Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Children receive busulfan orally as part of myeloablative therapy before bone marrow transplantation for malignant and nonmalignant conditions. Children have been reported to have a low incidence of severe toxicity and significant rates of failure to achieve full engraftment. We evaluated the disposition of busulfan in children between 2 months and 3.6 years of age with lysosomal storage diseases, leukemia, and immunodeficiency disorders receiving oral doses of 1 or 2 mg/kg using a gas chromatographic assay. Peak concentrations were lower than those previously reported for adults, ranging from 1.4 to 5.2 mumol/L. The harmonic mean of the elimination half-life was 92 minutes, which is only slightly faster than that for adults (140 minutes). However, the area under the curve ranged from 400 to 1,000 (715 +/- 240) mumol.min/L, substantially lower than in adults receiving 1 mg/kg (range, 710 to 5,100 mumol.min/L; mean +/- SD, 2,180 +/- 1,200). The apparent volume of distribution (assuming complete bioavailability) ranged from 0.28 to 3.53 L/kg (1.42 +/- 0.86), which is more than twice that reported for adults (0.60 +/- 0.42). Busulfan clearance rate normalized to surface area is twice as high in children (200 +/- 100 mL/min/m2) as it is in adults (95 +/- 54 mL/min/m2). Alterations in bioavailability (absorption or first pass elimination) or in actual volume of distribution may account for these differences in drug disposition. The observed differences suggest the need for separate phase I dose escalation studies in children with accompanying pharmacokinetic assessment.
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PMID:Busulfan disposition in children. 232 21

The pharmacokinetics of high-dose busulphan was studied in adult patients with acute myeloblastic leukaemia after oral doses of 1 mg.kg-1 every 6 h for 4 days. The mean steady-state plasma concentration was 1080 ng/ml-1 during the treatment. Individual steady-state concentrations after the last dose on average were 32% lower than those predicted from total AUC measurements following the first dose. Mean elimination half-life in plasma was 2.3 h after the last dose and 3.4 h after the first dose which suggests that busulfan may increase its own metabolic rate on repeated treatment. The cerebrospinal fluid/plasma concentration ratio of busulphan was 1.3. Busulphan showed insignificant protein binding in plasma (7.4%). About 2% of the dose was excreted unchanged in the urine. For the first time sulpholane, 3-hydroxysulpholane and tetrahydrothiophene 1-oxide were identified as urinary metabolites of busulphan in man.
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PMID:Pharmacokinetic and metabolic studies of high-dose busulphan in adults. 275 72

Thirty children aged one to 15 years with acute lymphoblastic leukemia and acute nonlymphoblastic leukemia were transplanted from HLA matched donors using two different preparative regimens: 18 patients were prepared with cyclophosphamide and Total Body Irradiation while 12 patients received Busulphan and Cyclophosphamide. 15 patients survive 7 to 74 months after transplant. Although for the second group of patients a longer follow-up is needed in order to evaluate eradication of the disease and long-term toxicity, the combination chemotherapy alone results in improving survival (71% versus 28%) and decreasing relapse rate (30% versus 56%) compared with the group of patients who received the chemoradiotherapy regimen. Also the incidence of Interstitial Pneumonia has been lower in the group receiving chemotherapy alone. We conclude that this protocol is generally well tolerated in young patients, without increasing secondary toxicity.
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PMID:[Bone marrow transplant in acute leukemia in children. Experience of the Pesaro group]. 307 29

Cytogenetic effects of busulfan in vitro were studied in normal bone marrow (nine cases) and Philadelphia chromosome (Ph)-positive cells (10 cases) of patients with chronic myeloid leukemia. The frequency of chromosome aberrations and sister chromatid exchange (SCE) increased dose dependently. While there were no significant differences between normal and leukemic cells with regard to the induction of chromosome aberrations, the frequency of SCE was significantly lower in Ph-positive cells than in normal bone marrow. This difference was not only apparent on the basis of the SCE frequency per cell, but also when the SCE frequency was correlated to the relative chromosome length as shown by the SCE rate per chromosome group. Longitudinal studies of three patients who received long term busulfan treatment did not show a significant change in the frequency of induced SCE. It can be suggested that the lower frequency of induced SCE in Ph-positive cells reveals less sensitivity of the leukemic cells to DNA damage by busulfan. Our data provide evidence for the inability of busulfan treatment to eradicate or even reduce Ph-positive cells in chronic myeloid leukemia. Evaluation of cell proliferation by sister chromatid differentiation shows longer cell cycle times for the Ph-positive cells. Busulfan affected the cell cycle duration of leukemia and normal cells very little.
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PMID:Induction of sister chromatid exchanges and chromosomal aberrations by busulfan in Philadelphia chromosome-positive chronic myeloid leukemia and normal bone marrow. 316 16

Morphological and cytochemical characteristics of both bone marrow and peripheral blood cells as well as an appreciation of the course of the disease, were found to be important in making the correct diagnosis in a dog with acute myeloblastic leukaemia similar to the M-2 type (FAB classification) of man. Busulfan treatment resulted in only a limited effect, mainly consisting in a reduction of the number of nucleated cells in the peripheral blood. Even under busulfan treatment, however, the relative blast count in marrow and peripheral blood increased, indicating that most blast cells were not susceptible to the action of busulfan. The total survival time of the dog was 94 days, including 24 days from hospitalization and diagnosis until euthanasia in a moribund state. Based on the assessment of morphological abnormalities in leukaemic cells and of mitotic indices in bone marrow smears, it is tentatively concluded that the acute myeloblastic leukaemia in this dog arose in the pluripotent haematopoietic stem cell compartment giving rise to the formation of erythrocytes, eosinophils, neutrophils and monocytes as well as megakaryocytes and that the proliferation rate of cells of the myeloblastic clone was decreased, although an increase in the size of the potentially dividing compartment might have occurred.
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PMID:Acute myeloblastic leukaemia in a dog. 386 96

The reversible and non-reversible binding of busulfan to plasma proteins and to blood cells has been evaluated in man. The reversible binding to plasma proteins was insignificant in both healthy subjects and in patients with chronic myelocytic leukaemia. The percentage of busulfan irreversibly bound to plasma ligands was 32.4. Busulfan was distributed evenly between blood cells and plasma. The fraction of busulfan irreversibly bound to the blood cells was 46.9%. The major portion of busulfan that is degraded in whole blood reacts with the blood cells and the main part of that binds to macromolecular components in the cells.
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PMID:Binding of busulfan to plasma proteins and blood cells. 615 90

Analysis of controlled studies performed by the Polycythemia Vera Study Group (P.V.S.G.) and the European Organization for Research in Treatment of Cancer (E.O.R.T.C.) indicate that busulphan (Myleran) (BU) is the treatment of choice for polycythemia vera (PV). BU is particularly effective as compared to aspirin and dipyridamole (Persantine) or radioactive phosphorus (32P) in preventing the thrombotic and atherosclerotic complications of PV. In contradistinction to chlorambucil (CM), BU is not associated with an unacceptable increase in the incidence of leukemia. The pharmacology of BU remains unclear, but certainly it cannot be considered a classic alkylating agent. BU suppresses the activity of the reverse transcriptase-like RNA dependent DNA polymerase in the platelets of these patients. A clearer understanding of the role of BU in the treatment of the myeloproliferative disorders will provide important insights into the etiology and pathogenesis not only of preneoplastic states, but also thrombosis and atherosclerosis.
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PMID:Busulphan: effect on platelet RNA dependent DNA polymerase--implications in the treatment of polycythemia vera, thrombosis and atherosclerosis. 618 58

A transplantable granulocytic leukemia (GL-13-BC) in strain 13 guinea pigs, which has many similarities to human CML, was used to test the antineoplastic effects of two alkylating agents, busulfan and cyclophosphamide, administered in the late and early stages of the disease. Busulfan had a pronounced cytoreductive effect on circulating leukemic cells in the late, pre-blast crisis stage of this disease but all treated animals, succumbed to the leukemia with only a marginal increase in survival time relative to that of untreated controls. In this respect the guinea pig model resembles human CML. Survival time was moderately increased with early busulfan treatment but, as in the late treatment group, all animals succumbed to the leukemia. A pronounced cytoreductive action on leukemic cells was also observed in guinea pigs treated with cyclophosphamide. Late treatment with this drug produced highly variable effects on the survival time of leukemic guinea pigs; of the nine animals treated, no effect was observe in five, three showed a significant increase in survival time and one animal was still in remission without treatment when the experiment was concluded. Early treatment with cyclophosphamide produced the most striking finding of this study. Two treatments with this drug produced a complete remission in all of the treated guinea pigs. This remission lasted without further treatment for the duration of the study (greater than 200 days) while all untreated controls died within 27-37 days after receiving leukemic cell transplants. The relevance of these findings to the treatment of human CML is discussed.
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PMID:Busulfan versus cyclophosphamide treatment in the early and late stages of granulocytic leukemia in guinea pigs. 659 77

Survival of patients with chronic myeloid leukemia seen in the University of Colorado Leukemia Clinic were reviewed with respect to therapy. A total of 55 patients seen consecutively through mid 1980 were included in this study. Of these patients 30 were treated with busulfan, 14 were treated with hydroxyurea and 11 received under modalities. Busulfan treated patients who are now deceased, have had a median survival of 35 months (range, 13-108) and actuarial analysis shows the total busulfan treated population to have an expected median survival of 48 months. Hydroxyurea treated patients who are still alive have been followed for a median period of 69 months (range, 25-136 months) and a projected median survival for periods of 56 and 90 months, respectively. These data suggest that hydroxyurea may be an important treatment modality in the treatment of chronic myelogeous leukemia.
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PMID:Busulfan versus hydroxyurea in long-term therapy of chronic myelogenous leukemia. 695 30

The effect of cytotoxic and other drugs on the accumulation of melphalan by L1210 murine leukaemia cells was studied. We have confirmed that uptake is an active process competitively inhibited by L-leucine. In 36 experiments in amino acid-free medium the mean concentration of melphalan taken up was 225 pmoles/10(6) cells. High pressure liquid chromatographic analysis showed that the majority of the drug is present as free native melphalan. 1,3-Bis(2-chloroethyl)-1-nitrosourea (BCNU) was the only drug that stimulated accumulation, but without significant effect on influx or efflux rates. Busulphan, chlorambucil, cyclophosphamide, interferon, methotrexate and prednisolone had no effect on accumulation after 30 min melphalan transport. Adriamycin, CCNU, methyl CCNU, mustine and vincristine all impaired melphalan accumulation as did the non-cytotoxic drugs aminophylline, chlorpromazine and ouabain. Adriamycin, aminophylline, chloropromazine, indomethacin and ouabain all reduced melphalan influx.
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PMID:The effect of alkylating agents and other drugs on the accumulation of melphalan by murine L1210 leukaemia cells in vitro. 713 68


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