberrant expression of antigens normally found on other hematopoietic progenitors has led to speculation about the true nature of the stem cell in myeloma. The overriding challenge, however, is to fully understand the plasma cell disorders at the molecular level. Although changes have already been noted in the functions of C-myc, the ras family of oncogenes, Bcl-2 expression, and several so called anti-oncogenes such as p53, it is likely that we have only begun to scratch the surface in the area of molecular changes. The potential for involvement at multiple molecular sites and the possibility of complex interactions between gene segments is truly overwhelming. However, it is hoped that at the molecular level a pattern will ultimately emerge. It is most interesting, as previously discussed, that there is an interplay among C-myc, N-ras, Bcl-2, and the Epstein-Barr virus in the predilection for a plasma cell phenotype. Undoubtedly there is much more to learn, and it is truly exciting to finally have some tools and probes at hand to more effectively study the genome in multiple myeloma and related disorders.

Chromosome Aberrations↗
PubMed1991

Workshop on growth factors.

The 'Workshop on Growth Factors' which took place at the Lugano Lymphoma Conference on June 8, 1990, included a presentation by Michael Sporn on the concept that loss of inhibitory control mechanisms may be important in the development and growth of human cancer. Examples illustrating this were taken from current experimental biology research into transforming growth factor beta (TGF-beta) interactions. Brian Durie presented recent data on the biology of interleukin-6 (IL-6) and its putative role in plasma cell diseases. These studies have culminated in the first clinical study of the role of an antibody to a growth factor as therapy for a human cancer (anti-IL-6 antibody as therapy for patients with myeloma). Derek Crowther presented data concerning the current clinical role of the haematopoietic growth factors in patients undergoing chemotherapy for cancer. Recent clinical research has established the role of granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) in improving the safety of high-dose or accelerated chemotherapy, and their use is associated with enhanced neutrophil recovery following ablative therapy and bone marrow rescue. This session was followed by the presentation of three papers concerning the use of G-CSF and GM-CSF in association with chemotherapy for patients with malignant lymphoma.

Animals↗
PubMed1990

Plasma cells in multiple myeloma express a natural killer cell-associated antigen: CD56 (NKH-1; Leu-19).

Bone marrow samples from 55 patients with multiple myeloma (MM) and 23 patients with monoclonal gammopathy of undertermined significance (MGUS) were evaluated with a broad panel of monoclonal antibodies. Plasma cells from 78% (43/55) of patients with MM strongly expressed the natural killer cell antigen CD56 (NKH-1, Leu-19). Of the 23 patients with MGUS, none showed strong CD56 reactivity, although three had weak reactivity in less than 20% of plasma cells. Myeloma cells expressing CD56 did not coexpress the CD57 or CD16 antigens. Patients with CD56-positive plasma cells had both indolent and aggressive disease. However, the 12 CD56-negative patients had predominantly aggressive disease with an unexpected preponderance of kappa Bence Jones only myeloma (5/10[50%] evaluable patients). Polyclonal plasma cells from non-neoplastic tissue sites (normal bone marrows, lymph nodes, tonsillar biopsies, and gut-mucosa biopsies) showed a near absence of CD56. We conclude that isolated, strong CD56 expression is common in MM, but not in MGUS or reactive plasma cells. The potential biologic importance of CD56 positivity in myeloma is reviewed.

ADP-ribosyl Cyclase↗
PubMed1979

Altered polyamine metabolism in cystic fibrosis.

Children with cystic fibrosis excreted elevated urinary levels of all three polyamines--putrescine, spermidine, and spermine. Heterozygote parents excreted intermediate concentrations of the polyamines, but not levels significantly different from levels in normal controls. Patients with cystic fibrosis who were administered a tracer amount of [14C]spermidine excreted 11--13% of the radiolabel within 72 hr whereas normal controls excreted 60--76% of the radiolabel within 72 hr. Spermine excretion was positively correlated with increased pathology as assessed by the National Institutes of Health (NIH) clinical score, whereas urinary putrescine and spermidine levels were negatively correlated with increased pathology.

Adult↗
PubMed1978

A new basis for treatment of multiple myeloma.

In order to get a better understanding of tumor biology, prognostic factors and approaches to treatment, total body tumor cell number, cell kinetics and drug sensitivity have been studied in a series of patients with multiple myeloma. We found that the presenting tumor mass stage was inversely proportional to survival, but did not predict drug sensitivity. Patients with both a high tumor cell mass and a large proliferative compartment of tumor cells had a particularly poor prognosis. Studies of myeloma stem cells in agar culture showed individual patterns of drug sensitivity with a correlation between in vitro sensitivity to melphalan, adriamycin, and BCNU, with in vivo sensitivity to these same classes of agents. Use of such measurements may permit selection of useful new drugs as well as an individualized basis for treatment of multiple myeloma.

Carmustine↗
PubMed1978

Cystic fibrosis: decreased conjugation and excretion of [14C]spermidine.

Free and conjugated [14C]spermidine were measured in plasma samples from normal individuals and cystic fibrosis patients. Within 4 minutes, the 14C-labeled material in the plasma from normal individuals was 70 percent conjugated compared to no detectable conjugation by cystic fibrosis patients. Further, the patients excreted only 11 to 13 percent of the [14C]spermidine in their urine within 72 hours whereas normal excretion was 60 to 76 percent. In both cases, the labeled material was in a conjugated form.

Cystic Fibrosis↗
PubMed1978

Quantitation of differential sensitivity of human-tumor stem cells to anticancer drugs.

With a direct in vitro tumor-colony assay developed to measure sensitity of human-tumor stem cells to anticancer drugs, we performed 32 retrospective or prospective clinical studies in nine patients with myeloma and nine with ovarian cancer treated with standard agents that were tested in vitro. The results were clearly correlated (P is less than 0.00001). Unique patterns of sensitivity and resistance to the six drugs tested were observed for individual patients. In eight cases of myeloma and three of obarian carcinoma in vitro sensitivity corresponded with in vivo sensitivity whereas in one case of myeloma it did not. In vitro resistance correlated with clinical resistance in all five comparisons in myeloma and all 15 in ovarian cancer. We conclude that this assay shows sufficient promise to warrant larger-scale testing to determine its efficacy for selection of new agents and individualized cancer chemotherapy regimens.

Antineoplastic Agents↗
PubMed1978

Immunoquantitation of free light chain immunoglobulins: applications in multiple myeloma.

A single radial immunodiffusion (RID) assay for the free lambda (lambda) and kappa (kappa) light chain (LC) immunoglobulins was developed for study of clinical samples of serum, urine, and bone marrow of patients with multiple myeloma. Using highly specific rabbit anti-LC sera, we were able to quantitate: (a) free serum LC after fractionating the serum sample using an Amicon ultrafiltration chamber equipped with an XM100A diaflow membrane and an 125I-LC standard for calculating filtration efficiencies, (b) directly, Bence Jones (BJ) proteins in the urine, and (c) the in vitro LC synthesis by myeloma plasma cells obtained from bone marrow aspirates. The median values of free LC levels in sera (n = 12), urines (n = 25), and marrow culture synthetic rates (n = 17) were 116.2 mg/dl, 0.775 g/day and 15.3 pg/plasma cell/day, respectively. These data were useful in initial evaluation of patients and serial follow-up studies. The assays have also been of use in our research on the determination of total body tumor mass in patients with BJ multiple myeloma.

Bence Jones Protein↗
PubMed1978

Discrimination between human T and B lymphocytes and monocytes by computer analysis of digitized data from scanning microphotometry. I. Chromatin distribution patterns.

Digitized images of Feulgen-stained normal human B and T lymphocytes and monocytes were analyzed by computer and microphotometry. The algorithms assessed the chromatin distribution patterns. A substantial number of parameters descriptive of the chromatin distributions were found to show statistically highly significant differences between B and T cells and monocytes. Although the effects of a number of biologic variables, such as cell cycle phase and immune stimulation, need to be carefully evaluated, the preliminary results indicate potential for automatic classification and subclassification of human B and T lymphocytes in normal and disease states.

Adult↗
PubMed1978

Metabolism of [14C]spermidine and [14C]putrescine in normal volunteers and in cancer patients.

The administration of [14C]putrescine or [14C]spermidine (i.v., 100 muCi) to normal volunteers or patients with advanced cancer resulted in alpha-phase half-lives of 40 and 30 sec and beta-phase half-lives of 30 and 60 min, respectively. No significant differences were found between the plasma decay curves of normals and those of cancer patients. Urinary excretion was similar with both groups excreting approximately 45% of [ 14C]putrescine within 24 hr and 60 to 76% of [14C]spermidine within 48 hr. Dowex chromatography indicated that more than 90% of the radiolabel in the urine was in a conjugated form. Plasma conjugation studies of [14C]putrescine and [14C]spermidine in both groups indicated near-total conjugation of the radiolabel within 4 to 5 min of i.v. injection. Since putrescine and spermidine are markers of disease activity, characterization of the conjugates will be important for the development of rapid, specific tests of altered disease activity in response to multimodality therapy.

Humans↗
PubMed1977

Successful treatment of acute leukemia during pregnancy. Combination therapy in the third trimester.

Aggressive treatment with cytarabine, vincristine sulfate, and prednisone for acute myelogenous leukemia, administered from the 31 st week of pregnancy, resulted in both sustained complete remission of the leukemia and delivery of a normal infant with a normal birthweight and a normal male karyotype. It is concluded that chemotherapy with cytarabine combinations can be administered in the third, and probably the second, trimester of pregnancy without risk of serious damage to the developing fetus.

Adult↗
PubMed1977

Phase II trial of piperazinedione in Hodgkin's disease, non-Hodgkin's lymphoma, and multiple myeloma: a Southwest Oncology Group study.

Piperazinedione given iv once every 3-4 weeks at a starting dose of 9-12 mg/m2 (4.5-12 mg/m2 for patients with myeloma) was evaluated in a Southwest Oncology Group phase II study for patients with far-advanced refractory lymphoma or multiple myeloma. Among 36 patients fully evaluable for tumor response (adequate trial), partial responses were observed in five (71%) of seven patients with Hodgkin's disease, in three (19%) of 16 patients with non-Hodgkin's lymphoma, and in none of 13 patients with multiple myeloma. Response was observed by the time of the second (five patients) or third (three patients) course. The median duration of response was 3.7 months (range, 1-17+ months). The dose-limiting toxic effects were hematologic, with 18 (50%) of 36 patients evaluable for toxicity experiencing severe leukopenia (wbc count less than 2000/mm3) and 22 (61%) experiencing severe thrombocytopenia (platelet count less than 50,000/mm3). Twenty patients had a decrease from their pretreatment hemoglobin level of greater than or equal to 2 g/100 ml. Hematologic toxic effects were often unpredictable and in several patients quite prolonged. This study indicates that piperazinedione had definite antitumor activity in patients with Hodgkin's disease and further trials in this disease using the drug at a reduced dose in combination with other effective drugs appear warranted.

Antibiotics, Antineoplastic↗
PubMed1977

Polyamines as markers of response and disease activity in cancer chemotherapy.

One hundred twenty-four patients with hematological and solid neoplasms had pretreatment urinary polyamine determinations. Putrescine, spermidine, and spermine were all significantly increased as compared to normals (p less than 0.001). Polyamine levels were directly related to disease activity and tumor burden. In patients with multiple myeloma, putrescine levels were significantly correlated with clinical disease activity as well as the in vitro labeling index of marrow plasma cells. Spermidine values reflected tumor cell burden. Serial studies in 56 patients indicated that greater than twofold rise in urinary spermidine during treatment was highly correlated with cell kill and subsequent clinical response (p less than 0.001). Serum polyamine levels in 17 patients were found to be comparable to urinary values. Our data indicate that polyamine determinations can potentially be clinically useful, i.e., baseline values as indicators of tumor cell mass and growth fraction, and increases in spermidine during treatment as an excellent marker of tumor cell kill.

Antineoplastic Agents↗
PubMed1976

Doxorubicin/B.C.N.U. chemotherapy for multiple myeloma in relapse.

A combination of doxorubicin ('Adriamycin") and B.C.N.U. (1,3 di[2-chloroethyl]-1-nitrosourea) (30 mg/m2 of each intravenously every 3-4 weeks) was used to treat thirteen multiple-myeloma patients who did not respond or were in relapse after remission produced by alkylating-agent/prednisone therapy. All cases were staged according to total-body myeloma-cell number and followed quantitatively for response to therapy. Seven of the thirteen patients responded (54%). Two had complete clinical remissions and a greater than 75% reduction in tumour-cell mass lasting 12 and 16 months. Five others had partial remissions with lesser degrees of tumour-mass reduction and bone pain and improved haemoglobin and serum-albumin concentrations. Toxicity was limited to occasional myelo-suppression, mild alopecia, and nausea. The results indicate the usefulness of doxorubicin/B.C.N.U. for myeloma patients who have relapsed during previously effective alkylating-agent therapy.

Alkylating Agents↗