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Biomedical subjects

C Haanen

Publications and source records attributed to C Haanen.

At least 91 records · Page 5Linked to original sources
PubMed1989

Interference of coumarin therapy with the "Heptest" owing to declining prothrombin concentrations.

The Heptest kit (Haemachem, Inc., St. Louis, MO) for quantifying heparin in plasma is based on heparin-mediated inhibition of factor Xa, resulting in prolongation of clotting time. In 19 of 55 plasma samples obtained from 32 patients concurrently receiving coumarin and heparin, Heptest results exceeded true heparin values by more than 0.2 int. unit/mL; four samples showed a deviation exceeding 0.4 int. unit/mL. We show here that these deviations are caused by coumarin-induced decreases of plasma prothrombin. This problem can be circumvented by adding purified prothrombin or normal plasma to the assay mixture.

Coumarins↗
PubMed1988

Recombinant human interferon-alpha induced cytoreduction in chronic myelogenous leukemia. Results of a multicenter study.

Fourteen patients with Ph'-chromosome positive chronic myelogenous leukemia (CML) in first chronic phase were treated with recombinant interferon-alpha 2c. Interferon-alpha 2c 5 to 10 X 10(6) units s.c. was given for 12 weeks as an induction therapy. Maintenance treatment consisted of interferon-alpha 2c 5 X 10(6) units twice weekly s.c.. Two patients (14%) attained a complete clinical remission and 6 (43%) a partial remission, 3 of whom developed progressive disease during maintenance therapy. A complete disappearance of Ph'-chromosome was achieved in 1 patient. All patients had a more than 45% initial decline of the leukocyte count. Four out of ten patients with an initially enlarged spleen demonstrated reduction in spleen size. Influenza-like symptoms, anorexia, nausea, weight loss and fatigue were common side effects. Interferon-alpha is active in CML but additional clinical investigations are warranted to assess more precisely the therapeutic value of the interferons in this disease.

Clinical Trials as Topic↗
PubMed1988

Mitochondrial biogenesis and mitochondrial activity during the progression of the cell cycle of human leukemic cells.

Mitochondrial (mt) biogenesis and mt function were investigated during the cell cycle of leukemic cells. The study shows that the activity of enzymes involved in oxidative phosphorylation increases in the early G1 phase. This increase in activity precedes that of other mt enzymes such as citrate synthase and adenylate kinase. Therefore, the synthesis of mt enzymes, needed for the reduplication of the mt mass in the course of the cell cycle, occurs in a sequential order. The enzymes of the system for oxidative phosphorylation are composed of several subunits. Some of these subunits are encoded on mtDNA and synthesized by mt-specific RNA and protein synthesis. This explains why inhibition of mt protein synthesis during the progression of the cell cycle of G1-enriched cells results in an increasing shortage of ATP. This lack of ATP results first in progression delay and, subsequently, in a cell cycle block in early G1. Furthermore, shortage of ATP impairs the increase in activity of at least one mt matrix enzyme. This study offers new information about a number of aspects of mt biogenesis and mt function during cell cycle progression and elucidates the cytostatic mechanism resulting from prolonged inhibition of mt protein synthesis.

Adenosine Diphosphate↗
PubMed1988

In vivo cellular adriamycin concentrations related to growth inhibition of normal and leukemic human bone marrow cells.

Inhibition of clonogenicity of normal and leukemic human hematopoietic progenitor cells was studied after in vivo and in vitro exposure of bone marrow to adriamycin (ADM). Flow cytometric determination of cellular ADM concentrations in blast cells, expressed in fluorescence units/cell (FU/cell), correlated well with the extent of cytotoxicity. After 2 h in vitro exposure to 500 ng ADM/ml, the ADM concentration of leukemic (n = 7) and normal (n = 4) bone marrow blast cells amounted to 231 +/- 180 and 249 +/- 53 FU/cell respectively, producing moderate decreases in clonogenicity by 44 +/- 30 and 54 +/- 27%. Exposure to 2000 ng/ml produced ADM concentrations of 1184 +/- 472 FU/cell for leukemic blast cells and 1024 +/- 281 FU/cell for normal blast cells. Inhibition of clonogenicity was 96 +/- 7% in leukemic blasts and 99 +/- 1% in normal blasts. In vivo ADM concentrations in leukemic blast cells at 1-2 h after administration were 216 +/- 98 FU/cell (n = 8 patients). This implies that inhibition of clonogenicity after administration of conventional dosages of ADM will be approx. 60-70% for both leukemic and normal bone marrow progenitor cells. Such values were noted in four patients of whom bone marrow was cultured, which was obtained shortly after ADM monotherapy.

Bone Marrow↗
PubMed1988

The development of non-responsiveness to immunotherapy with monoclonal anti-idiotypic antibodies in a patient with B-CLL.

A patient having a B cell chronic lymphocytic leukaemia was treated with a monoclonal anti-idiotypic antibody (MoAb anti-id). Up to 24.5 g of MoAb anti-id has been administered to the patient over a period of 1 year without serious side effects. Despite a substantial amount of serum idiotype (id = 100 micrograms/ml) and a low expression of id on the tumour cells (+/- 6000 molecules per cell) clearance of serum id and a marked tumour reduction was obtained. Therapy resistance developed and coincided with a decreased clearance rate of circulating id-anti-id immune complexes and an increased modulation of cellular id expression, in vivo. This suggests that a decreased clearance rate of anti-id coated tumour cells provided more time for id modulation in vivo, resulting in therapy resistance. Therefore, the overall capacity of the natural effector system may have an important influence on the ultimate therapeutic effect of immunotherapy with MoAb anti-id. Although the partial remission obtained was not long-lasting, this study shows that MoAb anti-id therapy can be effective even when id expression on the tumour cells is low and a substantial amount of serum id is present.

Antibodies, Monoclonal↗
PubMed1988

Different susceptibilities of normal T cells and T cell lines to immunotoxins.

In the context of ex vivo T cell elimination from bone marrow, the anti-T cell cytotoxic potential of immunotoxins (IT) prepared by conjugation of the monoclonal antibodies (MoAb) WT32 (CD3), T101 (CD5), and WT1 (CD7) to ricin A chain was evaluated. The cytotoxicity of IT was based on protein synthesis inhibition in human T cell lines: GH1, CEM, HPB-ALL, and Jurkat, and appeared closely related to the antigen density and internalization rate of and appeared closely related to the antigen density and internalization rate of the IT. Normal unstimulated T cells appeared to be rather insensitive to IT not due to a low antigen density or decreased internalization. The cytotoxicity of IT to T cells could be enhanced considerably by NH4Cl. Treatment of T cells with a cocktail of IT (10(-8) M) and 20 mM NH4Cl resulted in a 5000-fold cytoreduction as measured by clonogenic assays of limiting T cell dilutions, whereas the haematopoietic progenitor cells remained unaltered. Stimulation of T cells with phytohaemagglutinin (PHA) prior to incubation with IT considerably increased the sensitivity to IT treatment. Thus, normal T cells are less sensitive to anti-T cell IT than T cell lines and activated T cells. This suggests that a low protein synthesis is responsible for the resistance to IT. However, a high specific cytotoxicity of IT to normal T cells can be achieved in the presence of 20 mM ammonium chloride.

Ammonium Chloride↗
PubMed1988

Human T lymphocyte differentiation antigens as target for immunotoxins or complement-mediated cytotoxicity.

Graft-versus-host disease (GVHD) after allogeneic bone marrow transplantation (BMT) is initiated by immunocompetent T cells present in the graft. Selective elimination of distinct T-cell subsets or a sufficient, but not complete T-cell depletion, might abolish severe GVHD without graft rejection and loss of the anti-tumour potential. In this study we analysed the efficacy of different monoclonal antibodies (MoAb) WT32 (CD3), OKT4 (CD4), T101 (CD5), WT1 (CD7), and WT82 (CD8) with respect to their cytotoxicity to T cells either as immunotoxin (IT) or in combination with complement. The cytotoxic potential was assessed by protein synthesis inhibition and clonogenic assays. The ricin A conjugated MoAb exerted only a minor effect on blood or bone marrow T cells, although they were highly inhibitory to T-cell lines. However, in the presence of 20 mM ammonium chloride, IT directed against CD3, CD5, and CD7 were highly cytotoxic. IT directed against CD4 and CD8 were less effective, due to a low internalization. The complement-mediated cytotoxicity was efficient for all antigens used. The natural killer (NK) activity, as measured by cytotoxicity to K562, was hardly depressed by anti-CD3, anti-CD4, anti-CD5, and anti-CD8, but was eliminated by anti-CD7. All procedures used had only a minimal effect on haematopoietic progenitors as measured by CFU-GM and BFU-E assays. We concluded that, although the T-cell population can be eliminated with the combination of anti-CD3, anti-CD5, and anti-CD7 antibodies plus complement, IT with 20 mM NH4Cl appear to kill higher amounts of T cells. Selective elimination of CD4- and CD8-positive cells is effectively obtained by MoAb with complement.

Antibodies, Monoclonal↗
PubMed1988

Clinical pharmacokinetics of doxorubicin.

Doxorubicin (adriamycin) has a very wide antitumour spectrum, compared with other anticancer drugs; however, except for Hodgkin's disease, it is not associated with curative chemotherapy. Doxorubicin has been in clinical use for more than 2 decades, and only recently has it been recognised that the cytotoxic effect is produced at the cellular level by multiple mechanisms which have not yet been conclusively identified. Key factors are a combination of doxorubicin-induced free radical formation due to metabolic activation, deleterious actions at the level of the membrane, and drug-intercalation into DNA. Multiple aspects of the clinical pharmacokinetics of this drug have been described. Wide interpatient variations in plasma pharmacokinetics have been noted, but without firm relation to clinical outcome. An apparent volume of distribution of approximately 25 L/kg points to extensive uptake by tissues. Up to several weeks after administration, significant concentrations of doxorubicin have been found in haematopoietic cells and in several other tissues. The maximum cellular doxorubicin concentrations reached in vivo remain significantly below those at which all clonogenic leukaemic cells are killed in vitro. Doxorubicin has been administered as frequent (weekly) low doses, single high doses, and as a continuous infusion. The optimal schedule with respect to tumour cytotoxicity and dose-limiting side effects such as myelosuppression or cardiotoxicity, has never been investigated in a prospective, randomised manner. Clinical trials large enough to study optimal, and possibly individualised, doxorubicin chemotherapy need to be performed. This review summarises pharmacological and pharmacodynamic data of doxorubicin, and discusses these in relation to possible improvement of its therapeutic index. Furthermore, drug interactions, dose-response relationships, mechanisms of action, multidrug resistance, and treatment scheduling are discussed in the perspective of the development of novel treatment strategies.

Cell Survival↗
PubMed1988

GM-CSF enhances sensitivity of leukemic clonogenic cells to long-term low dose cytosine arabinoside with sparing of the normal clonogenic cells.

Leukemic clonogenic cells (CFU-L) and normal myeloid progenitor cells (CFU-GM) were exposed to Ara-C in the presence of crude CSF obtained from placentas (HPCM) or recombinant human GM-CSF for varying periods. The cytotoxicity of Ara-C to CFU-L increased considerably when the exposure time to Ara-C in the presence of HPCM was extended from 20 hours to 10 days. The ID50 of the CFU-L was 1.5 +/- 2.2 x 10(-8) M Ara-C compared to 5.5 +/- 2.9 x 10(-8) M Ara-C for the CFU-GM after an exposure to Ara-C for 10 days (p less than 0.05). Replacement of crude CSF from placenta conditioned medium by rh GM-CSF resulted in identical observations. Interesting was the observation that secondary leukemic colony forming cells were more or at least equally sensitive to Ara-C in the presence of GM-CSF when compared to the primary leukemic clonogenic cells. This contrasted the secondary normal CFU-GM, which were less sensitive to Ara-C than the primary CFU-GM. This indicates that GM-CSF induces leukemic clonogenic cells with selfrenewal capacity into proliferation, and in doing so, it may enhance the cytotoxicity of a cell cycle specific drug like Ara-C with sparing of the normal clonogenic cells.

Bone Marrow↗
PubMed1988

A new multichamber counterflow centrifugation rotor with high-separation capacity and versatile potentials.

A new closed system for counterflow centrifugation (elutriation) is described. The system was developed to increase the capacity of counterflow centrifugation in order to be able to separate bone marrow intended for allogeneic bone marrow transplantation within 3 h. The rotor has the capacity for up to four separation chambers, offering the possibility of separating either a single-cell suspension under equal or differing conditions, or four different suspensions simultaneously. Profiles of low-density nucleated cells from normal blood were shown to be identical after elutriation in four different chambers. Leucocytes could be depleted from platelet concentrates without significant loss. Most (98%) of the lymphocytes were removed from donor marrow intended for transplantation within 3 h and the recovery of myeloid and erythroid clonogenic cells in the graft was similar to that obtained from the standard single chamber centrifuge.

Bone Marrow Cells↗
PubMed1987

Determination of amsacrine in human nucleated hematopoietic cells.

A new method has been developed for the determination of amsacrine (AMSA) in human nucleated hematopoietic cells. In order to prevent efflux during the cell separation procedure, white blood cells (WBCs) were separated from red blood cells by dextran sedimentation, leaving the WBCs in their natural environment. After cell counting, pelletting the cell suspension and correcting for the admixture of supernatant, AMSA was extracted from the WBCs and determined by high-performance liquid chromatography. Linearity of extraction was observed up to 40.10(6) cells. The inter-assay variation was 4.7%. Plasma and cellular concentrations were measured in five patients at the end of a 3-h infusion of 100 mg/m2 AMSA. A pharmacokinetic study of plasma and cellular AMSA concentrations up to 19 h after infusion was carried out. AMSA concentrations in WBCs correlated well with the plasma levels (n = 20, r = 0.967) with an accumulation factor compared to the plasma concentration of 2.6-9.8 in the patients studied. The method described is useful for studying cellular pharmacokinetics of AMSA in man.

Amsacrine↗
PubMed1987

Prognostic factors in adult patients with acute leukemia at first relapse.

The case histories of 252 adolescent and adult patients with acute leukemia diagnosed and treated between 1975 and 1985 are analyzed with special attention to prognostic factors determining the second complete remission (CR) rate. A first CR was achieved in 65% of cases, 60% for acute myelogenous leukemia (AML), and 75% for lymphoblastic leukemia (ALL). In 86 patients a relapse occurred (50 AML, 36 ALL), and 50% of them entered a second CR after reinduction therapy. Median survival after first relapse of these reinduction-responders was significantly prolonged in comparison to the reinduction-nonresponders for both AML (15 versus 2 months) and ALL (11 versus 3 months). Median duration of the first CR of the reinduction-responders was significantly longer than that of the second CR (13 versus 6 months). The major determinant for the probability to obtain a second CR after reinduction therapy was the duration of the first CR. The latter was significantly longer in the reinduction-responders than in the nonresponding group (13 versus 5 months). Furthermore patients younger than 40 years, and those who relapsed after ending the maintenance therapy, tended to have better chances to achieve a second CR. Rapid achievement of the first CR, and sex of the patients seemed not to be of predictive value. The authors conclude that aiming for a second CR is worthwhile in young patients who relapse after a long first CR.

Adolescent↗
PubMed1987

Improved flow cytometry of cellular DNA and RNA by on-line reagent addition.

Acridine orange (AO) staining enables flow cytometric measurement of cellular DNA and RNA. With the conventional procedure, red and green fluorescence intensities alter considerably in time, affecting the reliability and reproducibility of the results. A standardized simple technique of AO staining is described that keeps the time between addition of detergent and AO and the subsequent measurement constant. Measurements by means of this on-line method appear to be much more reproducible in comparison to those obtained using the conventional procedure.

Cell Line↗