摘要:

Recently, high dose Ara-C (HIDAC) has been shown to induce leukemic cell death in vitro by the alternative process of programmed cell death (PCD) or apoptosis which correlates with the inhibition of their clonogenic survival. Since co-treatment with hemopoietic growth facts (HGFs) GM-CSF and IL-3 have been demonstrated to enhance the metabolism and cytotoxic effects of HIDAC against leukemic progenitor cells, we examined the effect of HGFs pIXY 321 (a GM-CSF/IL3 fusion protein) and G-CSF on HIDAC induced PCD and related gene expressions as well as HIDAC mediated colony growth inhibition of human myeloid leukemia cells. Treatment with G-CSF or pIXY 321 alone for up to 24 hours neither suppressed nor induced PCD in HL-60 or KG-1 cells. However, exposure to either of the HGFs for 20 hours followed by a combined treatment for 4 hours with HIDAC plus either of the HGFs versus HIDAC alone significantly enhanced the intracellular Ara-CTP accumulation and the oligonucleosomal DNA fragmentation characteristic of PCD. This was temporally associated with a marked induction of C-jun expression but a significant repression in BCL-2 and c-myc expressions. In addition, the treatment with either of the HGFs plus HIDAC versus HIDAC alone produced a significantly greater inhibition of the clonogenic survival of the myeloid leukemia cells. These findings underscore an additional mechanism of leukemic cell death induced by HIDAC which can be modulated by the HGFs to improve the antileukemic activity of HIDAC.

ISSN:1042-8194    

DOI:10.3109/10428199309149124

出版商:Taylor&Francis    

年代:1993

数据来源: Taylor

摘要:

193 patients with relapsed or refractory acute myeloid leukemia (AML) were entered into a prospective randomized comparison of high-dose versus intermediate dose cytosine arabinoside (AraC) both combined with mitoxantrone (mitox) according to the previously established sequential HD-AraC/mitox regimen (S-HAM). AraC was administered by 3 hr inf. q 12 hrs on days 1, 2, and 8, 9 at randomly assigned doses of cither 3.0 versus 1.0 g/m2in pts.<60 years of age or 1.0 versus 0.5 g/nm2in older pts. Mitox was given to all cases at a dose of 10 mg/m2/d on days 3, 4, and 10, 11. Randomization was stratified for primary refractoriness against induction therapy and the length of first remission in relapsed cases (18 mths.). From 151 presently evaluable cases 72 pts (48%) achieved a complete remission (CR), 38 cases (25%) were non-responders (NR) and 41 pts. (27%) died within the first 6 weeks after the start of treatment (early death = ED). No significant differences were found in CR rates being 52% and 44% for the 3.0 versus 1.0 g/m2AraC regimens in pts.<60 years and 48% and 45% after 1.0 versus 0.5 g/m2AraC in older pts. No differences between the respective regimens emerged either for the time to CR (median 46 days) nor remission duration (median 4.5 mths.). Analysis of treatment failures, however, demonstrated a significantly higher rate of NR after the lower dose regimens in both age groups of 41% and 32% versus 11% and 14% in pts. receiving AraC at higher doses (p<0.01). Correspondingly, more ED were observed in the latter groups. Furthermore, a significant advantage in favor of 3.0 g/m2AraC was found when analyzing cases<60 years of age with refractory AML separately as defined by patients with primary non-response to induction therapy, early relapse within 6 months or secondary and subsequent leukemic recurrences. In this subgroup CR rates were 48% after 3.0 g/m2AraC and 23% after the lower dose regimen (p<0.05). In cases with later occurring relapses CR rates were almost identical with 55% remissions after 3.0 g/m2AraC and 60% after 1.0 g/m2AraC.Based on these results the AraC dose should be adjusted according to disease status and age in future trials and patients with refractory AML and less than 60 years of age are recommended to receive 3.0 g/m2AraC while older patients and cases with first relapses after 6 months remissions duration should be treated with 1.0 g/m2AraC.

ISSN:1042-8194    

DOI:10.3109/10428199309149125

出版商:Taylor&Francis    

年代:1993

数据来源: Taylor

摘要:

The nucleoside analogs fludarabine monophosphate, 2-chlorodeoxyadenosine, and 2-deoxycoformycin (pentostatin) all have activity in chronic lymphocytic leukemia. The most widely studied drug is fludarabine which is able to obtain complete or partial responses in more than 50% of previously treated patients. The response rate is 44% for 2-CDA and approximately 25% for pentostatin. Fludarabine has also been used to treat patients as initial therapy, and has resulted in overall response rate of 79% with 75% of the patients achieving complete remission. The NCI and International Working Group for CLL criteria for complete remission allow for persistent nodules or lymphoid infiltrates in the bone marrow biopsy. Studies have now demonstrated persistent lymphoid aggregates are associated with a shorter time to progression for responders but no survival disadvantage. There is a strong association of documented refractoriness to alkylating agents with probability of response to fludarabine and also survival. The major morbidity associated with the use of these drugs are infections, which, in some circumstances, are associated with neutropenia but in other circumstances are probably related to the hypogammaglobulinemia and T-cell immunodeficiency which are part of the disease. The T-cell immunodeficiency is aggravated by the nucleoside analogs. Even after discontinuation of therapy the immunodeficiency as measured by CD4 cell number is sustained for 12 to 24 months. Opportunistic organisms such as herpes simplex, herpes zoster, Listeria monocyto-genes, and pneumocystis carinii are being noted in patients treated with these agents. The potency of these drugs and low incidence of toxicities to other organs suggests that they will be effectively combined with other agents. Studies of the impact of these drugs on survival of patient populations with CLL requires longer follow-up.

ISSN:1042-8194    

DOI:10.3109/10428199309149126

出版商:Taylor&Francis    

年代:1993

数据来源: Taylor

ISSN:1042-8194    

DOI:10.3109/10428199309149127

出版商:Taylor&Francis    

年代:1993

数据来源: Taylor

ISSN:1042-8194    

DOI:10.3109/10428199309149128

出版商:Taylor&Francis    

年代:1993

数据来源: Taylor

摘要:

L-asparaginase is an enzyme which hydrolyses asparagine. Since the 1960s it has been known that some leukemic cells are deficient in asparagine synthetase and therefore cannot manufacture sufficient quantities of this essential amino acid to maintain cell viability. L-asparaginase is predominantly useful in acute lymphocytic leukemia (ALL) although responses have been noted in patients with acute myeloid leukemia, lymphoma, and rarely other tumors. L-asparaginase has been used in conjunction with methotrexate and ara-C in combination programs in leukemia. The major side-effect limiting the usefulness of L-asparaginase is allergic reactions. In addition, it is probable that neutralizing antibodies develop which shorten the half life of the drug so that the goal of depletion of plasma levels of asparagine cannot be attained or maintained. Polyethylene glycol (M.W. 5000) can be conjugated to L-asparaginase at sites not involving the active site of the enzyme. This enables free access of a small molecule, asparagine, to the active site of the enzyme but prevents uptake by the reticuloendothelial system, greatly decreasing the probability of developing antibodies against the asparaginase and prolongs the circulating half life of the drug. In a phase I/II study conducted at the M.D. Anderson Cancer Center, 37 heavily pretreated patients with refractory hematologic malignancy were treated. The age range from 15 to 73 years, median 49 years. Nineteen patients had ALL, 15 lymphoma, two myeloma, and one Hodgkin's disease. The dose levels of PEG L-asparaginase varied from 250 IU/m2up to 8000 IU/m2. The pharmacokinetic profile demonstrated a mono-phasic half life consistent with a one compartment model with a single elimination phase. The mean t1/2 of PEG L-asparaginase was 357 hours compared with 20 hours for L-asparaginase. The major side effects were nausea and vomiting, peripheral edema, hypoalbuminemia and hepatic dysfunction. Three patients developed allergic reactions. There was no clear relationship between the dose of PEG L-asparaginase and toxicity. Three patients achieved complete remission, two with lymphoma, and one with ALL. Doses were repeated at two week intervals. Asparaginase depletion was documented to persist until the next dose. Thus PEG L-asparaginase allows for less frequent dosing, good tolerance, and persistent asparagine depletion with an acceptable toxicity profile. Further evaluation of the role of PEG L-asparaginase in patients who are documented to be hypersensitive to native L-asparaginase is indicated and additional clinical trials are being conducted to evaluate response.

ISSN:1042-8194    

DOI:10.3109/10428199309149129

出版商:Taylor&Francis    

年代:1993

数据来源: Taylor

ISSN:1042-8194    

DOI:10.3109/10428199309149103

出版商:Taylor&Francis    

年代:1993

数据来源: Taylor