Background
Cytarabine (AraC), an analogue of deoxycytidine, is the most effective cytotoxic agent in the treatment of acute myeloid leukemia (AML), which blocks DNA synthesis by inhibiting the function of DNA and RNA polymerases [1].
Cytarabine is incorporated into DNA, it blocks DNA synthesis by inhibiting the function of DNA and RNA polymerases. The most essential step in the AraC activation is phosphorylation into the monophosphate form, which is catalyzed by deoxycytidine kinase (dCK).
In AraC-sensitive rat leukemic cells, sole expression of inactive or spliced dCK forms make a cell resistant to the cytotoxic effects of AraC. It was reported that Ara-C also causes placental growth retardation, induce apoptosis and also impair cell proliferation in the zone of placental labyrinth. By injecting Ara-C into pregnant rats, the placentas were examined from 1 to 48h. the apoptosis of trophoblastic cells in the placental labyrinth zone increased from 3 h after the injecting and then peaked at 6 h and returned to control level at 48 h. Immunoreactivity of p53 protein in the placental labyrinth zone was significantly enhanced and peaked at 3 h after treatment, while no increase in p53 mRNA expression was detected by a reverse transcription polymerase chain reaction [1, 2].
A retrospective analysis was performed in 40 patients which treated with cytarabine 1000 mg/m2/day, mitoxantrone 8 mg/m2/day and etoposide 100 mg/m2/day for five days. 30% of remission rate and 11.2 months of median remission duration was got. In univariate analysis, compared to ≥second relapse (p = 0.02), patients in first relapse had improved overall survival [3].
阿糖胞苷（AraC）是脱氧胞苷的类似物，在急性髓系白血病（AML）治疗中是最有效的细胞毒性药物，通过抑制DNA和RNA聚合酶的功能来阻止DNA合成[1]。 阿糖胞苷被引入到DNA中，通过抑制DNA和RNA聚合酶的功能来阻止DNA合成。阿糖胞苷活化的最基本步骤是通过脱氧胞苷激酶（dCK）催化成单磷酸形式。 在对阿糖胞苷敏感的大鼠白血病细胞中，仅表达无活性或剪接的dCK形式会使细胞对阿糖胞苷的细胞毒作用产生抵抗。有报道称，阿糖胞苷也会导致胎盘生长受阻，诱导细胞凋亡，并在胎盘迷路区域抑制细胞增殖。通过将阿糖胞苷注入孕鼠体内，从注射后1至48小时检查胎盘。在注射后3小时起，胎盘迷路区滋养层细胞的凋亡增加，达到峰值，然后在48小时后恢复到对照水平。胎盘迷路区p53蛋白的免疫反应性显著增强，在治疗后3小时达到峰值，而反转录聚合酶链反应检测未检测到p53 mRNA表达的增加[1, 2]。 在40名接受阿糖胞苷1000 mg/m2/天、米托蒽醌8 mg/m2/天和依托泊苷100 mg/m2/天治疗5天的患者中进行了回顾性分析。获得30%的缓解率和11.2个月的中位缓解期。在单变量分析中，与≥第二次复发相比（p = 0.02），第一次复发的患者具有改善的总生存率[3]。
参考文献:
[1].Veuger MJT, Heemskerk MHM, Honders MW, et al. Functional role of alternatively spliced deoxycytidine kinase in sensitivity to cytarabine of acute myeloid leukemic cells. Blood, 2002, 99(4): 1373-1380.
[2].Yamauchi H, Katayama K, Ueno M, et al. Involvement of p53 in 1-beta-D-arabinofuranosylcytosine-induced trophoblastic cell apoptosis and impaired proliferation in rat placenta. Biology of Reproduction, 2004, 70(6): 1762-1767.
[3]. Liedtke M, Dunn T, Dinner S, et al. Salvage therapy with mitoxantrone, etoposide and cytarabine in relapsed or refractory acute lymphoblastic leukemia. Leukemia Research, 2014, 38(12): 1441-1445.
Protocol
| Cell experiment [1]: |
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Cell lines
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rat sympathetic neurons
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Preparation method
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Limited solubility in DMSO. General tips for obtaining a higher concentration: Please warm the tube at 37 ℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20℃ for several months.
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Reacting condition
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10 μM
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Applications
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Cytarabine apparently induced apoptosis of rat sympathetic neurons at 10 μM, of which 100 μM showed the highest toxicity and killed over 80% of the neurons by 84 hours, involving the release of mitochondrial cytochrome-c and the activation of caspase-3.
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| Animal experiment [2]: |
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Animal models
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Pregnant Slc:Wistar rats
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Dosage form
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Intraperitoneal injection, 250 mg/kg
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Application
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Cytarabine (250 mg/kg) caused placental growth retardation and increased placental trophoblastic cells apoptosis in the placental labyrinth zone of the pregnant Slc:Wistar rats, which increases from 3 hour after the treatment and peaks at 6 hour before returning to control levels at 48 hour, with remarkably enhanced p53 protein, p53 trancriptional target genes such as p21, cyclinG1 and fas and caspase-3 activity.
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Other notes
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Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal.
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参考文献:
[1]. Besirli C G, Deckwerth T L, Crowder R J, et al. Cytosine arabinoside rapidly activates Bax-dependent apoptosis and a delayed Bax-independent death pathway in sympathetic neurons[J]. Cell death and differentiation, 2003, 10(9): 1045.
[2]. Yamauchi H, Katayama K, Ueno M, et al. Involvement of p53 in 1-β-D-arabinofuranosylcytosine-induced trophoblastic cell apoptosis and impaired proliferation in rat placenta[J]. Biology of reproduction, 2004, 70(6): 1762-1767.
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