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11.
Månsson E Flordal E Liliemark J Spasokoukotskaja T Elford H Lagercrantz S Eriksson S Albertioni F 《Biochemical pharmacology》2003,65(2):237-247
Mechanisms of acquired resistance to three purine analogues, 2-chloro-2'-deoxyadenosine (cladribine, CdA), 9-beta-D-arabinofuranosyl-2-fluoroadenine (fludarabine, Fara-A), and 2-chloro-2'-arabino-fluoro-2'-deoxyadenosine (clofarabine, CAFdA) were investigated in a human T-lymphoblastic leukemia cell line (CCRF-CEM). These analogues are pro-drugs and must be activated by deoxycytidine kinase (dCK). The CdA and CAFdA resistant cell lines exhibited increased resistance to the other nucleoside analogues activated by dCK. This was also the case for the Fara-A resistant cells, except that they were sensitive to CAFdA and guanosine analogues. The CdA and CAFdA resistant cells displayed a deficiency in dCK activity (to <5%) while the Fara-A resistant cells showed only a minor reduction of dCK activity (20% reduction). The activity of high K(m) 5'-nucleotidase (5'-NT) (cN-II) using IMP as substrate, was 2-fold elevated in the resistant cell lines. The amount of the small subunit R2 of ribonucleotide reductase (RR) was higher in the Fara-A resistant cells, which translated into a higher RR activity, while CdA and CAFdA cells had decreased activity compared to the parental cells. Expression of the recently identified RR subunit, p53R2 full-size protein, in CAFdA cells was low compared to parental cells, but a protein of lower molecular weight was detected in CdA and CAFdA cells. Co-incubation of Fara-A with the RR inhibitor 3,4-dihydroxybenzohydroxamic acid (didox) enhanced cytotoxicity in the Fara-A resistant cells by a factors of 20. Exposure of the cells to the nucleoside analogues studied here also caused structural and numerical instability of the chromosomes; the most profound changes were recorded for CAFdA cells, as demonstrated by SKY and CGH analysis. We conclude that down-regulation of dCK in cells resistant to CdA and CAFdA and increased activity of RR in cells resistant to Fara-A contribute to resistance. 相似文献
12.
Pretreatment leukaemia cell drug resistance is correlated to clinical outcome in acute myeloid leukaemia 总被引:3,自引:0,他引:3
Nørgaard JM Langkjer ST Palshof T Pedersen B Hokland P 《European journal of haematology》2001,66(3):160-167
In 85 adult patients diagnosed with acute myeloid leukaemia (AML) and treated at the same institution during a 5-yr period, the clinical significance of in vitro cellular drug resistance to the anthracyclines aclarubicin (Acla) and daunorubicin (Dau) as well as the nucleoside analogue cytarabine (Ara-C) was investigated using a 4-d MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide) assay. In 59 patients of whom 40 were treated by the combination of Acla and Ara-C we found that leukaemia cell drug resistance towards Acla was higher (by a factor 2.80) in patients who failed to enter complete remission (CR) after the first cycle of induction chemotherapy as compared to patients who entered complete remission. The relationship was significant in univariate as well as multivariate analysis (p=0.02 and 0.03, respectively). By contrast, no in vitro single drug resistance values were consistently correlated to other parameters of clinical outcome (overall CR rate, overall survival (OS), or continuous complete remission (CCR)), whereas the combined Acla and Ara-C drug resistance profile (Acla/Ara-C DRP) was of prognostic significance to overall survival of all 85 patients (p=0.004) as well as to the CCR of 39 complete responders (p=0.04). These findings remained statistically significant in multivariate analyses correcting for other variables influencing clinical outcome including patient age, leukocyte count, karyotype, FAB-subtype, and presence/absence of secondary AML. We conclude that the in vitro drug resistance of leukaemia cells at time of disease presentation appears to be independent of prognostic significance to short- and long-term clinical outcome in AML. 相似文献
13.
张立明 《浙江中医药大学学报》2010,34(3)
[目的]探讨难治复发性急性髓细胞性白血病有效治疗方法。[方法]应用MA方案联合小剂量反应停治疗难治复发急性髓细胞白血病共15例。[结果]1个疗程有效率60%,未缓解并死于感染2例(13.3%),2个疗程总33.3%,总有效率80%。[结论]应用MA方案联合小剂量反应停治疗难治复发急性髓细胞白血病临床有效。 相似文献
14.
Miyawaki S Kawai Y Takeshita A Komatsu N Usui N Arai Y Ishida F Morii T Kano Y Ogura M Doki N Ohno R 《International journal of hematology》2007,86(4):343-347
This study was designed to determine the optimal high dose for cytosine arabinoside (ara-C) in combination with fludarabine, granulocyte colony-stimulating factor, and mitoxantrone (FLAGM) in adult patients with relapsed or refractory acute myeloid leukemia. Nine patients were enrolled at increasing dosage levels of ara-C (8, 12, and 16 g/m2 per dose level). Ara-C and fludarabine were administered once a day at level 1, once or twice a day at level 2, and twice a day at level 3. All patients had grade 4 hematologic toxicity. The most common adverse events were of grade 2 or less, with nausea and vomiting being the most common (6 events), followed by diarrhea (5 events), and rash (5 events). Of the 13 grade 3 nonhematologic toxicities reported, the 2 most common were febrile neutropenia (6 events) and disseminated intravascular coagulation (3 events). No early deaths were observed. FLAGM with high-dose ara-C was considered safe for patients, and the recommended dosage of ara-C in this study was 2 g/m2 every 12 hours for a total dose of 16 g/m2. 相似文献
15.
Summary
Introduction Cytarabine liposome injection (DepoCyt?), a sterile suspension of the antimetabolite cytarabine, encapsulated into multivesicular, lipid-based particles, has been
developed to improve the treatment of neoplastic meningitis (NM) through sustained release of cytarabine. The objective of
this study was to determine the pharmacokinetics (PK) of cytarabine after intrathecal administration of 50 mg encapsulated
cytarabine (DepoCyt?) in patients with neoplastic meningitis up to 336 h (14 days) after dosing.
Methods This was an open-label study wherein two 50-mg doses of DepoCyt? were administered 14 days apart via the intraventricular (IVT) route or by lumbar puncture (LP). Cerebrospinal fluid (CSF)
samples were collected from eight adult patients at various times up to 14 days after each dose. Plasma samples were also
collected within the same time period. CSF samples were analyzed for unencapsulated (free) and encapsulated cytarabine and
the cytarabine metabolite, ara-U. Plasma samples were analyzed for free cytarabine and ara-U. The limit of detection was 0.003 μg/mL cytarabine and 0.016 μg/ml for ara-U.
Results The concentration of free and encapsulated cytarabine in the ventricular and lumbar CSF ranged from 0.01 to 1500 μg/mL and were detectable up to 14 days post-dosing. Free cytarabine concentrations in plasma were only sporadically detectable.
CSF and plasma concentrations of ara-U were low in all samples.
Conclusions The administration of intrathecal encapsulation cytarabine prolongs sustained tumor exposure to cytotoxic concentrations of
cytarabine (>0.02 μg/ml) with a slow continuous release of cytarabine from the DepoFoamTM particles, so drug exposure is prolonged over time, resulting in lower peak cytarabine levels and a longer duration of exposure
compared with standard cytarabine (Ara-C).
This work was performed at Moffitt Cancer Center, Tampa, Florida and University of Florida College of Medicine, Gainesville,
Florida. This work was presented in part at the 12th␣International Conference on Brain Tumor Research and Therapy at Keble
College, Oxford, United Kingdom on September 20–23, 1997. 相似文献
16.
Peter I. Karl Barrington Harvey Stanley E. Fisher 《Alcoholism, clinical and experimental research》1996,20(7):1269-1274
Chronic ethanol abuse during pregnancy can cause fetal injury. A contributing factor in this fetal injury may be the effect of ethanol on the placenta. Ethanol treatment increases human chorionic gonadotropin (hCG) production by cultured human placental trophoblasts. In this study, we show that ethanol treatment reduces total DNA and total protein while stimulating hCG production in term trophoblasts. Ethanol treatment inhibits growth in rapidly proliferating trophoblastic cells from a first trimester placenta and JEG-3 choriocarcinoma cells. In both cell types, the normal increases in total DNA were inhibited in an ethanol dose-dependent manner. Normal increases in total protein were inhibited as well. In contrast, hCG production, an indicator of differentiation, was stimulated by ethanol treatment. Treatment of JEG-3 cells with antimitogenic agents, methotrexate (MTX) or cytosine arabinoside (Ara-C), inhibited cell growth as indicated by decreased total DNA and total protein accumulation. Similar to that with ethanol treatment, inhibition of cell proliferation was accompanied by increases in hCG production. Taken together, these data suggest that one mechanism by which ethanol increases hCG production in human placental trophoblasts may involve alterations in cellular growth and/or differentiation; such alterations may also occur in other proliferating cells in the growing fetus. 相似文献
17.
J. Batlle E. Lourés P. Vila M. C. Hernández J. A. Méndez J. Torea E. Rendal M. J. Couselo A. Filgueira M. F. López Fernández 《Annals of hematology》1997,75(3):111-115
Older patients with RAEB-T or AML are extremely difficult to treat. They are at high risk of infection and/or bleeding complications
and have a low probability of cure and short overall survival with conventional treatments. We treated 12 patients with an
outpatient low-dose chemotherapy regimen consisting of Ara-C 100 mg subcutaneously on day 1, and 6-thioguanine 80 mg orally
on days 2–5, repeated every week. Nine patients had MDS, six RAEB-T, and three RAEB (median age 57 years) and three had de
novo AML (median age 73 years). All patients were transfusion dependent. The mean peripheral blast count at the beginning
of treatment was 29% (4–51%). The median follow-up is 13 months (2–34 months) for all the patients and 14 months (2–34 months)
for those with RAEB-T. Nine of the 12 patients are alive, including seven RAEB-T patients with a median of 18 months (range
6–34+ months). During treatment, the peripheral blast count was markedly reduced to a mean of 5% (0–23%). The mean pre-therapy
platelet count, with transfusion support, was 24.0×109/l, while the mean post-therapy platelet count without transfusion support is 95.0×109/l. All patients except two became transfusion independent at some time. Treatment for 6–10 weeks was required to show reduction
of blast number and increase in hemoglobin, platelet, and WBC counts. Initial cytopenias were the only side effects of this
regimen. One patient had granulocytopenic fever. In conclusion, this low-dose regimen is effective and well tolerated for
outpatient palliation in high-risk or elderly patients with RAEB-T or AML.
Received: 11 September 1996 / Accepted: 8 January 1997 相似文献
18.
Sequential intermediate-dose cytosine arabinoside and mitoxantrone for patients with relapsed and refractory acute myelocytic leukemia 总被引:1,自引:0,他引:1
Based on in vitro evidence of time-dependent synergistic kill of HL-60 leukemia cells exposed to Ara-C and mitoxantrone, 44 patients with relapsed or refractory AML and 3 with blastic CML were treated with a timed sequence of both drugs. There were 25 females and 22 males, with a median age of 53 (range 21-75). Of 31 patients with relapsed AML, 24 had one prior remission, 6 had two and 1 had three. Of these, 15 had failed a second reinduction attempt. Thirteen patients were primarily refractory to induction with Ara-C plus daunorubicin. Each dose of Ara-C, 500 mg/m2, was followed after 6 hr by mitoxantrone, 5 mg/m2, and the sequence was repeated four to six times (44-68 hr) in different cohorts of patients. All but two patients (one with blastic CML and one in relapse and refractory) are evaluable for response and toxicity. Of 16 patients in relapse without prior reinduction 7 achieved CR and 3 PR (62% response rate); there were 3 CR in the 14 patients who were in relapse and refractory (21% response rate) and 4 CR and 1 PR (35% response rate) in the 14 patients with primary anthracycline resistance. Five of seven patients previously exposed to mitoxantrone achieved CR. Response lasted from 2 to 42 months, with two patients alive and in continuing remission at 34 and 42 months. Average marrow recovery was seen after 25 days and time to remission was 30 days. Six patients died in induction (four from sepsis and two from the tumor lysis syndrome) and 21 had progressive disease. Chemotherapy was well tolerated with minor nausea and vomiting in 13 patients, moderate in 20, and severe in 2. Most patients did not have evidence of drug-induced mucositis: it was minor in 9 and moderate in 2. Renal dysfunction was attributable to the use of nephrotoxic antibiotics. Hepatic dysfunction was reversible and was minor in 10 patients, moderate in 13, and severe in 3. Sequential, timed administration of intermediate-dose Ara-C and mitoxantrone is an active and well-tolerated antileukemic regimen. 相似文献
19.
Regulation of pluripotent stem cell (CFU-S) proliferation kinetics by humoral factors is now well documented. However, the mechanism of choice of CFU-S differentiation pathways is still a controversial issue. We suggest that long-range humoral factors (pluripoietins) are capable of preferentially channelling CFU-S towards one of the cell lineages after various perturbations such as irradiation and drug treatment. The differentiation pathway depends on the treatment protocol. We present data concerning one of the protocols: injection of 20 mg of cytosine arabinoside (Ara-C). When conditioned medium from bone marrow of treated mice is incubated with normal marrow, CFU-S of the latter generate spleen colonies with an E/G ratio above normal values. Clonal analyses of spleen colonies demonstrate that they are generated by pluripotent stem cells. Therefore, any modification in the E/G ratio is due to modifications of CFU-S channelling and not to the variations of committed cells. It was of interest to determine the mechanism of pluripoietin activity. This was studied at three levels: membrane receptors, gene activation and protein synthesis. These studies suggest that CFU-S have receptors for pluripoietins which activate genes responsible for specific mRNA synthesis. De novo synthesis of proteins is a necessary prerequisite for pluripoietin activity to be expressed. Hypotheses for these mechanisms are presented. 相似文献
20.
G. Zbinden 《Archives of toxicology》1980,46(1-2):139-149
DNA damage induced by methylmethane sulfonate, cyclophosphamide, doxorubicin and procarbazine in male germ cells was assessed in rabbits by the demonstration of unscheduled DNA synthesis (UDS), in meiotic and postmeiotic phases of maturation. Immediately after treatment by the intravenous route tritiated thymidine was injected into both testicles. Subsequently, rabbits were ejaculated serially, sperm heads were isolated and assayed for radioactivity by liquid scintillation counting. Dose-dependent UDS was demonstrated in late spermatocytes and early spermatids. High doses of hycanthone also induced UDS, but isoniazid and metronidazole had no effect. The rabbit testis UDS test takes into account metabolic and pharmacokinetic aspects of the test substances and provides information about their penetration through the blood-testicular barrier. It is therefore useful for secondary evaluation of potential mutagens. UDS induced by procarbazine was abolished by simultaneous treatment with Ara-C. Thus, the test also recognizes substances that inhibit DNA repair synthesis. 相似文献