Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023473 (chronic myeloid leukemia)
 18,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Deoxycytidine kinase, which phosphorylates deoxycytidine (CdR) and its analog, cytosine arabinoside (ara-C), has been purified 71-fold from human leukemic cells. Biochemical properties of the partially purified enzyme included a molecular weight of 68,000, Kms of 7.8 muM for CdR and 25.6 muM for ara-C, and optimal activity with ATP and GTP as phosphate donors. Ara-C phosphorylation was strongly inhibited by CdR (Ki = 0.17 muM) and dCTP (Ki = 7.3 muM) and was weakly inhibited by ara-CTP (Ki = 0.13 mM). Purification by calcium phosphate gel elution and DEAE chromatography effectively separated this enzyme from cytidine deaminase, which deaminates both CdR and ara-C, and from uridine-cytidine kinase, the enzyme which phosphorylates 5-azacytidine. CdR kinase activity was found to decrease and cytidine deaminase to increase with maturation of normal and leukemic granulocytes. Myeloblasts purified by Ficoll sedimentation revealed an average kinase activity of 15.4 U/mg protein in acute myelocytic leukemia and 12.3 U/mg protein in blastic crisis of chronic myelocytic leukemia (CML). The average ratio of CdR kinase to deaminase activity in crude cell extracts varied from 0.197 in AML and 0.089 in blastic crisis to 0.0004 in normal granulocytes, reflecting the changes which take place with cellular maturation. The absolute levels of kinase and deaminase and the ratio of these two enzymes varied considerably among patients with AML, indicating that quantitative differences may be found in the metabolism of CdR and its analogs in leukemic cells.
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PMID:Deoxycytidine kinase: properties of the enzyme from human leukemic granulocytes. 5 55

2-Chloro-9-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)-adenine (Cl-F-ara-A) has activity against the P388 tumor in mice on several different schedules. Biochemical studies with a chronic myelogenous leukemia cell line (K562) grown in cell culture have been done in order to better understand its mechanism of action. Cl-F-ara-A was a potent inhibitor of K562 cell growth. Only 5 nM inhibited K562 cell growth by 50% after 72 h of continuous incubation. The 5'-triphosphate of Cl-F-ara-A was detected by strong anion exchange chromatography of the acid-soluble extract of K562 cells incubated with Cl-F-ara-A. Competition studies with natural nucleosides suggested that deoxycytidine kinase was the enzyme responsible for the metabolism to the monophosphate. Incubation of K562 cells for 4 h with 50 nM Cl-F-ara-A inhibited the incorporation of [3H]thymidine into the DNA by 50%. Incubation with 0.1, 1, or 10 microM Cl-F-ara-A for 4 h depressed dATP, dCTP, and dGTP pools but did not affect TTP pools. Similar inhibition of deoxyribonucleoside triphosphate pools was seen after incubation with 2-chloro-2'-deoxyadenosine. Both Cl-F-ara-ATP and Cl-dATP potently inhibited the reduction of ADP to dADP in crude extracts of K562 cells (concentration producing 50% inhibition, 65 nM). The effect of Cl-F-ara-ATP on human DNA polymerases alpha, beta, and gamma isolated from K562 cells grown in culture was determined and compared with those of Cl-dATP and 9-beta-D-arabinofuranosyl-2-fluoroadenine triphosphate (F-ara-ATP). Cl-F-ara-ATP was a potent inhibitor of DNA polymerase alpha. Inhibition of DNA polymerase alpha was competitive with respect to dATP (Ki of 1 microM). The three analogue triphosphates were incorporated into the DNA by DNA polymerase alpha as efficiently as dATP. The incorporation of Cl-F-ara-AMP inhibited the further elongation of the DNA chain, similarly to that seen after the incorporation of F-ara-AMP. Extension of the DNA chain after the incorporation of Cl-dAMP was not inhibited as much as it was with either Cl-F-ara-AMP or F-ara-AMP. Cl-F-ara-ATP was not a potent inhibitor of DNA polymerase beta, DNA polymerase gamma, or DNA primase.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Effects of 2-chloro-9-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)adenine on K562 cellular metabolism and the inhibition of human ribonucleotide reductase and DNA polymerases by its 5'-triphosphate. 170 52

Thirteen patients with leukemia were treated with a combination of cytosine arabinoside (ara-C) (3 g/m2 by 1-h infusion every 12 h for 12 doses) and etoposide (100 mg/m2 daily over 1 h for 3 doses). Toxicity of the regimen consisted of severe hematologic suppression, moderate abdominal colic with vomiting and diarrhea, and occasionally severe central nervous system (CNS) toxicity. Two patients received the regimen as consolidation for acute myelogenous leukemia in remission. Of the remaining 11 patients with chronic myeloid leukemia (CML)-blast crises or relapsed/refractory acute myeloid leukemia (AML), nine patients (82%) obtained CR (or chronic phase) and two patients obtained partial remission (PR). High-dose ara-C and etoposide is an effective but toxic regiment for the treatment of relapsed or refractory myeloid leukemias.
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PMID:High-dose cytosine arabinoside and etoposide in the treatment of relapsed or refractory adult leukemia. 198 40

We previously administered ara-C at a dose rate of 250 mg/m2/hr for 36-72 hr to patients with leukemia. Gastrointestinal toxicity was dose-limiting. This regimen was modified to an every other day schedule, administering 24-hr periods of high dose continuous infusion ara-C, each followed by a 24-hr rest period. Sixteen patients with relapsed/refractory acute myeloid leukemia (AML) (N = 4), secondary AML (N = 2), relapsed/refractory acute lymphoblastic leukemia (N = 7), or CML in blast crisis (N = 3) received this regimen of three 24-hr infusions with two intercurrent 24-hr rest periods. Grade 3 gastrointestinal toxicity was encountered in 57% of the courses, and hypoplasia was achieved in all patients. Three of the patients died while hypoplastic, two with septicemia and another with intracranial hemorrhage. There were five responding patients (2 CRs, 3 PRs). Median steady-state plasma ara-C levels were 24 microM, 22 microM, and 20 microM during the first, second, and third 24-hr infusions, respectively. Ara-C levels ranged from 4-118 microM during the infusions and were always below 4.5 microM during the rest periods. A significant level of ara-C incorporation into DNA was detected in each of the five patients studied, thus demonstrating that (ara-C)DNA formation is detectable in blasts from patients receiving high dose continuous infusion ara-C therapy. These findings suggest that alternate day continuous infusion ara-C may be useful in the treatment of acute leukemia and CML in blast crisis.
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PMID:A phase I study of intermittent continuous infusion high dose cytosine arabinoside for acute leukemia. 224 7

35 patients with refractory or relapsed acute leukemia received salvage chemotherapy using high-dose cytosine arabinoside 2 g/m2 intravenously for 3 hours every 12 h, in 8 doses, followed by continuous infusion of mitoxantrone 12 mg/m2/day for 2 d. 9 patients had acute myeloblastic leukemia (AML), (4 relapsed, 5 refractory), 20 had acute lymphoblastic leukemia (ALL) (11 relapsed, 9 refractory) and 6 had chronic myelogenous leukemia (CML) in the blastic phase (BP). 4 out of 9 AML and 16 out of 20 ALL achieved complete remission. Median survival was 6 months for all patients and 10 months for responders. A short (1.5 months) chronic phase was achieved in 3 patients with CML. The main toxic effect was hematologic. A pharmacokinetic study was performed on mitoxantrone. No correlation was found with clinical response. The combination of mitoxantrone and ara-C is an effective antileukemic regimen, especially in ALL.
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PMID:High-dose cytosine arabinoside and mitoxantrone in previously-treated acute leukemia patients. 234 86

Ara-C sensitivity test and suicide tests of L-CFU using [3H] deoxycytidine (dCyd) and [3H] thymidine (TdR) were performed in patients with acute nonlymphocytic leukemia (ANLL) and with chronic myeloid leukemia in blastic crisis (CML-BC). We found a correlation between ara-C sensitivity and the [3H] dCyd suicide test of L-CFU (p less than 0.001); and between ara-C sensitivity and the [3H] TdR suicide test (p less than 0.05). These results suggest that the [3H] dCyd suicide test reflects the degree of activity of ara-C metabolism in L-CFUs.
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PMID:[Relationship between Ara-C sensitivity of leukemic-colony forming units (L-CFU) and [3H] deoxycytidine suicide test of L-CFU]. 261 40

A high dose of cytosine arabinoside (ara-C) was given to 51 patients during consolidation therapy or with refractory or relapsed acute leukemia. Ara-C was administered as a 3-hour infusion at a dose ranging from 2 to 3 g/m2 every 12 hours, diluted in 500 ml of 5% dextrose in water for 2 to 6 days. Complete remission was attained in 3 (25%) of 12 evaluable patients. Two with blast crisis of chronic myelogenous leukemia of these did not obtain complete remission. Death due to marrow aplasia occurred in five patients, and two of these had relatively good performance status and were given a dose of 3.0 g/m2 x 8 or 12 of ara-C. At a dose of 3.0 g/m2 x 6, the mean duration of granulocytes of less than 100/mm3 was 6.7 days. This duration seemed to be manageable myelosuppression. Therefore, 3.0 g/m2 x 6 was thought to be an adequate dose. Seizure occurred in one patient, and conjunctivitis was seen in another. In conclusion, from the manageable myelosuppression observed, administration of 3.0 g/m2 x 6 of ara-C seemed to be an adequate dose.
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PMID:[High-dose cytosine arabinoside treatment of leukemia with special reference to the optimal number of doses]. 277 89

We conducted a Phase I-II trial of 4-demethoxydaunorubicin (idarubicin, IDR) in combination with 1-beta-D-arabinofuranosylcytosine (ara-C) in 51 patients with relapsed or refractory acute nonlymphocytic leukemia, acute lymphocytic leukemia, or chronic myelogenous leukemia in blast crisis. Only 1 of 12 patients treated at the first dose level (idarubicin, 10 mg/m2/day for 3 days and ara-C, 25 mg/m2 i.v. bolus followed by 200 mg/m2 continuous infusion daily for 5 days) achieved aplasia and complete remission. The dose of idarubicin was subsequently increased to 10 mg/m2/day for 4 days with the ara-C dose held constant. Complete remission incidence for this dose schedule was: 7 of 31 patients with acute nonlymphocytic leukemia, 0 of 5 patients with acute lymphocytic leukemia, 0 of 1 patient with chronic myelogenous leukemia in blast crisis, and 1 of 2 patients with biphenotypic leukemia. Nonhematological toxicity included nausea, vomiting, mucositis, and abnormal liver function tests. Detailed pharmacological studies were performed to determine whether ara-C altered IDR metabolism or that of its main metabolite, 13-hydroxyidarubicinol or IDR clearance. A high degree of variability among patients was apparent and no consistent effect could be demonstrated. In summary, 9 of 37 patients (24%) with relapsed or refractory ANLL, including 1 patient with biphenotypic leukemia, achieved remission. We conclude that idarubicin in combination with ara-C is an active combination in patients with relapsed or refractory leukemia.
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PMID:4-demethoxydaunorubicin (idarubicin) in combination with 1-beta-D-arabinofuranosylcytosine in the treatment of relapsed or refractory acute leukemia. 291 Apr 65

Between April 1982 and March 1983, 10 of 26 (38.4%) allogeneic bone marrow transplant recipients housed on a newly opened bone marrow transplant unit developed invasive aspergillosis. By contrast, between September 1977 and March 1982, only 3 of 46 (6%) transplant recipients developed invasive aspergillosis. A case-control study to identify host factors related to Aspergillus infection found that aspergillosis was more common in patients with chronic myelogenous leukemia and aplastic anemia, older patients, patients having cytomegalovirus disease, patients who experienced prolonged granulocytopenia, patients conditioned with ara-C (100-200 mg/day), and patients who received longer duration of antimicrobial therapy. A series of logistic regression analyses revealed that underlying disease was the single best predictor of Aspergillus infection. This study demonstrates that underlying disease is an important risk factor for aspergillosis and that special measures may be warranted when transplanting certain patients.
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PMID:An outbreak of invasive aspergillosis among allogeneic bone marrow transplants: a case-control study. 299 69

Twenty-nine patients were conditioned for allogeneic marrow transplant with cytarabine (ara-C) (3 g/m2 every 12 hours for 12 doses) and total body irradiation (TBI) (200 cGy daily for six days) with or without cyclophosphamide (CY) (60 mg/kg) to determine toxicity and efficacy. Four patients had chronic myelogenous leukemia (CML) in accelerated phase or blast crisis, and 25 patients had acute leukemia, 24 at stages later than first remission. Three patients (10%) had fatal regimen-related toxicity and another 10% experienced severe toxicity in at least one organ system. The addition of CY to the ara-C and TBI regimen was not associated with an increase in the frequency of severe toxicity. Twenty-five of 29 patients engrafted eight to 33 days posttransplant: three died early before engraftment, and one patient failed to engraft. Ten of 29 patients are alive without disease, and the actuarial probability of disease-free survival for the entire group at 3 years is 33%. Three of ten patients with acute nonlymphocytic leukemia (ANL), six of 15 with acute lymphocytic leukemia (ALL), and one of four with CML are alive and disease free 25 to 42 months (median, 30 months) after transplant. High-dose ara-C (HDara-C) and TBI with or without CY can be administered with approximately the same toxicity as CY plus TBI. Phase III studies appear warranted to determine if these newer regimens provide improved results compared with currently used regimens.
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PMID:High-dose cytarabine and total body irradiation with or without cyclophosphamide as a preparative regimen for marrow transplantation for acute leukemia. 328 31


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