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)

Amsacrine and high-dose cytarabine (HiDAc), when administered as single agents, are effective treatment of acute leukemia. When used in combination, a high remission rate is also possible. We treated 47 patients with acute myelogenous leukemia (AML), acute lymphoblastic leukemia (ALL), and blastic phase of chronic myelogenous leukemia (CML) with a combination of amsacrine and HiDAc. The patients received amsacrine 200 mg/m2 daily for three days and, concurrently, HiDAc 3 g/m2 over three hours once daily for five days. Of 20 evaluable patients with AML in relapse, there were 12 remissions; of seven additional patients with primary refractory AML, there were two remissions, and of 12 patients with ALL in relapse, there were eight remissions. The three patients with blastic phase CML and the three patients with biphenotypic leukemia did not respond. Nausea, vomiting, stomatitis, hepatic dysfunction, and diarrhea were common, but cutaneous, conjunctival, and significant cerebellar and cerebral side effects were absent. We conclude that this regimen is highly effective therapy for AML and ALL and is also safe, eliminating the major toxicities encountered with HiDAc.
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PMID:A new regimen of amsacrine with high-dose cytarabine is safe and effective therapy for acute leukemia. 354 13

CNS dysfunction, especially impaired cerebellar function, is the dose-limiting toxicity associated with high-dose cytosine arabinoside, which precludes doses of greater than 48 g/m2. Four hundred eighteen patients between the ages of 2 and 74 years with leukemia or lymphoma received 36 to 48 g/m2 cytosine arabinoside either alone or with anthracycline antibiotics, 4'-(9-acridinylamino) methane sulfon-m-anisidine (m-AMSA), or total body irradiation. In only 35 of 418 patients (8%) did severe cerebellar toxicity develop; it was irreversible or fatal in four (1%) patients. The age of the patient was a critical factor in the incidence of severe cerebellar toxicity. Patients greater than 50 years old had a statistically significant greater incidence of cerebellar toxicity compared with younger patients (26/137, 19%, v 9/281, 3%; P less than .0005, chi 2). Neither the diagnosis, disease status, sex, nor the regimen altered the incidence of severe cerebellar toxicity (when corrected for age). A second course of high-dose cytosine arabinoside, administered to 62 patients, did not increase the incidence of severe cerebellar toxicity, which occurred in five (8%) of these patients. Two of the five patients had severe toxicity with the initial course. Of the 60 patients with no antecedent cerebellar dysfunction, three (5%) had severe toxicity with the second course: one of 41 patients were less than 50 years old; two of 19 patients were greater than or equal to 50 years. Since the occurrence of severe cerebellar dysfunction is greatly affected by age, reduced doses of high-dose cytosine arabinoside should be given to patients greater than 50 years old, and methods for reducing the cerebellar toxicity should be investigated in these patients.
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PMID:Cerebellar toxicity with high-dose cytosine arabinoside. 358 47

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 calcium channel blocker verapamil has been reported to circumvent acquired resistance to different antitumor agents in tumor cell lines in vitro. We studied its effect on in vitro uptake of m-AMSA and adriamycin in fresh leukemic cells from 11 leukemia patients. Six previously untreated patients were sensitive to m-AMSA (obtained remission). Four were clinically resistant to m-AMSA, and two of these also to adriamycin. Leukemic cells were incubated in pharmacological doses of 14C-adriamycin and 14C-m-AMSA for up to 2 h. Samples were supplemented with verapamil (750 ng ml-1) 30 min prior to the addition of m-AMSA or adriamycin. Drug uptake was measured at 15 min intervals up to 2 h and drug retention was measured during 30 min after the end of incubation, following washing and resuspension in fresh medium without cytotoxic drugs. Adriamycin uptake was the same irrespective of verapamil in all four cell samples, two of which were derived from patients resistant to adriamycin. The cellular m-AMSA uptake was higher in cells from clinically sensitive than from resistant patients (510 +/- 155 fg cell-1 vs 275 +/- 125 fg cell-1; P less than 0.01). Retention of m-AMSA 30 min after incubation was higher in cells from sensitive compared to resistant patients (187 +/- 78 vs 25 +/- 7; P less than 0.05). Our data suggest: (1) in vitro uptake greater than or equal to 350 fg cell-1 and subsequent retention greater than 75 fg cell-1 correlate to clinical sensitivity to the drug; and (2) neither m-AMSA nor adriamycin uptake could be significantly increased by verapamil.
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PMID:Sensitivity and resistance to chemotherapy in acute leukemia: correlation with in vitro drug uptake and lack of potentiation by verapamil. 360 53

m-AMSA (4'-[9'-acridinylamino]-methansulfon-m-anisidide) is an acridine derivative which has shown a wide spectrum of activity in preclinical testing. The mechanism of action is thought to be via interference with synthesis and integrity of DNA chains by intercalation between base pairs and external binding. Initial phase I clinical trials revealed granulocytopenia to be the dose limiting toxicity with occasional thrombocytopenia. Phlebitis, liver function abnormalities, and cardiac abnormalities have also been noted. Early reports suggested activity in leukemia and lymphoma. Based on these results ECOG evaluated m-AMSA in a phase II trial of Hodgkin's disease and non-Hodgkin's lymphoma.
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PMID:m-AMSA in refractory lymphoma. A phase II trial of the Eastern Cooperative Oncology Group. 384 Jun 44

The pharmacokinetics of amsacrine have been studied after the first and third infusions (200 mg . m-2) in 10 patients receiving combined chemotherapy for the treatment of acute myelogenous leukaemia (AML). Postinfusion amsacrine elimination was best described by a biexponential expression with a mean t1/2 alpha of 0.8 h and a terminal t1/2 beta of 5.3 h. After the third infusion there was a significant reduction (P less than 0.05) in the plasma clearance (Cl) and a prolongation of the terminal half-life (t1/2 beta) (P less than 0.01), but no change in the initial half-life (T1/2 alpha) or volume of distribution (Vd). No significant overall changes were recorded in any of the biochemical indices of renal or hepatic function between the first and third infusions, but the patient who exhibited the largest reduction in Cl showed a marked increase in AST levels and a reduction in albumin concentration. Two distinct groups were apparent after the first infusion, patients with a Cl greater than 294 and those with a Cl less than 208 ml . h-1 . kg-1. The latter patients were significantly older (P less than 0.05), and four of the five had subnormal albumin concentrations. Urinary determination of amsacrine indicated that renal elimination plays a minor role in the total clearance of this drug. Amsacrine was also found to be highly bound to plasma proteins (96.4%-97.7%), but changes in binding were not responsible for the reduced Cl and prolonged t1/2 beta observed between the first and third infusions. We suggest that the elimination of amsacrine may be susceptible to small changes in hepatic function, perhaps due to the high amsacrine concentrations (5-18 mumol . l-1) achieved with this regimen, which may be approaching saturation of the capacity for hepatic elimination.
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PMID:Pharmacokinetics of amsacrine in patients receiving combined chemotherapy for treatment of acute myelogenous leukemia. 385 88

27 patients (aged 15-55 years) with relapsed acute myelogenous (AML) and lymphoblastic leukaemia (ALL), and with lymphoblastic non Hodgkin's lymphoma (NHL) have been treated with intermediate dose cytosine arabinoside (AraC, 1 g/m2 q 12 h X 12) and 3 d of m-AMSA (20 patients), 90-115 mg/m2 daily, or daunorubicin (7 patients). 18 of them attained a complete remission (AML 10/14, ALL 3/5, NHL 5/8). 7 patients received consolidation treatment with 1-2 courses comprising 4 d of AraC (3 g/m2 q 12 h X 8) and m-AMSA (90-115 mg/m2) on d 5 of each course. 2 patients underwent allogeneic bone marrow transplantation and 9 received no further treatment after remission induction. In addition to vomiting, fever and conjunctivitis, toxicity in 6 patients included a combination of severe diarrhoea, fever and signs of paralytic ileus. 3 of them died during the pancytopenic phase. The pancytopenic period ranged from 16-25 d (median 21 d) after the remission induction and 14-21 d (median 19 d) after the consolidation course. Median remission duration was 5 months for those patients who received no treatment after remission induction and greater than 9 months (4+ - 16+ months) for the patients who received consolidation courses. Increased dosages of AraC are active in relapsed leukaemia and lymphoma, although optimal dose and schedule are still undetermined.
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PMID:Intermediate and high-dose ARA-C and m-AMSA (or daunorubicin) as remission and consolidation treatment for patients with relapsed acute leukaemia and lymphoblastic non-Hodgkin lymphoma. 385 71

Of the many high-dose Ara-C regimens that have been proposed, the one published by Herzig [24] has been applied most widely. Every 12 h patients receive 3 g/m2 Ara-C for 75-90 minutes for a total of 12 doses. Using that regimen, 25% of patients with refractory acute myelogenous leukemia (AML) and 60% of patients in untreated relapse achieve a complete remission (CR). With few exceptions, complete remissions are obtained after one cycle, median remission duration is between 4 and 6 months. Consolidation or maintenance therapy was not usually given. Currently, numerous modifications of that regimen are under investigation: combinations with other cytostatic agents like anthracyclins, m-AMSA, vincristine; the Capizzi-regimen and intermediate dose Ara-C. Preliminary results of those trials are promising but need to be confirmed by other groups. This survey does not comment on Ara-C toxicity and on Ara-C treatment of CNS leukemia, which are both reviewed in two further articles of this issue.
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PMID:[Results of high-dose cytarabine therapy. A review]. 388 25

Between March 1980 and December 1981, 22 patients were treated with 4'(9-acridinylamino)methanesulfon-m-anisidide (m-AMSA) and 5-azacytidine (AZA), each given by I.V. push in a dosage of 150 mg/m2 for 5 days. Seven of 12 prior-remitting, acute nonlymphoblastic leukemia (ANLL) patients achieved complete remission (58%). Six ANLL patients who failed to remit on standard daunorubicin-cytosine arabinoside programs also failed to remit on the m-AMSA-AZA combination. Two patients with relapsed acute lymphatic leukemia (ALL) also failed while two patients with chronic myelocytic leukemia (CML) in evolution were cytoreduced. The seven patients who achieved remission had additional relapse-free survival for a median of six months (range 1-23+ months). One patient obtained a second remission with m-AMSA-AZA after relapse which followed a 9-month period of nonmaintained remission. Most patients demonstrated mild to moderate nausea and vomiting. Hepatic toxicity was mild to infrequent. Only four patients showed cardiac toxicity which was not life-threatening. The most troublesome toxicity was mucositis and was seen in 11 patients; four whom required I.V. hyperalimentation. We conclude that this combination is an effective salvage program for relapsed prior-remitting ANLL. Future studies should be conducted in three areas. The first study might be a comparison of relapsed prior-remitting ANLL with single-agent m-AMSA. The second, in untreated ANLL, following induction with DAT, might use m-AMSA-AZA in consolidation and maintenance arms of future protocols. The final study should explore m-AMSA-AZA activity in evolved CML in a greater number of patients.
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PMID:4'-(9-acridinylamino)methane-sulfon-m-anisidide (m-AMSA) and 5-azacytidine (AZA) in the treatment of relapsed adult acute leukemia. 619 61

Effects of ruthenium red on accumulation and cytotoxicity of m-AMSA, vinblastine and daunorubicin were examined in the P388 murine leukemia cell line and in an adriamycin-resistant subline, P388/ADR, which is cross-resistant to all three agents. Ruthenium red increased m-AMSA accumulation by both P388 and P388/ADR cells; the extent of this effect was a function of the concentration of both agents. Uptake enhancement occurred within 5 min of exposure of cells to ruthenium red and was readily reversed when cells were suspended in fresh medium. A 24-hr exposure to ruthenium red was needed to affect vinblastine or daunorubicin accumulation, and the effect was substantially less than that observed with m-AMSA. Ruthenium red protected P388 cells from m-AMSA toxicity. These data, together with reports indicating a protective effect of ruthenium red against vinblastine and anthracycline toxicity, suggest that the dye promotes tight binding of m-AMSA and other agents to cellular loci on which toxic effects are not exerted.
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PMID:Effects of ruthenium red on accumulation and cytotoxicity of m-AMSA, vinblastine and daunorubicin in leukemia cells. 620 58


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