Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023467 (acute myeloid leukemia)
 35,200 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The in vivo development of an ara-C-resistant leukemic cell line is reported in a rat leukemia model (BNML) that is generally accepted as a relevant model for human acute myelocytic leukemia. It took 32 continuous leukemia transplant generations, performed over 20 months, and a total dose of 28.5 g ara-C/kg to induce complete resistance. Preliminary data indicate that the development of ara-C resistance is related with decreased intracellular levels of deoxycytidine kinase. Deoxycytidine deaminase levels were not increased. Thus this enzyme does not seem to be involved with induction of resistance. This preclinical rat model for human AML provides a solid basis for studies in depth on the mechanism(s) and possible prevention and effective treatment of resistance to ara-C.
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PMID:In vivo development of cytosine arabinoside resistance in the BN acute myelocytic leukemia. 347 77

In vitro uptake and retention of 3H-cytosine arabinoside (ara-C) was studied in 68 acute myelogenous leukemia (AML) patients (ten were studied twice) treated with a regimen containing conventional (54 patients) or high doses (24) of ara-C. Drug uptake and retention after four hours were measured following 30 minutes exposure to 1 and 50 micrograms/mL of ara-C. A good correlation was observed between high uptake in the acid soluble (AS) fraction (P less than .01), or high retention in the acid insoluble (Al) fraction (P less than .03) of 1 microgram, but not 50 micrograms, of the drug and obtainment of complete remission (CR) in patients treated with conventional doses of ara-C. Patients with a high percentage of ara-C retained in the AS fraction (greater than 26%) have a significantly longer CR duration than patients with a lower level of retention (P less than .02). In 17 patients who achieved a CR in spite of a low tritiated ara-C uptake, the clonogenic leukemic (CFU-L) cells were especially sensitive to drugs (15 of 17 v three of 11 among resisting patients).
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PMID:Prognostic value of in vitro uptake and retention of cytosine arabinoside in acute myelogenous leukemia. 347 80

In the present study 55 patients with refractory acute myeloid leukemia (AML) (n = 44) and acute lymphoblastic leukemia (ALL) (n = 11) were treated with high-dose cytosine arabinoside (HD-ara-C) and mitoxantrone (HAM) to assess the toxicity and antileukemic activity of the two-drug combination. All patients had received a standardized first-line therapy according to the corresponding multicenter trials of the German AML and ALL cooperative groups and were considered refractory to conventional treatment. Therapy consisted of HD-ara-C 3 g/m2 every 12 hours on days 1 to 4; mitoxantrone was started at 12 mg/m2/d on days 3, 4, and 5 and was escalated to four and five doses of 10 mg/m2/d on days 2 to 5 and 2 to 6. From the 44 patients with AML, 24 (54%) achieved a complete remission, two a partial remission, and five were nonresponders. Thirteen patients died of infections (n = 11), pericardiac effusion, or acute cardiomyopathy. In refractory ALL, seven of 11 patients (64%) went into a complete remission, one patient was resistant, and three patients were early deaths. Nonhematologic side effects consisted predominantly of nausea and vomiting, mucositis, and diarrhea. More severe CNS symptoms were encountered during five treatment courses. The median time to complete remission was 36 days. Excluding five patients who underwent bone marrow transplantations, the median remission duration was 4.5 months in AML and 2.3 months in ALL. The median survival time was three months for all patients and nine months for responders only. These data emphasize a high antileukemic activity of HAM in refractory AML and ALL and support the incorporation of the HAM regimen into first-line treatment.
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PMID:High-dose cytosine arabinoside in combination with mitoxantrone for the treatment of refractory acute myeloid and lymphoblastic leukemia. 347 85

Cytarabine (ara-C) is the first line agent with its excellent activity for acute myelogenous leukemia. Combination therapy of MFC (mitomycin C, 5-FU, ara-C) has been used for GI tract cancer with a synergistic effect on L-1210 mouse leukemia. In the results of research on the administration, a high dose ara-C is an effective agent in the refractory cases to the standard dose ara-C and the combination with daunorubicin is applied to a remission consolidation therapy. A small dose ara-C is used against an atypical leukemia with its mechanism of induction of differenciation. On the other hand, in the development of its derivertive compounds ancitabine or enocitabine (BH-AC) were induced to a treatment of acute myelogenous leukemia. Especially BH-AC is the first choice agent for acute myelogenous leukemia combined with other agents.
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PMID:[Cytarabine]. 347 3

Mitoxantrone is a synthetic aminoanthraquinone we have previously reported to be effective for patients with acute leukemia in relapse. We presently report the results of a trial of mitoxantrone in combination with cytosine arabinoside (ara-C) in patients with refractory or relapsed acute myelocytic leukemia (AML). Forty-nine patients, 24 males and 25 females, with a median age of 56, of whom 32 were in first relapse, four were in second relapse, and 13 had primarily refractory AML, were treated with mitoxantrone 10 mg/m2 daily for 3 days and ara-C 100 mg/m2 daily by continuous infusion for 7 days. Twenty patients (62.5%) with first relapse AML achieved M1 marrow, whereas only two of 13 patients with refractory AML did; none of four patients with more than one prior remission responded. Marrow recovery was observed in a median of 32 days. Remissions were maintained with monthly ara-C plus mitoxantrone alternating with ara-C plus 6-TG; median duration of remission was 8 months and two patients are in continuing remission at 8 and 16 months. Treatment was well tolerated, with minimal nausea and vomiting, diarrhea, drug-induced mucositis. Treatment-related cardiac toxicity was not observed. Transient hepatic dysfunction was observed in greater than 50% of courses. Mitoxantrone plus ara-C is an active combination with great promise for the therapy of previously untreated patients with AML.
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PMID:Mitoxantrone and ara-C in previously treated patients with acute myelogenous leukemia. 347 40

52 patients entered a study for remission induction and intensified consolidation in AML. Group I (age less than or equal to 50 years) received a combination of DNR, ara-C and VP16-213 for induction and early consolidation and HDara-C/DNR for late consolidation. Of 34 evaluable patients (25 first diagnosis, 9 first relapse), 27 achieved CR. 13 patients received 1-2 courses of HDara-C/DNR. Toxic symptoms of HDara-C/DNR were severe myelosuppression, infections, skin reactions, diarrhea and hepatotoxicity. CNS toxicity was not observed. 2 patients died from infection. The duration of granulocytopenia (less than 500/microliter) was 7-43 days (range) and of thrombocytopenia (less than 25,000/microliter) 5-34 days (range). Patients of group II (age greater than 50 years) received a modified regimen with reduced toxicity. Their number is too small for evaluation as yet.
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PMID:Age adapted induction and intensified consolidation therapy in acute myelogenous leukemia. 352 59

In a multi-institutional study 26 patients with refractory acute myeloid leukemia were entered into a phase I/II study of HD-ara-C and mitox. HD-ara-C 3 g/m2 q 12h was given by 3h infusion on days 1-4. Mitox was started at 12 mg/m2/d on days 3, 4 and 5, and escalated to 4 and 5 doses of 10 mg/m2/d on days 2-5 and 2-6, respectively. From 24 patients presently evaluable for response, 12 achieved a CR and 2 a PR. 7 patients died of infectious complications within the first 4 weeks of treatment while persistent AML was found in 3 cases. Except for one death, possibly related to acute cardiomyopathy, toxicity was mild to moderate consisting of nausea and vomiting, mucositis and diarrhea. These data indicate a high anti-leukemic activity of HD-ara-C/mitox in AML refractory against conventional chemotherapy.
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PMID:High-dose cytosine-arabinoside and mitoxantrone in refractory acute myeloid leukemia: a clinical phase I/II-study. 352 60

High-dose (HD) cytosine arabinoside (ara-C) is more effective treatment than conventional-dose ara-C regimens for patients with relapsed acute nonlymphocytic leukemia (ANLL). Previously, we have reported that HD-ara-C administered during the first remission of ANLL has resulted in long remission durations and a high proportion of patients with long-term disease-free survival. In this update, those patients have been observed further and additional patients have been treated, affirming the initial conclusions. Since August 1979, 55 adult patients with ANLL in first remission received one to three courses of HD-ara-C (3 g/m2 by one-hour infusion every 12 hours for 12 doses on days 1 to 6) alone or with daunorubicin (30 mg/m2 for two or three doses on days 7 to 9). Three patients died of sepsis or hemorrhage during consolidation and 19 patients have relapsed from 5 to 48 months after diagnosis. The remaining 33 patients remain in continued complete remission (CCR) from 5 to 75 months. Denoting all deaths in remission as relapse, the actuarial probability of CCR is 51% at 75 months with an apparent plateau in the survival curve. Of the first 22 patients is 27 months. Using univariate and multivariate analysis, age is the only statistically significant prognostic parameter with the actuarial CCR of ages less than 25, 25 to 44, and greater than 44 being 100%, 48%, and 23%, respectively. Due to its heightened antileukemic activity, HD-ara-C allows brief but effective consolidation of ANLL in first remission with long-term disease-free survival comparable with other approaches including bone-marrow transplantation.
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PMID:High-dose cytosine arabinoside and daunorubicin as consolidation therapy for acute nonlymphocytic leukemia in first remission: an update. 358 87

In consideration of the full spectrum of hematologic and nonhematologic toxicity juxtaposed to the response rates (Tables 2-5), it appears that for relapsed patients with AML, six to eight consecutive doses of HDara-C or four doses started on days 1 and 8 have the optimal therapeutic index. These regimens are associated with a 25% CR rate and have comparable tolerable and reversible toxicity spectra. An increase in the total number of doses to 12 does not appear to increase the remission frequency in relapsed patients but does decidedly increase the spectrum, frequency, and severity of toxic manifestations. Studies of important pharmacologic determinants such as membrane transport and cellular accumulation of ara-CTP suggest that a lower unit dose may be just as effective, an approach that could potentially lower the frequency and severity of toxicity. However, these concepts must be tested in suitably designed clinical trials. In contrast to the response rate noted in patients with relapsed AML, patients with refractory AML have a substantially lower CR rate (approximately 10%) when treated with HDara-C alone. These lower CR rates are comparable to those reported for other recently introduced new drugs such as m-AMSA and mitoxantrone. In this setting of primary refractory leukemia, multi-institutional and cooperative group trials of HD-ara-C----ASNase show a consistently higher response rate in the range of 30% to 50%. Why ASNase should especially contribute to this particular group is unknown at present. Studies show that the gene for asparagine synthetase is repressed in AML cells. It is speculated that in the initial leukemia cell population (as encountered in refractory AML), the gene for asparagine synthetase is repressed and hence, the leukemia is sensitive to ASNase. In contrast, in the relapsed patient with recurrent leukemia, the gene for asparagine synthetase may be derepressed and the leukemia would be ASNase-insensitive. The therapeutic index of HDara-C----ASNase is schedule dependent. In leukemic mice, pretreatment or concurrent administration of ASNase and HDara-C leads to antagonism of both the therapeutic and toxic effects of HDara-C. These effects are consistent with similar effects of other protein synthesis inhibitors on ara-C toxicity.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Sequential high-dose ara-C and asparaginase versus high-dose ara-C alone in the treatment of patients with relapsed and refractory acute leukemias. 358 97

The dose-response relationship between extracellular concentration of cytosine arabinoside (ara-C) and intracellular formation of the putative active metabolites of ara-C [ara-C incorporation into DNA and intracellular pools of ara-C in triphosphate form (ara-CTP)] was investigated in blast cells obtained from patients with acute nonlymphocytic leukemia (ANLL) by exposing these cells in vitro to 10, 100, or 1,000 nmol/L of ara-C. We studied 23 untreated patients who subsequently achieved complete remission (CR) with a regimen using daunorubicin and conventional doses of ara-C (ara-C-sensitive group), and 30 patients judged to be ara-C-resistant either by failing initial induction therapy (16 patients) or by having relapsed on an ara-C-containing maintenance regimen (14 patients). In both patient groups, ara-C incorporation into DNA and intracellular ara-CTP both displayed statistically significant increases in response to increasing extracellular concentrations of ara-C (P = .0001 in both cases), with the rate of increase of ara-CTP greater than that of ara-C incorporation. Moreover, blast cells from all patients, even those who were most clinically resistant to ara-C, were able to form ara-CTP and to incorporate ara-C into DNA. Each tenfold increment in extracellular ara-C concentration caused an 8.5-fold increase in ara-CTP, but only a 3.6-fold increase in ara-C incorporation into DNA. Thus, the efficiency of incorporation of ara-C into DNA (defined as the ratio of ara-C incorporation to ara-CTP pools) decreased by 58% with each tenfold increment in the extracellular concentration of ara-C (P less than .0001), presumably as a result of the inhibitory effect of ara-CTP on DNA polymerase. Using an analysis of covariance, modest differences were found in the levels of the ara-C metabolite variables in the ara-C-sensitive group as compared with the resistant group. However, because there was considerable overlap in ara-C metabolite formation among the patient groups, it was not possible to predict clinical outcome by these in vitro assessments of ara-C metabolism.
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PMID:Metabolism of ara-C by blast cells from patients with ANLL. 371 4


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