Pharmacologic and Clinical Studies of N4-Behenoyl-1-Beta-D-Arabinofuranosylcytosine

Yamada, Kazumasa; Kawashima, Kohei; Kato, Yukio; Morishima, Yasuo; Tanimoto, Mitsune; Ohno, Ryuzo

doi:10.1007/978-3-642-81392-4_23

Cited by 16 publications

(7 citation statements)

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“…The pharmacokinetic study of BHAC in humans has revealed a prolonged plasma half-life and a slow plasma clearance. 16,20 In contrast, Ara-C has been reported to show a rapid plasma c l e a~a n c e .~~-~~ In a comparative pharmacokinetic study in monkeys, BHAC showed a longer plasma half-life and smaller elimination rate than those of Ara-C. 16 Although its exact antitumor mechanism is not fully understood, BHAC has been assumed to become active mainly through metabolization to Ara-C.I2 However, BHAC-triphosphate (BHAC-TP) was detected in the acid soluble fraction of human leukemia cells and it was proposed that BHAC-TP might inhibit the activity of DNA p~lymerase. '~,~'…”

Section: Discussionmentioning

confidence: 99%

Treatment of acute myelogenous leukemia in adults with N4-behenoyl-1-β-D-arabinofuranosylcytosine

Kimura

Ohno

Amaki

et al. 1985

Cancer

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Forty-five previously-untreated adult patients with acute myelogenous leukemia (AML) were treated with N'-behenoyl-l-B-Darabinofuranosyl-cytosine (BHAC) in a multi-institutional cooperative study. Among 41 evaluable patients, 15 (36.6%) achieved complete remission (CR) and 10 (24.4%) achieved partial remission by daily administration of 3 to 8 mg/kg of BHAC. Higher daily doses (5 mg/kg or more) produced higher CR rates, and all of the CR were observed among the patients receiving a top1 BHAC dosage of 50 mg/kg or more in a period of 10 days or more. The side effects were mild and acceptable: nausea-anorexia was observed in 27% of the patients and vomiting in 17%. The results of this study thus indicate BHAC to be effective for remission induction of AML, and to deserve further clinical trials in combination with other anti-leukemic drugs.

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Section: Discussionmentioning

confidence: 99%

Treatment of acute myelogenous leukemia in adults with N4-behenoyl-1-β-D-arabinofuranosylcytosine

Kimura

Ohno

Amaki

et al. 1985

Cancer

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“…To avoid these disadvantages, BH-AC has been synthesized; the acylation of the 4-amino position of ara-C prevents enzymatic degradation (Aoshima et al, 1977), and the higher lipophilicity helps to maintain the serum level of the derivative, ara-C (Yamada, 1980;Nakamura, 1980;Ueda et al, 1983). Experimental and clinical studies indicated its efficacy (Yamada, 1980;Aoshima et af., 1976;Kimura et al, 1981). Therefore, we cytokinetically studied the effect of BH-AC on L 1210 cells, and compared the results with those of ara-C to establish a rational drug therapy.…”

Section: Introductionmentioning

confidence: 99%

Cytokinetic study on the effects of N⁴‐behenoyl‐1‐β‐d‐arabinofuranosylcytosine on murine leukemic cells L 1210: A comparison with the effects of 1‐β‐d‐arabinofuranosylcytosine

Maruo

Horiuchi

Nakabo

et al. 1985

Hematological Oncology

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The effects of N4-behenoyl-1-beta-D-arabinofuranosylcytosine (BH-AC) on the cell cycle of murine leukemic cells (L 1210 cells) were compared with those of 1-beta-D-arabinofuranosylcytosine (ara-C), known to be effective for acute leukemia. In a cytokinetic study, a combination of Feulgen microcytofluorometry and tritiated thymidine autoradiography (3H-TdR ARG) was used to measure DNA content and to determine DNA synthesis simultaneously in a single cell. Administration of 200 mg/kg of BH-AC significantly prolonged the survival time of mice bearing L 1210. In addition, the cells in the G1 + S1 phases increased with time, accounting for 94.4 per cent of all cells measured at 48 h after the administration, compared to 73.7 per cent before administration. On the other hand, following the administration of 86 mg/kg of ara-C (equivalent to 200 mg/kg of BH-AC), the percentage of cells in the S1 + S2 phases increased maximally to 75.9 per cent at 18 h. Cytokinetic studies further showed that BH-AC administration blocks DNA synthesis of the cells in the S-phase for a longer period than does ara-C. These results suggest that the prolonged inhibition by BH-AC on DNA synthesis allows cells to accumulate in the S-phase to a greater degree.

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“…21) There are several reports on the pharmacokinetic study of BHAC, including ours. [22][23][24] We have already reported the pharmacokinetics of plasma BHAC and plasma ara-C as a metabolite of BHAC, during a 90-min intravenous infusion of conventional-dose BHAC. 24) In that study, BHAC was well maintained in the plasma and, at the same time, it was converted slowly into ara-C. Consequently, the plasma ara-C concentration was maintained continuously by BHAC administration.…”

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Close Correlation of 1‐β‐D‐Arabinofuranosylcytosine 5′‐Triphosphate, an Intracellular Active Metabolite, to the Therapeutic Efficacy of N⁴‐Behenoyl‐1‐β‐D‐arabinofuranosylcytosine Therapy for Acute Myelogenous Leukemia

Yamauchi¹,

Kawai²,

Goto³

et al. 2001

Japanese Journal of Cancer Research

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N4 -Behenoyl-1-β β β β-D-arabinofuranosylcytosine (BHAC), a prodrug of 1-β β β β-D-arabinofuranosylcytosine, is used effectively for the treatment of leukemia in Japan. BHAC therapy may be more effective if it is delivered in conjunction with monitoring of 1-β β β β-D-arabinofuranosylcytosine 5′ ′ ′ ′-triphosphate (ara-CTP), the intracellular active metabolite of ara-C derived from BHAC. However, previous monitoring methods for ara-CTP were insufficiently sensitive. Here, using our new sensitive method, we evaluated the ara-CTP pharmacokinetics in relation to the therapeutic response in 11 acute myelogenous leukemia patients who received a 2-h infusion of BHAC (70 mg/m 2 ) in combination remission induction therapy. ara-CTP could be monitored at levels under 1 µ µ µ µM. BHAC maintained effective levels of plasma ara-C and intracellular ara-CTP for a longer time, even compared with historical values of high-dose ara-C. The area under the concentration-time curve of ara-CTP was significantly greater in the patients with complete remission than in the patients without response. This greater amount of ara-CTP was attributed to the higher ara-CTP concentrations achieved in the responding patients. There was no apparent difference of plasma ara-C pharmacokinetics between the two groups. Thus, for the first time, the ara-CTP pharmacokinetics was evaluated in relation to the therapeutic effect of BHAC, and the importance of ara-CTP was proven. Administration of optimal BHAC therapy may require monitoring of the ara-CTP pharmacokinetics in each individual patient.

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Pharmacologic and Clinical Studies of N4-Behenoyl-1-Beta-D-Arabinofuranosylcytosine

Cited by 16 publications

References 3 publications

Treatment of acute myelogenous leukemia in adults with N4-behenoyl-1-β-D-arabinofuranosylcytosine

Treatment of acute myelogenous leukemia in adults with N4-behenoyl-1-β-D-arabinofuranosylcytosine

Cytokinetic study on the effects of N⁴‐behenoyl‐1‐β‐d‐arabinofuranosylcytosine on murine leukemic cells L 1210: A comparison with the effects of 1‐β‐d‐arabinofuranosylcytosine

Close Correlation of 1‐β‐D‐Arabinofuranosylcytosine 5′‐Triphosphate, an Intracellular Active Metabolite, to the Therapeutic Efficacy of N⁴‐Behenoyl‐1‐β‐D‐arabinofuranosylcytosine Therapy for Acute Myelogenous Leukemia

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Pharmacologic and Clinical Studies of N4-Behenoyl-1-Beta-D-Arabinofuranosylcytosine

Cited by 16 publications

References 3 publications

Treatment of acute myelogenous leukemia in adults with N4-behenoyl-1-β-D-arabinofuranosylcytosine

Treatment of acute myelogenous leukemia in adults with N4-behenoyl-1-β-D-arabinofuranosylcytosine

Cytokinetic study on the effects of N4‐behenoyl‐1‐β‐d‐arabinofuranosylcytosine on murine leukemic cells L 1210: A comparison with the effects of 1‐β‐d‐arabinofuranosylcytosine

Close Correlation of 1‐β‐D‐Arabinofuranosylcytosine 5′‐Triphosphate, an Intracellular Active Metabolite, to the Therapeutic Efficacy of N4‐Behenoyl‐1‐β‐D‐arabinofuranosylcytosine Therapy for Acute Myelogenous Leukemia

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Cytokinetic study on the effects of N⁴‐behenoyl‐1‐β‐d‐arabinofuranosylcytosine on murine leukemic cells L 1210: A comparison with the effects of 1‐β‐d‐arabinofuranosylcytosine

Close Correlation of 1‐β‐D‐Arabinofuranosylcytosine 5′‐Triphosphate, an Intracellular Active Metabolite, to the Therapeutic Efficacy of N⁴‐Behenoyl‐1‐β‐D‐arabinofuranosylcytosine Therapy for Acute Myelogenous Leukemia