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

A comparison has been made between the cloning capacity and changes in tritiated deoxyuridine (6-[3H]-UdR) incorporation of L1210 (murine leukaemia) and PMC-22 (human melanoma) cells treated with methotrexate (MTX), 5-fluorouracil (5-FU) and cytosine arabinoside (ARA-C). The labelling-cloning relationship was poor, with brief drug exposure times, but improved progressively after drug treatment of 1 cell-cycle time's duration. Labelling changes resulting from short-term exposure to drug (several hours) provided poor predictions of the cytotoxicity resulting from longer drug exposure.
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PMID:Assessment of antimetabolite cytotoxicity: a comparison of clonogenic assays and tritiated deoxyuridine incorporation. 668 75

Resistance of leukemia cells to cytosine arabinoside (ARA-C) may be due to any one or combination of biochemical processes, which in certain instances may be substantially reversed by an appropriate increase in ARA-C dosage. Based on these and other laboratory observations indicating pharmacologic synergy between sequential high-dose ARA-C and asparaginase (HiDAC----ASNase), a therapeutic program was developed for the treatment of patients with acute nonlymphocytic leukemia (ANLL) refractory to conventional doses of ARA-C, as well as patients with high risk ANLL and advanced acute lymphocytic leukemia (ALL). Treatment consisted of 3-hr intravenous infusions of 3 g/sq m of ARA-C given at 12-hr intervals for 4 doses, followed by 6,000 IU/sq m ASNase given i.m. at hour 42. The same schedule was repeated on day 8. In 32 induction attempts, only 4 patients proved to be truly refractory, i.e., failed to achieve substantial leukemia cell cytoreduction. Complete remissions were achieved with HiDAC---- ASNase in 9 of 13 patients with refractory ANLL, 6 of 9 patients with antecedent hematologic disorders, and 3 of 10 patients with advanced ALL. These include 9 of 14 patients who had either failed induction or who had relapsed on active ARA-C therapy and 6 of 8 patients who had had no prior exposure to ARA-C. The median duration of unmaintained remission in ANLL was 5 mo. In a patient with central nervous system (CNS) leukemia, there was clearance of cerebral spinal fluid (CSF) blasts without intrathecal therapy, suggesting a role for HiDAC in CNS prophylaxis. In general, toxicity was tolerable and reversible. These data suggest that HiDAC----ASNase is an exceptionally effective and well tolerated regimen in leukemic patients with antecedent hematologic disorders and in those refractory to conventional doses of ARA-C.
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PMID:Treatment of poor risk acute leukemia with sequential high-dose ARA-C and asparaginase. 669 96

Children suffering from leukaemia in Hungary are treated according to uniform therapeutic protocols in the framework of a national multi-centre study. Their most important clinical data are stored in the central registry and are analyzed by computerized methods. Since January, 1971, 846 new patients were entered in the registry. Initially treatment results were very poor but showed gradual improvement during the past few years, somewhat parallel to more intensive chemotherapy. The latest treatment protocol includes medium-dose MTX and the combination of ARA-C and VM-26. Preliminary data are encouraging.
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PMID:The treatment of childhood leukaemia in Hungary. On behalf of the Hungarian Working Party on Childhood Leukaemia. 681 80

Four patients with acute nonlymphoblastic leukemia and one malignant teratoma refractory to conventional chemotherapy were treated with high doses of cytosine arabinoside (HD ARA-C). They received up to 12 cycles of 1.8 to 3 g/m2 every 12 hours applied by 2-hour infusions. A total of 55 HD ARA-C infusions was performed. All leukemic patients responded. A complete clearance of blasts from the bone marrow was observed in two patients following 8-12 cycles of 3 g/m2. However, relapses occurred after three and seven weeks, in one case with resistance to HD ARA-C. The patient with malignant teratoma did not respond. No severe toxicity emerged even after repeated applications. Adverse reactions included moderate nausea and vomiting (4 patients), diarrhea (2 patients), hepatic dysfunction (1 patient), bone pain (1 patient), blurred vision (1 patient), conjunctivitis (1 patient), and exanthema with partial epidermiolysis (1 patient). Granulocytopenia occurring between 3-8 days after having started the therapy, subsided within 4-25 days. Plasma levels of ARA-C and the metabolite uracil arabinoside (ARA-U) were monitored. At steady state plasma concentrations of ARA-C were 32-97 microM (8-24 micrograms/ml). ARA-C disappeared from the plasma mono- or biphasic with a terminal half-life (t50%) of 7.8-12.6 minutes. The total clearance (Cl) of ARA-C varied between 1.7 and 2.9 liters/kg . h, and the distribution volume (Vss) between 0.44 and 0.86 liters/kg. Cerebrospinal fluid (CSF) levels of ARA-C reached 10-15% of steady state concentrations in plasma.
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PMID:Clinical results and pharmacokinetics of high-dose cytosine arabinoside (HD ARA-C). 710 69

Sixty-seven patients with acute nonlymphoblastic leukemia (ANLL) and above the age of 60 years were randomly allocated to treatment with either prednimustine + vincristine or cycles with cytosine arabinoside and thioguanine. Of the 67 patients, 13 (19%) entered a complete remission and four a partial remission. Of 33 patients randomized to prednimustine and vincristine (15 adequately treated), three entered a complete remission and one a partial remission. Four further patients went into complete remission after a switch to other treatment modalities. Of 34 patients randomized to cycles of ARA-C and thioguanine (22 adequately treated), four entered a complete remission and three a partial remission with the correct program. One patient entered a remission with intermittent cytosine arabinoside + thioguanine (wrong program) and one further patient entered a complete remission after a switch to prednimustine and vincristine. Prednimustine + vincristine did not appear to be superior to treatment with cytosine arabinoside thioguanine cycles for elderly patients with ANLL.
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PMID:Prednimustine and vincristine compared with cytosine arabinoside and thioguanine for treatment of elderly patients with acute nonlymphoblastic leukemia. 717 10

Twenty-nine late chronic and accelerated phase chronic myelogenous leukaemia (CML) patients were entered in a pilot study designed to test the therapeutic efficacy of treatment with interferon-alpha (IFN-alpha) and low-dose cytosine arabinoside (ARA-C). IFN-alpha was administered at a dose of 2-10 x 10(6) IU/day and ARA-C at 15 mg/m2/day for 14 days each month. The treatment was well tolerated by 73% of the patients. Side effects were mainly asthenia, anorexia, anaemia and piastrinopenia. Haematological and cytogenetic responses were evaluated in the 19 patients who received more than 6 cycles. Four complete haematological response, 7 partial haematological response, 6 minor haematological response, 2 stable disease were obtained in this patient group. Two complete cytogenetic responses and 2 minor cytogenetic responses were detected in these patients. Suppression of secondary Ph' positive clones which appeared during the previous IFN-alpha treatment was documented in 3 accelerated phase patients after ARA-C was added to their IFN-alpha treatment. It would therefore seem that late chronic and accelerated phase CML patients benefit from combined IFN-alpha/ARA-C treatment and achieve haematological and cytogenetic responses not obtained during previous treatment without being exposed to undue toxicity. However, we cannot judge whether it offers any advantage in terms of survival.
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PMID:Interferon-alpha plus low-dose cytosine arabinoside in advanced phase chronic myelogenous leukaemia patients. 767 91

Because of interest in new approaches to treatment of patients with acute promyelocytic leukemia (APL), we analyzed APL treatment outcome in SWOG with chemotherapy from 1982-1991. To evaluate effects of change in nonspecific patient care factors over time we evaluated outcome in two temporal groups (1982-1986, 1986-1991), corresponding to two groups of treatment protocols encompassing all new de novo AML patients entered on acute myeloblastic leukemia (AML) protocols during those years. Surprisingly, APL patients in the 1982-1986 group (n = 45) had much better treatment outcome (complete remission (CR) rate 71%, median overall survival (OS) 106 months, median disease-free survival (DFS) > 105 months) than the later group (n = 96) (CR rate 47%, median OS 13 months, median DFS 28 months) (p = 0.0063, 0.0015, and 0.0001 respectively). All APL patients but two in the 1982-1986 time period were treated on SWOG protocol 8124, which included induction with total daunorubicin (DNR) 210 mg/m2 i.v./course, consolidation with two courses with identical dosage of DNR, and intensification at 4 months including another course of identical dosage DNR. We analyzed factors affecting treatment outcome for all patients with APL treated from 1982 to 1991. In multivariate analysis, higher DNR induction dose was significantly associated with CR rate, OS, and DFS (p < 0.001, < 0.0001, and < 0.0001, respectively). Cytosine arabinoside (ARA-C) dose and inclusion of other agents did not correlate significantly with outcome. Because these studies were not randomized for DNR dosage, other factors contributing to outcome cannot be completely excluded, although none were found. Most deaths occurred within 3 months of initiation of therapy on 8124; there were no relapses with higher DNR dosage after 3 years. This excellent outcome should be considered in evaluating newer modalities of therapy such as all-trans retinoic acid (ATRA) for APL. If the high CR induction rate and minimal early deaths with ATRA therapy can be combined successfully with this chemotherapy, most patients with APL may be curable.
Leukemia 1994
PMID:Treatment outcome with chemotherapy in acute promyelocytic leukemia: the Southwest Oncology Group (SWOG) experience. 781 35

The Brazilian Cooperative Group for Treatment of Childhood Acute Lymphocytic Leukemia (GBTLI) has started clinical activities trials in 1980. Three consecutive multicenter studies in children with unprevious treated ALL have been completed including 994 patients. The first GBTLI-80 accrued 203 children from 1980 to 1982. It was delineated with the standard three drugs induction therapy, CNS protection for all pts comprised cranial irradiation and intrathecal Methotrexate. For low risk pts cranial irradiation with 18Gy was compared in a randomized trial with 24Gy. Maintenance therapy continued for 120 weeks. The 12 years of the event free survival rates for all risk groups is 50% (SD 5%). Regarding CNS relapses there was no significant statistical difference between pts that received 18 or 24Gy. The treatment strategy of GBTLI-82 (n = 360) from 1982 to 1985, consisted of the same previous induction, consolidation, CNS therapy with cranial irradiation 18 Gy (low risk) or 24Gy (high risk), followed by continuous maintenance for 2 years. The main question in this study was the comparison between sequential rotation or pulses of 3 pairs of drugs during maintenance. At a median follow-up of 10 years, the overall event free survival rates for all children is 58% (SD 4%). There was no significant difference between the two maintenance regimens. The successor GBTLI-85 ran from 1985 to 1988 and registered 431 pts. For the first time no cranial radiation was given to children with very good prognosis. For them, CNS protection was done with triple intrathecal therapy during all treatment. A consolidation therapy with high dose ARA-C was introduced for high risk pts and infants The 6.5 years event free survival for all children is 70% (SD 4%). Significant better results were achieved for high risk and infants pts (EFS 50%). Early intensification therapy and rotational combination chemotherapy improved the outcome in childhood ALL in Brazil.
Leukemia 1993 Aug
PMID:Treatment results of three consecutive Brazilian cooperative childhood ALL protocols: GBTLI-80, GBTLI-82 and -85. ALL Brazilian Group. 836 Dec 20

Serum-free growth of Ewing's sarcoma (ES) and primitive peripheral neuroectodermal tumour (pPNET) cell lines was achieved by supplementing a basal medium with insulin-like growth factor-I (IGF-I). These cultures were used to investigate the sensitivity of 3 ES (EW-2, RD-ES, SK-ES-1) and 3 pPNET (SIM-1, KAL, SAL) cell lines to a panel of anti-tumour agents in short-term (48-h) proliferation assays. Of the four cytostatic drugs included in the currently used multi-drug regimens, cyclophosphamide, doxorubicin and actinomycin-D inhibit the proliferation of the cell lines with high efficacy, whereas the vinca alkaloids were less effective. Cisplatin, etoposide, mitomycin-C and mitoxanthrone were also found to have a high inhibitory activity in this in vitro ES/pPNET system. The most remarkable effect was observed for cytosine arabinoside (ARA-C), which gave a half-maximal inhibition at drug concentrations approximately 5000 times below the clinical peak plasma concentrations (250 micrograms/ml). The ARA-C sensitivity of ES and pPNET cell lines is comparable with the established ARA-C sensitivities of leukaemia-derived cells. The different ES and pPNET cell lines showed a rather uniform response to the different cytostatic drugs with decreased sensitivity of individual pPNET cell lines to vinblastin, ARA-C and mitoxanthrone. Modulation of the IGF-I/IGF-I receptor/IGF-I binding protein system, which seems to constitute an important stimulator of cell growth in neuroectoderm-derived or -related tumours, can be used to enhance the drug sensitivity of the tumour cells in vivo or in vitro therapeutic procedures. According to our results, serum-free conditions for autologous bone marrow purification are expected to result in significantly increased chemosensitivity of ES and pPNET cells in response to anthracyclines and cisplatin.
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PMID:Insulin-like growth factor-I-dependent growth and in vitro chemosensitivity of Ewing's sarcoma and peripheral primitive neuroectodermal tumour cell lines. 838 Jun 98

Paclitaxel dose responses in culture have been investigated alone and in association with cytosine arabinoside (ARA-C) and all-trans retinoic acid (ATRA), with the objective of identifying a role for paclitaxel in the treatment of acute myeloblastic leukaemia (AML). Initial studies were done to determine if paclitaxel dose responses of AML blast cell precursors were altered by regulatory compounds known to modify the dose responses of ARA-C. In contrast to ARA-C, paclitaxel dose responses were independent of cell culture method, the growth factors G-CSF and GM-CSF, and the ligands all-trans retinoic acid (ATRA) and hydrocortisone. Most blast cell populations were sensitive to paclitaxel; compared with normal marrow progenitors the dose responses were markedly heterogenous with some more, and others less, sensitive. Remission marrow progenitor paclitaxel responses resembled those of AML blasts in heterogeneity. The cell culture model tested the effect of pacliataxel and ATRA on the ARA-C dose responses of OCI/ AML-5; paclitaxel exposure was either before or after ARA-C to test for an effect of schedule; ATRA was added to the MEC cultures after paclitaxel and ARA-C. Repeat experiments were done to test three dose levels each of paclitaxel and ATRA. When paclitaxel was given after ARA-C, synergism was found for all but one of the dose combinations tested; only three examples of synergy were seen when paclitaxel preceded ARA-C. The studies justify trials combining ARA-C, paclitaxel and ATRA using a schedule suggested by the cell culture findings.
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PMID:A role for paclitaxel in the combination chemotherapy of acute myeloblastic leukaemia: preclinical cell culture studies. 890 92


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