Pharmacologic and Cytokinetic Studies of Arabinosyl Cytosine

2015 ◽  
pp. 1085-1097 ◽  
Author(s):  
E. Frei ◽  
D. H. W. Ho ◽  
G. P. Bodey ◽  
E. Freireich
Keyword(s):  
Arabinosyl Cytosine

scholarly journals Arabinosyl Cytosine: A Useful Agent in the Treatment of Acute Leukemia in Adults

Blood ◽  
1968 ◽  
Vol 32 (4) ◽  
pp. 507-523 ◽  
Author(s):  
ROSE RUTH ELLISON ◽  
JAMES F. HOLLAND ◽  
MARISE WEIL ◽  
CLAUDE JACQUILLAT ◽  
MICHEL BOIRON ◽  
...  
Keyword(s):  
Remission Rate ◽  
Hemoglobin Level ◽  
Lymphocytic Leukemia ◽  
Acute Myelocytic Leukemia ◽  
Pyrimidine Nucleoside ◽  
Myelocytic Leukemia ◽  
Daily Dose ◽  
Significant Superiority ◽  
Infusion Duration ◽  
Arabinosyl Cytosine

Abstract Arabinosyl cytosine (ara-C), a synthetic pyrimidine nucleoside related to the normal metabolites cytidine and deoxycytidine, has been found capable of producing marrow remission at tolerable doses in acute myelocytic and acute lymphocytic leukemia in adults. There were 16 per cent remissions complete in all aspects, 3 per cent complete except for hemoglobin level, and 6 per cent partial remissions among 180 adults with acute myelocytic leukemia treated with any one of 8 variants of infusion duration or daily dose of ara-C. Twenty-four per cent of 37 adults with acute lymphocytic or unclassified leukemia had complete or partial remissions. The comparison of 1, 4, 12 and 24 hours infusion of ara-C (to total dose tolerated) does not show significant superiority for any one group. The complete remission rate with 1 or 12 hour infusions, however, is 25 per cent (superior to that obtained with 6-mercaptopurine) and the recommended schedule of treatment for ara-C based on these data is, therefore, daily infusions of 100 or 50 mg./m.2 in one hour for approximately 3 to 6 weeks followed by maintenance therapy of once weekly subcutaneous injection of 30 mg./m.2 of ara-C. Platelet transfusions should be available when ara-C is used.

A randomized study of interferon-α versus interferon-α and low-dose arabinosyl cytosine in chronic myeloid leukemia

Blood ◽  
2002 ◽  
Vol 99 (5) ◽  
pp. 1527-1535 ◽  
Author(s):  
Michele Baccarani ◽  
Gianantonio Rosti ◽  
Antonio de Vivo ◽  
Francesca Bonifazi ◽  
Domenico Russo ◽  
...  
Keyword(s):  
Overall Survival ◽  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Low Dose ◽  
Response Rate ◽  
Randomized Study ◽  
Philadelphia Chromosome ◽  
Cytogenetic Response ◽  
Interferon Α ◽  
Arabinosyl Cytosine

Interferon-α (IFN-α) has significantly prolonged survival in chronic myeloid leukemia (CML), but some patients do not respond and many responses are not durable. To improve the results, IFN-α has been combined with other treatments, but so far only the association with low-dose arabinosyl cytosine (LDAC) has been shown to increase the response rate and to prolong survival. Here are reported the results of a study of 538 Philadelphia chromosome–positive CML patients who were assigned at random to treatment with IFN-α2a alone or in combination with LDAC. The scheduled dose of IFN-α2a was 56IU/m2/d. The scheduled dose of AC was 40 mg/d for the first 10 days of each month of treatment. The efficacy endpoints were a complete hematologic response rate at 6 months (62% in the IFN-α–plus–LDAC arm versus 55% in the IFN-α arm; P = .11), major cytogenetic response (MCgR) rate at 24 months (28% versus 18%; P = .003), and overall survival (5-year survival, 68% versus 65%; P = .77). Treatment did not affect overall survival within different prognostic risk groups: low, intermediate, or high. Also the duration of MCgR was identical. The results of this study confirm the results of a similar French study only for the response rate, not for survival, suggesting that the relationship between cytogenetic response and survival may be extremely variable and that a meta-analysis of these and other studies of IFN-α versus IFN-α plus LDAC is required to settle the issue of the role of LDAC in the treatment of CML.

Novel Population Pharmacokinetic Modeling of Arabinosyl Cytosine Triphosphate: Insights On Potential Preferential Formation of Ara-CTP Directly From Elacytarabine As Well As From Ara-C

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3547-3547
Author(s):  
Corinne Seng Yue ◽  
Varsha V. Gandhi ◽  
Susan O'Brien ◽  
Farhad Ravandi ◽  
Tove Flem Jacobsen ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Research Funding ◽  
Hematologic Malignancies ◽  
Employment Equity ◽  
Cholesterol Levels ◽  
Population Pk ◽  
Equity Ownership ◽  
Quality Of Fit ◽  
Arabinosyl Cytosine

Abstract Abstract 3547 Objectives: Elacytarabine (CP-4055) is an elaidic acid ester of arabinosyl cytosine (Ara-C), administered as a liposomal formulation, that is being developed to treat hematologic malignancies. CP-4055 is metabolized to Ara-C, which is transformed intracellularly to active arabinosyl cytosine triphosphate (Ara-CTP) and inactive deaminated metabolite arabinosyl uracil (Ara-U). The present analysis aimed to elucidate the pharmacokinetics (PK) of Ara-CTP and identify its relationship with CP-4055, Ara-C, Ara-U and various blood parameters measured in the target patient population. Methods: Patients suffering from hematologic malignancies, including refractory/relapsing acute myeloid leukemia (AML), who participated in Phase I or II CP-4055 trials, were included in this analysis. CP-4055 monotherapy was given as an intravenous infusion over 2 h/day for 5 days, 4 h/day for 5 days or continuously over 120 hours at doses ranging from 200 to 2500 mg/m2/day. Blood samples were collected at various time-points (until 168 hours post-dose) and plasma was assayed for CP-4055, Ara-C, and Ara-U using a validated LC-MS/MS method. Ara-CTP was measured by HPLC in isolated leukemic blast cells from AML patients. Cholesterol levels were also measured. Population PK analyses were conducted using the iterative two-stage method in ADAPT 5®. First, a model was determined for cholesterol, which was incorporated into a PK model for CP-4055, Ara-C and Ara-U. Individual PK parameters from this model were fixed and then used for the analysis of Ara-CTP. For Ara-CTP modeling, 1-compartment (cpt) models were tested with various routes of formation. For all models, model discrimination was performed using standard criteria (residual variability, quality of fit graphs, Akaike information criterion test). Results: In the cholesterol analysis, 13 patients (57 concentrations) were included while 43 patients (around 27 concentrations per patient) were included in the modeling of CP-4055, Ara-C and Ara-U. A subset of 17 patients (46 concentrations) was part of the Ara-CTP analysis. Cholesterol was described by an indirect model with a rate of elimination and a rate of formation that was increased by phospholipids infused along with CP-4055. CP-4055 PK was best described by a 2-cpt model, where the central cpt was partitioned into 2 sub-cpts. The first sub-cpt represented a lipid depot cpt where liposomal-bound CP-4055 was infused, and which transferred CP-4055 into the other sub-cpt, which represented CP-4055 released from liposomes. The transfer of CP-4055 from the liposomes was unidirectional and saturable, and cholesterol level influenced the size of the second sub-cpt. Ara-CTP appeared to be formed from unbound CP-4055, presumably within cancer cells, and was also formed as expected from Ara-C which was best described by a 2-cpt model, while Ara-U followed a 1-cpt model with an elimination that was dependent upon creatinine clearance. The proposed model is depicted below. Based on the model, terminal elimination half-life values for CP-4055, Ara-C, Ara-U and Ara-CTP were around 9, 68, 5 and 3 hours, respectively, and were independent of dose and infusion time. Residual variabilities for cholesterol, CP-4055, Ara-C, Ara-U and Ara-CTP were 21.0%, 34.0%, 39.4%, 12.5% and 29.2%, respectively. Conclusions: For the first time, a population PK approach was used to describe the PK of a triphosphate metabolite in relation to a parent drug as well as other metabolites. Indeed, the novel multi-cpt model developed herein simultaneously described and explained the PK of cholesterol, elacytarabine, Ara-C, Ara-U and Ara-CTP. The inclusion of cholesterol levels in the model improved the overall quality of fit, especially for administered liposomal-elacytarabine. The proposed PK model describing Ara-CTP disposition suggests that Ara-CTP is formed not only from Ara-C but also from elacytarabine, presumably within cancer cells, although the exact mechanism is unknown. Disclosures: Seng Yue: Learn and Confirm: Employment; Clavis Pharma: Consultancy. Gandhi:Clavis Pharma: Research Funding. O'Brien:Clavis Pharma: Research Funding. Ravandi:Clavis Pharma: Research Funding. Jacobsen:Clavis Pharma: Employment, Equity Ownership. Dirven:Clavis Pharma: Employment. Hagen:Clavis Pharma: Employment, Equity Ownership. Hals:Clavis Pharma: Employment. Ducharme:Learn and Confirm: Employment, Equity Ownership; Clavis Pharma: Consultancy.

In vitro exposure of leukemic cells to low concentration arabinosyl cytosine: No evidence of differentiation inducing activity

1987 ◽  
Vol 54 (5) ◽  
pp. 299-306
Author(s):  
Maria Rosa Motta ◽  
Michele Baccarani ◽  
Simonetta Rizzi ◽  
Renato Fanin ◽  
Gianpiero Fasola ◽  
...  
Keyword(s):  
Leukemic Cells ◽  
Low Concentration ◽  
In Vitro Exposure ◽  
Arabinosyl Cytosine

Mechanism of DNA synthesis inhibition by arabinosyl cytosine and arabinosyl adenine

Nature ◽  
1976 ◽  
Vol 264 (5587) ◽  
pp. 679-680 ◽  
Author(s):  
STEPHAN A. RASHBAUM ◽  
NICHOLAS R. COZZARELLI
Keyword(s):  
Dna Synthesis ◽  
Synthesis Inhibition ◽  
Dna Synthesis Inhibition ◽  
Arabinosyl Cytosine
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