Cytosine arabinoside as a single agent in the therapy of adult acute leukemia

Sa, Armentrout; Cp, Burns

doi:10.1097/00000441-197409000-00005

Cited by 16 publications

(1 citation statement)

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“…Cytosine arabinoside (Ara-C) is a useful drug for the treatment of acute myeloid leukaemia, but when used alone remission occurs in only 25-46% of patients (Armentrout & Burns, 1974). Ara-C is not itself active and is phosphorylated intracellularly in leukaemic and normal marrow to cytosine arabinoside triphosphate (Ara-CTP), the active metabolite (Chou, Arlin, Clarkson & Phillips, 1977).…”

Section: Introductionmentioning

confidence: 99%

Cytosine Arabinoside Deamination in Human Leukaemic Myeloblasts and Resistance to Cytosine Arabinoside Therapy

Harris¹,

Grahame‐Smith

Potter

et al. 1981

Clinical Science

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1. The conversion of cytosine arabinoside into its active metabolite cytosine arabinoside triphosphate, and catabolism by deamination to uracil arabinoside, was measured in intact marrow myeloblasts from patients with acute myeloid leukaemia. The ratio of uracil arabinoside/cytosine arabinoside triphosphate ranged from 0.32 to 19.11. 2. The effect of tetrahydrouridine, and inhibitor of cytosine arabinoside deamination, on cytosine arabinoside triphosphate production was studied. The greatest increase of cytosine arabinoside triphosphate production caused by addition of tetrahydrouridine was 27%. 3. The increase in cytosine arabinoside triphosphate production wad not related to the ratio of uracil arabinoside/cytosine arabinoside triphosphate or to the deaminase activity per 10(6) cells. It wa proportional to the percentage change of cytosine arabinoside in the incubation medium. 4. The sensitivity of DNA synthesis to inhibition by cytosine arabinoside was measured in myeloblasts from 11 patients. Addition of tetrahydrouridine did not increase the sensitivity of the marrow to cytosine arabinoside. 5. Cytosine arabinoside deamination is unlikely to be an important mechanism of resistance in myeloblasts in vivo, although it may produce apparent resistance in vitro.

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Section: Introductionmentioning

confidence: 99%

Cytosine Arabinoside Deamination in Human Leukaemic Myeloblasts and Resistance to Cytosine Arabinoside Therapy

Harris¹,

Grahame‐Smith

Potter

et al. 1981

Clinical Science

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Studies on the mechanism of action of cytosine arabinoside

Küfe

Major

1982

Med. Pediatr. Oncol.

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We have demonstrated that Ara-C incorporates in leukemic cell DNA and that the extent of this incorporation correlates significantly with loss of clonogenic survival. This relationship between formation of (Ara-C)DNA and cytotoxicity is also obtained in the presence of modulating agents such as thymidine. Further, the (Ara-C)DNA is structurally abnormal and undergoes strand scission upon exposure to alkali. We have also demonstrated that the incorporated Ara-C residue serves as a poor primer terminus for further chain elongation and thereby results in inhibition of DNA synthesis. These findings provide new insights into the mechanism of action of the most effective agent in the treatment of acute myelogenous leukemia. These findings have also been extended to demonstrate that Ara-C results in the induction of leukemic cell differentiation as well as lethal cellular events.

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The pharmacokinetics of cytosine arabinoside in the plasma and cerebrospinal fluid during conventional and high-dose therapy

Slevin¹,

Piall

Aherne

et al. 1982

Med. Pediatr. Oncol.

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Subcutaneous bolus administration of cytosine arabinoside (Ara-C) has been used as an alternative to continuous intravenous infusion. However, the pharmacokinetics of subcutaneous bolus Ara-C have not been satisfactorily documented in man. The plasma concentrations of Ara-C were therefore compared following intravenous bolus injection, subcutaneous bolus injection, and intravenous infusion in five patients with acute myelogenous leukemia. A triphasic decline in plasma Ara-C levels was seen after intravenous bolus administration. Subcutaneous bolus Ara-C was rapidly absorbed (mean absorption half-life 3.4 f 1 minutes) and then declined biexponentially with initial and terminal half-lives similar to intravenous bolus injection. Ara-C concentrations were above the steadystate infusion levels for only 40 minutes following the intravenous bolus and for 100 minutes following subcutaneous bolus administration. The decline in plasma Ara-C concentrations continued rapidly following both these routes of administration and after five hours were approximately 10% of the steady-state infusion levels. This study demonstrates that it is not possible to achieve comparable steadystate levels of Ara-C with the same total dose given by twice or thrice daily subcutaneous bolus injection as by continuous intravenous infusion.High-dose Ara-C has been used to treat patients with relapsed acute leukemia resistant to Ara-C in conventional doses and may provide a means of overcoming such resistance. Significant concentrations of Ara-C are achieved in the cerebrospinal fluid (CSF) during conventional-dose intravenous infusions, and it seemed likely that much greater levels would be reached during these high-dose infusions. The pharmacokinetics of Ara-C in the plasma and CSF during high-dose intravenous infusions (1 g/m2) has therefore been investigated. Five patients were treated with a three-hour infusion preceded by a loading dose, and five patients received a one-hour infusion with no loading dose. The CSF Ara-C concentrations were similar during both infusions, and the concentrations in the CSF at the end of the infusions were higher than the plasma Ara-C levels obtained with intravenous infusion at conventional doses. In addition CSF Ara-C levels were measured in a patient with an Ommaya reservoir during intravenous infusion of 100 mg/m2 and 1 g/m2. It was demonstrated that Ara-C equilibrated rapidly between Slevin et al the plasma and CSF and crossed the blood brain barrier as effectively at 1 g/m2 as at 100 mglm2. Extrapolation of these data suggests that during therapy with high-dose Ara-C at a dose of 3 g/m2 12 hourly, Ara-C levels in the CSF in excess of 100 n g / d (410 nmoVliter are likely to be maintained almost continuously, and should therefore be effective therapy for CNS leukemia.

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Cytosine arabinoside as a single agent in the therapy of adult acute leukemia

Cited by 16 publications

References 0 publications

Cytosine Arabinoside Deamination in Human Leukaemic Myeloblasts and Resistance to Cytosine Arabinoside Therapy

Cytosine Arabinoside Deamination in Human Leukaemic Myeloblasts and Resistance to Cytosine Arabinoside Therapy

Studies on the mechanism of action of cytosine arabinoside

The pharmacokinetics of cytosine arabinoside in the plasma and cerebrospinal fluid during conventional and high-dose therapy

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