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C Haanen

Publications and source records attributed to C Haanen.

At least 109 records · Page 6Linked to original sources
PubMed1987

Cellular and plasma adriamycin concentrations in long-term infusion therapy of leukemia patients.

To determine whether long-term adriamycin (ADM) infusions resulted in cellular ADM concentrations at least comparable to those observed after bolus injections, ADM cellular and plasma concentrations were measured in 18 patients with leukemia. ADM was administered at 30 mg/m2 per day for 3 days, either as bolus injections or as 4-, 8-, or 72-h infusions. Negligible accumulation of plasma ADM was observed. Peak plasma ADM concentrations after bolus injections were 1640 +/- 470 ng/ml (n = 7). Maximum levels were 176 +/- 34 ng/ml during 4-h infusion (n = 5); 85 +/- 50 ng/ml during 8-h infusion (n = 4); and 47 +/- 5 ng/ml (n = 2) after 72-h infusion. ADM concentrations in nucleated blood and bone marrow cells correlated well (r = 0.82, n = 47). ADM accumulated in leukemic cells up to 30-100 times the plasma concentrations. The shorter the administration time-span, the higher the peak leukemic cell concentration and the greater the loss of drug immediately after the end of the administration. The final cellular ADM half-life was approximately 85-110 h. After long-term infusion and bolus injection of the same dose, similar areas under the curve for plasma or leukemic blast cell ADM concentrations were attained. Since comparable therapeutic efficacy was observed in all regimens, the antileukemic effect appeared not to be related to the peak plasma concentrations, while acute toxicity phenomena decreased with increasing duration of the infusion. Long-term ADM infusion deserves more attention in the treatment of patients with anthracyclines.

Adolescent↗
PubMed1987

Leukemic cell and plasma daunomycin concentrations after bolus injection and 72 h infusion.

The effect of the duration of daunomycin (DNM) infusion on leukemic cell drug concentrations was evaluated. Cellular and plasma DNM concentrations were measured in 20 patients with acute non-lymphocytic leukemia. DNM 45 mg/m2 was administered either as a bolus injection or as a 4-, 8- or 72-h constant-rate infusion during 3 consecutive days. Peak plasma DNM levels amounted to 227 +/- 116 ng/ml after bolus injection and were only 16 +/- 6 ng/ml after 72-h DNM infusions. Terminal plasma DNM half-lives were 14 +/- 4 h. Peak leukemic cell DNM concentrations at the 3rd day of administration were 16810 +/- 2580 ng/10(9) cells (bolus injections) and 10310 +/- 5510 ng/10(9) cells (72-h infusions). The areas under the cellular curve were similar and independent of the duration of the DNM infusion. Peak leukemic cell daunomycinol (DNMol) concentrations were respectively 3500 +/- 1600 ng/10(9) cells and 2850 +/- 1720 ng/10(9) cells. Cellular DNM terminal half-life was 13 +/- 4 h. DNM concentrations in nucleated blood and bone marrow cells correlated well (r = 0.93, n = 26). Long-term infusion produced less severe side effects. Therapeutic efficacy was maintained during long-term infusion.

Adolescent↗
PubMed1987

In-vitro studies on phosphorylation and dephosphorylation of cytosine arabinoside in human leukemic cells.

The cytotoxic effect of cytosine arabinoside (ara-C) depends on the capacity of cells to form and retain intracellularly the phosphorylated metabolite cytosine arabinoside triphosphate (ara-CTP). In this study accumulation and cellular retention of ara-CTP have been measured in vitro in the bone marrow cells of 69 patients with acute leukemia. Cells were incubated with 3H-ara-C and the amount of ara-CTP formed was determined after separation of the nucleotides by thin-layer chromatography. Phosphorylation of ara-C to ara-CTP appeared to be a saturable process. The Km-equivalents varied between 1.1 and 16.2 microM ara-C. Maximal ara-CTP formation ranged from 12 to 125 pmol ara-CTP/10(6) cells in 30 min. The phosphorylation activity did not correlate with the percentage of S-phase cells. The intracellular half-life time of ara-CTP measured in vitro ranged from 53 to 210 min. Phosphorylation of ara-C was comparable in patients with acute myeloid leukemia (n = 51) and in patients with acute lymphoblastic leukemia (n = 18). Ara-CTP elimination appeared slower in lymphoblasts than in myeloblasts. The average intracellular ara-CTP level in relapsed patients (n = 34) appeared higher than in previously untreated patients (n = 52). The less favourable outcome of second remission induction therapy with conventional doses of ara-C compared to the first remission induction treatment is not explained by an alteration in the intracellular metabolism of ara-C.

Bone Marrow↗
PubMed1987

Infusion-rate independent cellular adriamycin concentrations and cytotoxicity to human bone marrow clonogenic cells (CFU-GM).

The effect of adriamycin (ADM) infusion-rate on cellular ADM concentrations and on clonogenicity of human haematopoietic cells was studied in vivo and in vitro. In patients an ADM dose of 30 mg m-2 was administered as a bolus injection, or as a 4 h or a 24 h infusion. In vitro the effect of ADM on clonogenic cell growth was determined after exposure during 5 min, 2 h and 24 h of human bone marrow cells to increasing ADM concentrations. ADM showed rapid intracellular accumulation, to levels 100-fold the plasma concentration in vivo or the incubation medium concentration in the in vitro experiments. After a bolus injection or 5 min exposure only approximately 10% of the cellular peak ADM was retained after elimination of the drug from the plasma or the incubation medium. Ninety percent of the ADM was apparently 'loosely' bound. After 4 h and 24 h constant-rate infusions and also after 2 h and 24 h incubations in vitro, the cells accumulated ADM gradually, and the subsequent washing-out of the cellular ADM was substantially less, most of the ADM being 'tightly' bound. Despite these different patterns of uptake and retention after in vivo short- and long-lasting infusion of the same total dose, the 'tightly-bound' cellular ADM concentrations were the same. Moreover, comparable cellular ADM concentrations, retained after efflux of the 'loosely-bound' cellular ADM fraction were equally cytotoxic to normal human clonogenic cells. Short-lasting cellular peak ADM concentrations which occur after a bolus injection or after short exposure to high ADM concentrations are not essential for the cytotoxic effect, in contrast to the retained, 'tightly-bound' cellular ADM levels.

Bone Marrow↗
PubMed1987

Plasma and cellular adriamycin concentrations in patients with myeloma treated with ninety-six-hour continuous infusion.

Adriamycin (ADM) concentrations in neoplastic plasma cells, nucleated blood cells, bone marrow cells, and plasma were measured in seven patients with advanced multiple myeloma. ADM was administered as a 96-hour infusion of 9 mg/m2/24 hr. Maximum plasma ADM concentrations were 15.8 +/- 4.4 ng/ml. ADM concentrations in nucleated blood cells, bone marrow cells, and plasma cells increased continuously throughout the 96-hour infusion. Maximum cellular levels were up to 200-fold higher than the maximum plasma concentration and were similar to levels observed shortly after administration of the total dose in one rapid injection. The cellular AUC for 96-hour infusion and bolus injection were comparable. Thus continuous infusion is the equivalent of bolus injection in delivering ADM to the target cells in bone marrow, although plasma ADM concentrations remained very low. These results provide support for administering ADM as a continuous infusion with less toxicity and better patient tolerance.

Blood Cells↗
PubMed1987

Relationship of serum lactate dehydrogenase level with first remission length in adult acute lymphocytic leukaemia.

Several features have a prognostic value in adults with acute lymphocytic leukaemia (ALL). However, in about two-thirds of all cases prognosis remains quite variable, with a substantial number of early relapses. This study shows in 118 adult patients who attained complete remission (CR) between 1978 and 1984 that pretreatment serum total lactate dehydrogenase (LDH) activity was inversely correlated with first CR length. The prognostic value of LDH was higher than that of any other features both in univariable and in multivariable analysis. The value was significant in the whole series as well as in patients who lacked other high risk features. Among non-high risk and low-WBC count cases, patients with LDH less than or equal to 500 U/l had a median first CR duration of 27 months, and a projected 5-year relapse free survival of 36%, versus 9 months and 12% of patients with LDH greater than 500 U/l. These results fit well with the results of a study of ALL in children, and suggest that pretreatment serum total LDH activity is an important risk determinant in adult ALL.

Adolescent↗
PubMed1987

Drug-induced skin reactions in patients with acute non-lymphocytic leukaemia.

The incidence of drug-induced skin rashes and related factors were analysed in a retrospective study of 151 patients with acute non-lymphocytic leukaemia (ANLL). 91 (60%) developed a drug-related toxicodermia to one or more drugs during remission, induction and maintenance therapy. The incidence of rashes was mainly confined to the blastic stage of leukaemia and occurred significantly less often during remission. Patients with acute myeloid leukaemia, FAB classification M1, M2 and M3 (M1-3) developed skin reactions more often than those of types M4 and M5 (M4-5). Women suffered more frequently from drug-induced skin lesions than men. The incidence of drug-associated rashes was significantly higher in patients with ANLL than in the general population for: Allopurinol (16%), co-trimoxazole (14%), miconazole (28%), and ketoconazole (18%). The incidence for the penicillins (12%) and cephalosporins (3%) conformed to the upper limit as reported for the general population. Additional toxic effects of combined therapy could not explain the differences observed and a dearrangement of the immunesystem during the blastic stage of leukaemia is suggested.

Acute Disease↗
PubMed1987

Major complications and causes of death in patients treated for Hodgkin's disease.

A total of 340 patients with Hodgkin's disease were evaluated for the occurrence of intercurrent fatalities after treatment with radiotherapy, chemotherapy, combined modality therapy, and salvage chemotherapy. Mean follow-up time was 76.6 months. Causes of death were compared with the expected risk, calculated from mortality statistics of the Netherlands' population. Sixty-seven patients died of progressive Hodgkin's disease, whereas 37 patients died of causes unrelated to advanced disease. Patients showed an increased risk of dying of leukemia and solid tumors (P less than .001), whereas the risk of dying of cardiovascular complications was not increased. The 10-year actuarial risk of dying of leukemia varied between 0% for patients treated with radiotherapy only and 5.7% for those needing salvage chemotherapy. The 10-year risk of dying of solid tumors was 0% for patients treated with chemotherapy and 6.5% for those receiving radiotherapy. Treatment-related fatalities were highest after combined modality therapy (P less than .025); the corresponding 10-year risk was 6.1%. Compared with younger ones, patients greater than or equal to 40 years had an increased risk of dying of causes unrelated to progressive Hodgkin's diseases. The actuarial risk of developing intercurrent fatalities at 10 years was 4.9% in patients less than 40 years, and 34.7% in those greater than or equal to 40 years (P less than .001). Compared with population based statistics, patients successfully treated for Hodgkin's disease still showed an increased risk of dying (P less than .001). Treatment modality, stage, and histologic subtype were not predictors of intercurrent death.

Actuarial Analysis↗
PubMed1987

Influence of cytarabine on mitochondrial function and mitochondrial biogenesis.

Although replication of nuclear DNA is inhibited by cytarabine (ara-C), protein synthesis in the nucleocytoplasm appears to continue unabated for the duration of at least the time of the normal cell cycle. ara-C treatment of human leukemic cells resulted in increased mitochondrial membrane potential and adenosine-5'-triphosphate (ATP) production and increased activity of enzymes, coded on nuclear DNA (citrate synthetase), as well as of enzymes with subunits coded on mitochondrial DNA (cytochrome c oxidase). These mitochondrial changes occurred during a period of cell-cycle arrest, while cell size and cellular protein content continued to increase. These phenomena appeared to precede the ultimate cell death.

Cell Line↗
PubMed1987

Influence of dose and duration of exposure on the cytotoxic effect of cytarabine toward human hematopoietic clonogenic cells.

The cytotoxic effect of cytarabine (ara-C) on the clonogenic potential of human normal and leukemic hematopoietic cells was investigated. Cells were exposed to ara-C at different concentrations and for periods of one to 120 hours and continuously. Colony growth (CFU-GM/CFU-E/BFU-E) in semisolid culture was assessed after seven and 14 days. The exposure time to ara-C appeared much more important in colony growth inhibition than the drug concentration. For instance, one-hour exposure to 10(-5) mol/L ara-C appeared not cytotoxic, while cocultivation in the presence of 10(-7) mol/L ara-C resulted in a total inhibition of colony growth. Cell fractionation with use of counterflow centrifugation allowed enrichment in subfractions for cells with different amounts of DNA. The inhibition of the clonogenic potential by ara-C was most pronounced in the cell fractions with the highest proliferation activity. Colony-forming cells, assessed after 14 days of culturing appeared less sensitive for ara-C cytotoxicity than seven-day CFUs. This means that ara-C is more cytotoxic to cycling than noncycling cells because compared to the seven-day colonies, 14-day colonies originate from the more resting, more primitive progenitor cells. The cytotoxicity of ara-C to clonogenic cells appears to be related to the proliferating and the cycling state of the progenitor cells and increases with the time of exposure. This phenomenon may be explained by the fact that ara-C is a cycle-specific drug and by the fact that the probability of cells entering the cell cycle is a time-dependent process. The results of this study indicate that development of more effective antileukemic therapy should not aim so much at very high drug levels but rather at prolonged administration of ara-C.

Bone Marrow Cells↗
PubMed1986

[Hemapheresis].

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Bloodletting↗
PubMed1986

A randomized comparison of maintenance treatment with androgens, immunotherapy, and chemotherapy in adult acute myelogenous leukemia. A Leukemia-Lymphoma Group Trial of the EORTC.

Twenty-three European centers participated in a randomized clinical trial (AML-5) to study the effect of androgens and immunotherapy during maintenance in adult acute myelogenous leukemia. Induction treatment consisted of Adriamycin (doxorubicin) 50 mg/m2 day 1, vincristine VCR 1 mg/m2 day 2, and cytosine arabinoside 80 mg/m2 every 12 hours by push injection days 3-9. Patients in complete remission were randomized into four groups: (1) 6-mercaptopurine 70 mg/m2 days 1-14, methotrexate 15 mg/m2 twice weekly days 15-28, and reinduction with daunorubicin 35 mg/m2 and vincristine 1 mg/m2 day 29; (2) chemotherapy as in group 1 plus stanozolol 0.15 mg/kg/day; (3) 6-thioguanine 70 mg/m2 orally on 4 consecutive days and cytosine arabinoside 80 mg/m2 subcutaneously day 5 every week; and (4) chemotherapy as in Group 3 plus irradiated blast cells treated with neuraminidase. Three hundred forty-eight patients were eligible and 295 were evaluable. The median age was 45 yrs. A complete remission was achieved in 64% of the patients, with 158 complete remissions randomized. Patients not randomized and patients receiving bone marrow transplantation (BMT) were analyzed separately. There was no difference in disease-free survival (DFS) or survival in the four maintenance arms. For patients reaching complete remission, the median DFS was 40 weeks, and median survival was 22 months with 30% surviving at 4 years. The overall survival was 18% at 4 years. There was no beneficial effect for DFS or survival by adding either immunotherapy or androgens to chemotherapy during maintenance. However, patients receiving immunotherapy seemed to have a higher rate of responses to reinduction after relapse than those in the other treatment arms.

Adolescent↗
PubMed1986

Cellular and plasma pharmacokinetics of weekly 20-mg 4'-epi-adriamycin bolus injection in patients with advanced breast carcinoma.

Weekly low-dose injections of 20 mg 4'-epi-adriamycin (E-ADM) were given to 12 patients with advanced postmenopausal breast cancer for at least 8 weeks. In advance, all patients were given hormonal therapy and polychemotherapy not containing anthracyclines. E-ADM concentrations in plasma and urine and in blood and bone marrow cells were determined during 8 consecutive weeks. Plasma concentrations in the range of a few nanograms per milliliter were seen up to 72-96 h. Cellular concentrations appeared to be more than 100-fold the plasma concentrations, and were 190 +/- 66 ng/10(9) cells on day 8, before the next injection was given. Nevertheless, no serious bone marrow toxicity was observed. In two patients with an increased plasma bilirubin concentration, cellular E-ADM concentrations were 20%-40% higher than those observed in the other patients. Plasma concentrations of E-ADM and 4'-epi-adriamycinol showed terminal half-lives 2-3 times longer and could be followed throughout the week. In three patients biopsies of skin metastases were examined. In two patients E-ADM could be demonstrated in the tumor tissue up to 7 days after the last injection. Although the number of patients investigated is too small to relate the drug kinetics to clinical response, it is of interest that the two patients with the highest cellular E-ADM concentrations responded better than the others.

Adult↗
PubMed1986

Remission-induction of acute lymphoblastic transformation of chronic myeloid leukaemia, followed by long-term maintenance therapy.

Acute lymphoblastic transformation of chronic myeloid leukaemia (LT-CML) of 7 consecutive patients was treated according to a remission-induction and maintenance therapy used for de novo acute lymphoblastic leukaemia (ALL). All 7 patients achieved a second chronic phase with a median remission duration of 15 months. Two patients showed an isolated central nervous system (CNS) relapse. This did not occur in the 4 patients, who received prophylactic therapy with intrathecal methotrexate. The second transformation was nonlymphoblastic in nature in 4 out of the 5 patients. A treatment protocol similar to that of a bad risk ALL, including long-term maintenance therapy and CNS-prophylaxis is indicated in lymphoblastic transformation of CML.

Adult↗
PubMed1986

The effect of cytosine arabinoside upon mitochondrial staining kinetics in human hematopoietic cells.

The measurement of time correlated intracellular mitochondrial staining with 3,3'-dipentyloxacarbocyanine [Di-O-C5(3)] appeared of interest to define the optimal staining conditions. Mitochondrial staining of lymphocytes, monocytes and granulocytes results in different fluorescence signals, related to the numbers of mitochondria, that are present in the cells of these various cell types. Alterations of Di-O-C(5)3 staining in a distinct cell type are due to changes in the physiological or functional state of the mitochondria. It appeared that such alterations occur in cells, which are cultured in the presence of cytosine arabinoside. The effect of cytotoxic drugs upon the mitochondrial membrane potential may be relevance for the understanding of the mechanism of action, exerted by cytotoxic drugs upon cell biology.

Carbocyanines↗