Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.3.1.107 (DAT)
 1,471 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In June 1984, the Pediatric Oncology Group (POG) initiated a pilot study (8498) using high-dose cytarabine (HdA; 3 g/m2) for intensification of early therapy in childhood acute myelogenous leukemia (AML) (group I). Remission induction therapy consisted of two courses of daunorubicin, cytarabine (Ara-C), and thioguanine (DAT). Postremission therapy consisted of four sequential courses, each consisting of (1) four doses of HdA (HdA4) followed by asparaginase (L-Asp), (2) etoposide (VP) plus azacytidine (Az), (3) prednisone, vincristine, methotrexate, and mercaptopurine (POMP), and (4) Ara-C daily for 5 days by continuous infusion. Six doses of intrathecal Ara-C were given for CNS prophylaxis. In December 1986, the protocol was amended (group II) to substitute six doses of HdA (HdA6) for the second DAT (two + five) induction course; postinduction, a single course of HdA6 was given instead of four HdA/L-Asp courses, and the remainder of the therapy was unchanged. One hundred forty group I patients and 145 group II patients were assessable. The two groups were similar with regard to clinical prognostic groups. No significant differences were noted in the two groups with regard to remission induction (85% [SE = 2%] in each group), induction deaths (6.5% v 7.0%), or deaths in remission (one in each group). Cerebellar toxicity was reported in three patients in group II (with HdA6) but none in group I (HdA4). At present, patients who received HdA6 (group II) had higher event-free survival than patients in group I (EFS at 3 years, 34% [SE = 11%] v 29% [SE = 4%]), and disease-free survival (DFS at 3 years, 42% [SE = 14%] v 34% [SE = 4%]), but the differences were not statistically significant. In both groups, children less than 2 years and those with WBCs less than 100,000/microL had significantly better outcome (EFS of 55% [SE = 10%] and 36% [SE = 5%] at 3 years, respectively) than children greater than or equal to 2 years and those with WBCs greater than or equal to 100,000/microL (EFS of 27% [SE = 5%] and 20% [SE = 9%] at 3 years, respectively.
 ...
PMID:High-dose cytarabine for intensification of early therapy of childhood acute myeloid leukemia: a Pediatric Oncology Group study. 206 54

A multicentric prospective pilot study using three different schedules of high-dose Ara-C at dosage of 3 g/m2 every 12 hours during 3 h of infusion was undertaken by the Italian Cooperative Group GIMEMA in order: 1. to evaluate the safety and efficacy of such treatment in previously untreated ANLL patients more than 50 years old; 2. to investigate whether the addition of a standard maintenance treatment after consolidation with 4 courses of DAT (Daunorubicin + Ara-C + 6-Thioguanine) could improve the duration of complete remission (CR) and the proportion of long-term survival. Overall 43/125 evaluable patients (34.4%) achieved CR. 32/125 died during the induction phase, the remaining 50 patients (40%) failed to achieve CR. As for the toxicity, the most significant toxicity of all schedules was hematologic. No substantial neurological or cardiac toxicity was observed. The multivariated analysis of several pretreatment characteristics revealed that age more than 60 yr, male sex and presence of infections at diagnosis were the most significant adverse factors for achievement of CR. The median duration of DFS for all responders was 9 months, with relapse-free survival at 4 yr estimated at 29%. The addition of maintenance treatment to consolidated patients had no advantages in respect to the control group, even though the statistical analysis revealed a p = 0.058. However, because of the small number of randomized patients, no conclusions can be drawn concerning the importance of maintenance treatment.
 ...
PMID:High-dose Ara-C (HiDAC) plus asparaginase in elderly patients with acute non-lymphocytic leukemia: a pilot multicentric study by the Italian Cooperative Group GIMEMA. 264 29

Ninety-six patients with de novo acute nonlymphocytic leukemia (ANLL) were randomized to receive either daunorubicin (50 mg/m2, IV) on days 1-3; cytarabine (Ara-C) (25 mg/m2, IV) bolus, followed by 160 mg/m2 as a continuous IV infusion daily for 5 days and 6-thioguanine (6-TG) (100 mg/m2 po) every 12 hr daily for 5 days (DAT); or amsacrine (190 mg/m2, IV) on days 1-3 with Ara-C and 6-TG at the above doses (AAT). Patients achieving complete remission (CR) then received two courses of consolidation therapy with the same combination that had induced remission but at slightly reduced total doses. Patients less than or equal to age 40 with an HLA-identical sibling donor underwent allogeneic transplantation, usually after consolidation therapy. The remaining patients were then randomized to receive either maintenance therapy (alternating cycles of vincristine/methotrexate, cyclophosphamide/6-TG, daunorubicin/hydroxyurea and Ara-C/6-TG) or no further treatment. Ninety-two patients were evaluable for response. Twenty-five of the 46 patients (54%) who received DAT and 32 of the 46 patients (70%) who received AAT achieved CR (p = 0.13). When patients were stratified by age, however, remission induction advantage with AAT became statistically significant (p = 0.03). Additionally, more patients achieved CR following one course of AAT than following one course of DAT (48% vs 28%, p = 0.03). Overall survival in the AAT group was improved as well (p = 0.01). Too few patients were randomized on the maintenance arm of the protocol to make interpretation meaningful. Non-hematologic toxicity was generally comparable in both arms. In conclusion, patients with de novo ANLL who received AAT had a higher remission incidence and slightly longer survival compared to patients who received DAT. Further investigation of this drug combination in untreated patients with ANLL is warranted.
 ...
PMID:Comparative trial of cytarabine and thioguanine in combination with amsacrine or daunorubicin in patients with untreated acute nonlymphocytic leukemia: results of the L-16M protocol. 291 Dec 5

Thirty-five patients with acute myelogenous leukemia were treated with aclacinomycin A (60 mg/m2/day for 5 days) and VP-16-213 (100 mg/m2/day for 5 days). All were previously treated and had relapsed or were refractory to primary treatment. Most patients (28) had received prior DAT (daunorubicin, cytosine arabinoside, and 6-thioguanine) induction therapy followed by one or more courses of high-dose cytosine arabinoside (HD-Ara C) as consolidation therapy or as treatment for relapse. One patient was in her fourth relapse, one had relapsed acute megakaryoblastic leukemia (following remission with DAT and HD-Ara-C), one had a treatment-induced leukemia, and four patients were treated for primary treatment failures following two induction courses with DAT or a similar regimen. Fourteen patients had infections at start of therapy. Ten patients died within 14 days of treatment, all from sepsis or bleeding, before their marrow could be evaluated for leukemic response. Fourteen patients (40%) responded; 12 (34%) entered complete remission and two (6%) a partial remission (PR). Two of the four patients who were treated for primary treatment failures went into CR. The median CR duration was 99 days (range 30 to 455 days). Side effects from this treatment were similar to the conventional DAT regimen, although the gastrointestinal toxicity and mucositis appeared to be more severe. In addition, two of the patients had severe but reversible ventricular arrhythmias. The overall response (40%) and CR rate (34%) in this group of previously treated AML patients is encouraging, and further studies are needed to evaluate these preliminary findings.
 ...
PMID:Aclacinomycin A and etoposide (VP-16-213): an effective regimen in previously treated patients with refractory acute myelogenous leukemia. 316 95

There has been important progress in the treatment of Acute Myeloid Leukaemia (AML) in patients under 60 years. A remission rate of 80% can be achieved by several schedules, and 40-45% of patients diagnosed will survive. It may still be possible to improve remission induction treatment eg by intensifying the Ara-C dose although may this only be detectable in an improved disease free survival. The is to reduce relapse. The risk main challenge is pre-determined by a number of powerful risk factors. In the experience of the MRC age, cytogenetics and clearance of blasts from the bone marrow after course 1. Using the later two in combination good risk patients (FAB M3, t(8;21) t(15;17) inv(16)) have a relapse risk of 32%. Poor risk (blasts >15% after course 1 or abnormalities of Chs 5 or 7, 3q- and complex changes have a relapse risk of 82%. All other cases are standard risk and ve a relapse risk of 56%. FLT3 mutations have been detected in about 25% of cases and provide additional negative predictive value overall and within each risk group. The assessment of the most effective consolidation treatment must be made taking into account the heterogeneity of the relapse risk. The MRC investigated the role of allo and autoBMT in addition to intensive chemotherapy. The data was analysis on an intent-to-treat or donor vs no donor basis. Although both types of transplant were able to reduce relapse overall and in all risk groups, there was an overall survival advantage only in standard risk patients. Since chemotherapy has improved since this study, there remains uncertainty about the benefit of transplant in all risk groups. Overall this experience has demonstrated that relapse can be reduced with more therapy. It is probable that the limits of conventional chemotherapy have been reached. The new AML15 trial will assess the value of adding the immunoconjugate (Mylotarg) to induction and/or chemotherapy. Improvements in older patients have been less detectable. MRC trials over the last 20 years show an improvement in remission rate (now 65%) but persistent poor survival (12% at 5 years). In the MRC AML11 Trial three induction schedules were compared (DAT vs ADE vs MAC) with DAT being superior. A comparison of a total of 3 vs 6 courses of treatment or the addition of interferon maintenance did not improve results. Newer approaches currently being assessed include resistance modulation; addition of immunoconjugate and minigrafts. New targets for treatment are emerging of which the most interesting is FLT3 inhibitors.
 ...
PMID:Progress in the treatment of acute myeloid leukaemia in adults. 1243 Aug 60