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

The in vitro and in vivo cytotoxic effects of 5-aza-2'-deoxycytidine (DAC) on L1210 leukemia are reported and related to the pharmacokinetics of DAC in CDF mice. L1210-bearing mice (1 X 10(4) cells, i.v.) given DAC i.v. (6.5-225 mg/kg) on day 3 showed a 50-212% increase in lifespan (ILS), with an estimated 3-6 log cell kill of L1210. Optimal effects with late treatment were obtained when DAC was given either on a multiple-dose regimen (10 mg/kg i.v., q 3 hr X 4, day 3 or 5) or by a constant s.c. infusion (2.0 mg/kg/hr X 12 hr, day 3), ILS 328-414%. Following 10 or 100 mg/kg i.v., plasma DAC declined in a triexponential manner with an intermediate elimination t 1/2 of 31 min. Urinary excretion accounted for 28.5% of DAC plasma clearance. When L1210 cells were exposed to DAC in vitro (0.5-100 micrograms/ml for 24-120 hr) a maximum 3-4 log cell kill was obtained. Both in vivo and in vitro response to DAC demonstrated the importance of exposure time as a determinant of cell kill. DAC is estimated to be more cytotoxic in vivo than in vitro. The critical cytotoxic concentration of DAC appears to be between 0.5 and 1.0 microgram/ml.
 ...
PMID:Comparison of the in vitro cytotoxicity (L1210) of 5-aza-2'-deoxycytidine with its therapeutic and toxic effects in mice. 257 63

We have investigated the effects of 5-aza-2'-deoxycytidine (DAC) on the growth and clonogenic potential of L1210 leukemia in vitro. Cells were exposed to DAC (0.001-100 micrograms/ml) for periods of 1-120 hrs. Following drug removal, cell growth in suspension culture was measured for up to 7 days, and cell survival was estimated by a colony-formation assay. When cell clonogenicity was plotted against DAC concentration in log-log axis, curves for each exposure time were linear between 0.01 and 0.5 micrograms/ml of DAC, but survival leveled off to a constant percentage for drug concentrations greater than 0.5 micrograms/ml. Percent survival decreased as exposure time increased up to 24 hrs; however, increases in exposure time greater than 24 hrs did not consistently decrease survival any further. At the lower concentrations this leveling of cytotoxicity is due to the spontaneous decomposition of DAC and to the lack of cytotoxicity of the breakdown products. At the higher concentrations the cause of the leveling remains uncertain. Incubation of L1210 with DAC at concentrations greater than 0.5 micrograms/ml for greater than or equal to 24 hrs resulted in total inhibition of measurable cell growth for 72-96 hrs following drug removal. Sequential colony-formation assays at various intervals following drug removal demonstrated a time-dependent increase in cell clonogenicity at a rate approximating the growth rate of untreated L1210 cells. This suggests that despite total cytostasis of the major population of cells, a small fraction of cells is capable of dividing at a near normal rate if removed from the drug environment. Implications of these results for in vivo applications of DAC are discussed.
 ...
PMID:Effects of dose and duration of exposure on 5-aza-2'-deoxycytidine cytotoxicity for L1210 leukemia in vitro. 621 Jan 41

We have investigated whether cytarabine (AraC) or decitabine (DAC) induce deficiency of deoxycytidine kinase (DCK) through different mutations of the dck gene, related to their distinct interference with DNA replication. Also, it is not known whether mutations of the dck gene are the result of selection of mutants or de novo induction. To address these issues, three subclones of a rat leukemic cell line (RCL/O), sensitive to cytotoxicity mediated by AraC and DAC, were exposed to gradually increasing concentrations (from 0.1 to 10 microM) of either AraC or DAC over a 140 days vs a 180 days period. During the course of resistance induction DCK activity was monitored. We found that all clones acquired irreversible cross-resistance, at marginally cytotoxic AraC or DAC concentrations of 0.1 to 0.4 times the IC50 for the parental clones. Furthermore, all resistant cell lines were DCK deficient and harbored different mutations in the dck gene. AraC induced both rearrangements and point mutations in the dck gene when administered over 140 days and 180 days, respectively. 140 days DAC induction yielded point mutations only. All point mutations detected were nonrandomly distributed within the dck coding region. SSCP analysis showed that in the majority of resistant clones more than one bandshift was present. The data suggest the presence of multiple resistant clones, originating from one sensitive clone and thus arguing against selection of mutants as a mechanism for the development of AraC and DAC resistance.
Leukemia 1995 Jun
PMID:De novo induced mutations in the deoxycytidine kinase (dck) gene in rat leukemic clonal cell lines confer resistance to cytarabine (AraC) and 5-aza-2'-deoxycytidine (DAC). 754 Oct 96

Twenty two patients with acute relapsed leukemia (AML 20, ALL 2) were treated with 5-aza-2'-deoxycytidine (DAC) and either m-amsacrine or idarubicin. DAC was administered as a 6-h infusion, every 12 h for 6 days in combination with either m-amsacrine (120 mg/m2) as a 1-h infusion on days 6 and 7 (n = 19) or idarubicin (12 mg/m2) as a 15-min infusion on days 5, 6 and 7 (n = 3). Thirteen patients (59%) achieved a complete remission. The treatment was complicated by nausea, vomiting, diarrhoea with signs of peritonitis (n = 9), weight loss (n = 7), cerebellar or cerebral toxicity (n = 2), gastrointestinal bleeding (n = 3), liver toxicity (n = 2) and prolonged myelosuppression. Median duration of remission was 4 months (range 1-30). The preliminary data show that DAC is an anti-leukemic agent, comparable to high dose Ara-C with comparable severe toxicity.
Leukemia 1993 May
PMID:Preliminary results with 5-aza-2'-deoxycytidine (DAC)-containing chemotherapy in patients with relapsed or refractory acute leukemia. The EORTC Leukemia Cooperative Group. 768 57

Deoxycytidine kinase activity (dCk) was monitored in cell lines from a rat acute myeloid leukemia model of acquired resistance to cytosine arabinoside (AraC) and decitabine (DAC). In both AraC-resistant cell lines (RCL/A and its subclone RA/7), as well as in a DAC-resistant cell line (RCL/D) which we generated from the drug-sensitive RCL/0 cell line, a total deficiency of dCk activity and a cross-resistance for AraC and DAC was demonstrated. Furthermore, the metabolization of deoxycytidine (dC) was severely impaired in all these cell lines. Km values for dC (9.4 microM in RCL/0 cells) had increased 70- to 100-fold in RCL/D (Km = 673.2 microM), in RCL/A (Km = 947.2 microM) and in RA/7 (Km = 817.5 microM). Vmax values were unaltered in RCL/D and RA/7, and twofold increased in RCL/A. Addition of hydroxyurea (HU) to cell cultures stimulated dCk salvage pathway activity in RCL/0 cells for dC, AraC, and DAC by increasing Vmax values approximately 160% leaving Km constants unchanged. In all resistant cell lines, HU pre-incubation did not influence the level of dCk activity, leaving Km and Vmax values unaltered. These data indicate that deficiency of dCk activity is crucial in the mechanism of drug resistance in this model.
Leukemia 1993 Jul
PMID:Role of deoxycytidine kinase in an in vitro model for AraC- and DAC-resistance: substrate-enzyme interactions with deoxycytidine, 1-beta-D-arabinofuranosylcytosine and 5-aza-2'-deoxycytidine. 768 1

Multidrug resistance (MDR) is a major problem in patients with hematological malignancies. Although drug-resistance is known to be induced by the expression of P-glycoprotein (P-gp) encoded by the MDR-1 gene, little is known about the mechanisms regulating this gene. Herein, we studied the DNA methylation patterns at the enhancer and repressor binding sites of the MDR-1 gene using the human erythroleukemia cell line K562 and its multidrug resistant derivative K562/ADM (adriamycin). Direct DNA sequence analysis demonstrated methylation to be present at the repressor site (minus 110 GC-box) of the MDR-1 gene in K562/ADM cells, but not in parental K562 cells. Methylation-specific PCR (MSP) analysis yielded similar results. Treatment of K562/ADM cells with 5-Aza-2'-deoxycytidine (decitabine; DAC), an inhibitor of DNA methyltransferase, caused demethylation of the repressor binding site of MDR-1 gene, as assessed by MSP, and also decreased P-gp expression, as assessed by flow cytometric and Northern blot analysis. Although it is generally accepted that DAC upregulates gene expression by demethylating the activator binding sites, our present results suggest that DAC induces down-regulation of P-gp expression as a result of demethylation at the repressor binding site in K562/ADM cells. In this regard, methylation-dependent regulation of the MDR-1 gene in K562/ADM cells is unique.
Leukemia 2000 Nov
PMID:Decitabine (5-Aza-2'-deoxycytidine) decreased DNA methylation and expression of MDR-1 gene in K562/ADM cells. 1106 27

Decitabine [NSC 127716, DAC, dezocitidine, Aza dC, 2'-deoxy-5-azacytidine] is a deoxycytidine and cytarabine derivative with potent antileukaemic activity, which was originated by Pharmachemie. This antimetabolite is able to induce in vitro gene activation and cellular differentiation by a mechanism involving DNA hypomethylation. SuperGen acquired worldwide rights to decitabine from Pharmachemie in the third quarter of 1999 for 4 million US dollars worth of SuperGen shares and income from manufacture upon the launch of decitabine. SuperGen announced in May 2000 that it had entered a Cooperative Research and Development Agreement (CRADA) with the US National Cancer Institute (NCI). SuperGen will supply decitabine to the NCI, which will initiate and sponsor clinical trials in patients with solid tumours and haematological malignancies. The NCI will also conduct studies on decitabine's mechanism of action. In 2002, the US FDA has granted decitabine orphan drug status for the treatment of myelodysplastic syndromes and sickle cell anaemia. In February 2003, the European Commission granted orphan drug status to decitabine for myelodysplastic syndrome. Decitabine has also received orphan drug status in the US as a host-protective agent in the treatment of AML. Decitabine has been studied in solid tumours as well as in different types of leukaemia. In several phase II studies it has been shown to have very limited efficacy against solid tumours. However, decitabine has shown better activity in the treatment of haematological malignancies such as acute myeloid leukaemia (AML), chronic myeloid leukaemia (CML) and myelodysplastic syndrome (preleukaemia). In March 2001, SuperGen announced that it had begun patient enrolment into its pivotal open-label phase III trial of decitabine in advanced myelodysplastic syndrome patients. The study, which will compare decitabine with standard care therapy, will be conducted at 15 medical centres in the US and will enrol a total of 160 patients. In March 2003, SuperGen announced that patient enrolment was complete. The study, which will compare decitabine with standard care therapy, will be conducted at 22 medical centres in the US and will enrol a total of 160 patients. A European pivotal trial is also underway for the same indication, and is aiming to enrol 220 patients. A phase I/II trial of 8 patients, designed to establish safety and efficacy in the treatment of sickle cell anaemia, has been completed at the University of Illinois, USA. Plans for additional studies of decitabine as a treatment for sickle cell anaemia are underway. Decitabine is also undergoing phase II clinical trials in Canada, for the treatment of non-small cell lung cancer, and in the US for chronic myeloid leukaemia and prostate cancer. Glasgow University in Scotland has conducted preclinical trials in chemotherapy-resistant ovarian and colon cancers. The results suggest that decitabine administration may reverse chemotherapy resistance in these cancers. SuperGen was issued a US patent (No. 6 191 119) in 2001 covering the use of decitabine in combination with rubitecan and antibiotic agents, including doxorubicin.
 ...
PMID:Decitabine: 2'-deoxy-5-azacytidine, Aza dC, DAC, dezocitidine, NSC 127716. 1275 5

Decitabine [NSC 127716, DAC, dezocitidine, Aza dC, 2'-deoxy-5-azacytidine, Dacogen( trade mark )] is a deoxycytidine and cytarabine derivative with potent antileukaemic activity, originated by Pharmachemie. This antimetabolite is able to induce in vitro gene activation and cellular differentiation by a mechanism involving DNA hypomethylation. Decitabine has been studied in several phase II trials for solid tumours as well as in different types of leukaemia. The drug has been shown to have very limited efficacy against solid tumours. However, decitabine exhibits higher activity for the treatment of haematological malignancies. SuperGen announced that it had entered a Cooperative Research and Development Agreement (CRADA) with the US National Cancer Institute (NCI) in May 2000. SuperGen will supply decitabine to the NCI, which will initiate and sponsor clinical trials in patients with solid tumours and haematological malignancies. The NCI will also conduct studies on decitabine's mechanism of action. SuperGen had previously acquired worldwide rights to decitabine from Pharmachemie in the third quarter of 1999 for 4 million US dollars worth of SuperGen shares and income from manufacture upon the launch of decitabine. The drug is undergoing two phase II trials for the treatment of cytomegalovirus leukaemia (CML) in the US, one of which will assess the safety, response rate, duration of response, and survival of decitabine (injection) in combination with imatinib mesylate (oral). SuperGen initiated a phase II clinical study of decitabine in combination with imatinib mesylate in June 2003 that will be conducted under SuperGen's CRADA with the National Cancer Institute and will take place at the MD Anderson Cancer Center in the US. Approximately 80 patients with CML will be enrolled in the study. This followed on decitabine's orphan drug status for the same indication, which was granted by the US FDA in 2002. In addition, the European Commission has granted orphan drug status to decitabine for MDS treatment in February 2003. In March 2003, SuperGen announced that patient enrolment was completed for its open-label, phase III trial comparing decitabine with standard care therapy for treatment of advanced myelodysplastic syndrome, which was initiated in March 2001. The study will be conducted at 22 medical centres in the US and will enrol a total of 160 patients. A pivotal trial is also underway in Europe for the same indication and is aiming to enrol 220 patients. In addition, decitabine is undergoing phase II trials for the treatment of non-small cell lung cancer (NSCLC) in Canada and for prostate cancer in the US. In July 2003, SuperGen was issued a US patent relating to decitabine as part of a combination therapy with other anticancer agents to treat ovarian, breast, prostate, gastric, lung, pancreatic and colon cancers through the correction of DNA hypermethylation. SuperGen was issued a US patent (No. 6 191 119) in 2001 covering the use of decitabine in combination with rubitecan and antibiotic agents, including doxorubicin.
 ...
PMID:Decitabine: 2'-deoxy-5-azacytidine, Aza dC, DAC, dezocitidine, NSC 127716. 1458 64

In order to observe the effect of inhibitors for demethylation and histone deacetylase on the growth of leukemia cell line K562 and the expressin of tumor related genes, the K562 cells were treated with 5-aza-2' deoxycytidine (DAC) and trichostatin A (TSA) in co-culture; the growth curves were observed; the cell cycle was detected by flow cytometry (FCM); the gene expression pattern before and after drug treatment was measured with Atlas7742-1 microarray. The results showed that the combination treatment of DAC and TSA inhibited the proliferation of K562 cells, the growth of most cells were stopped in G(1)/S phases after drug treatment, the gene expression after treatment was more than before, and a few gene expression were down-regulated. In conclusion, combination treatment of DAC and TSA had an inhibitive effect on the leukemia cell line K562, combination of DAC and TSA with microarray could be used for screening candidate genes inhibiting leukemia cells.
 ...
PMID:[Effect of inhibitors for demethylation and histone deacetylase on proliferation of cell line K562 and expression of tumor related genes]. 1498 67

To assess the efficacy of an original DAC-7 regimen: daunorubicine (DNR) 60 mg/m2/day, days 1-3; cytarabine (AraC) 200 mg/m2/day, days 1-7; cladribine (2-CdA) 5 mg/m2/day, days 1-5, 400 untreated adult acute myeloid leukemia patients (including 63 with preceding myelodysplastic syndrome), aged 45 (16-60) years were randomized to either DAC-7 (n=200) or DA-7 (without 2-CdA, n=200). The overall CR rate equaled 72% for DAC-7 and 69% for DA-7 arm (P=NS). After a single course of DAC-7 induction, the CR rate equaled 64% and was significantly higher compared to 47% in the DA-7 arm (P=0.0009). Median hospitalization time during the induction was 7 days shorter for DAC-7 compared to the DA-7 group (33 vs 40 days, P=0.002). Toxicity was comparable in both groups. The probability of 3-year leukemia-free survival (LFS) for DAC-7 and DA-7 group equaled 43 and 34%, respectively (P=NS). There was a trend toward higher LFS rate for patients aged >40 years receiving DAC-7 compared with DA-7 regimen (44 vs 28%, P=0.05). This study proves that addition of 2-CdA increases antileukemic potency of DNR+AraC regimen, thus resulting in a higher CR rate after one induction cycle when compared to DA-7, without additional toxicity. It shortens hospitalization time and may improve long-term survival in patients aged >40 years.
Leukemia 2004 May
PMID:Addition of cladribine to daunorubicin and cytarabine increases complete remission rate after a single course of induction treatment in acute myeloid leukemia. Multicenter, phase III study. 1499 98


1 2 3 4 Next >>