Pentostatin (CI825; Deoxycoformycin)   中文名称: 喷司他丁

Adenosine deaminase (Ki = 2.5 pM)

本研究旨在通过实验性感染伊氏锥虫的小鼠，评估3'-脱氧腺苷（虫草素）联合脱氧辅酶霉素（戊唑醇：腺苷脱氨酶抑制剂）在体外治疗的抗锥虫作用。在体外，观察到虫草素对寄生虫具有剂量依赖性的杀锥虫作用[2]。

喷司他丁 (2 mg/kg) 联合虫草素 (2 mg/kg) 对伊氏锥虫感染的小鼠有 100% 的效果。一些生化参数，尤其是肝酶水平的升高，伴随着肝脏和肾脏的组织学病变。喷司他丁单独对感染群体没有作用。所有犬均从第 4 天开始出现粒细胞减少症，粒细胞计数 <500 个细胞/μL。血小板减少症（<20,000 个血小板/μL）在 HCT 后第 7 天开始，最低为 3000 至 14000 个血小板/μL [1]。

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在体内试验中，这两种药物分别使用和不同剂量的组合使用。单独使用这些药物对感染的小鼠没有疗效。然而，虫草素（2 mg kg-1）和戊唑醇（2 mg kg-1）的组合在伊氏锥虫感染组中是100%有效的。一些生化参数水平升高，特别是肝酶，伴有肝脏和肾脏的组织学病变。基于这些结果，我们得出结论，使用3'-脱氧腺苷与脱氧辅酶霉素的联合治疗对感染伊氏锥虫的小鼠具有疗效。然而，所测试的治疗方案导致了肝肾损伤，表现为肝毒性和肾毒性[2]。

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体外光凝术（ECP）和嘌呤类似物戊唑醇具有强大的免疫调节作用。我们评估了在用920 cGy TBI预处理后，在无关犬白细胞Ag错配造血细胞移植的犬模型中使用这些治疗方式预防GVHD的效果。我们之前在该模型中表明，36/40只狗在移植后仅接受MTX作为免疫抑制移植，40只狗中有25只患有严重的GVHD，中位生存期为21天。在目前的研究中，9只狗接受了920 cGy TBI的预处理和移植后MTX，或在-2至-1天单独使用ECP（n=5），或在-6和-5天使用ECP联合两剂戊司他丁（-4至-3天）（n=4）。九只狗中有七只成功植入。六只狗出现了严重的急性移植物抗宿主病（单独使用ECP组有四只，使用戊司他丁和ECP组两只）。与历史对照犬相比，我们未能证明ECP和戊唑醇对预防GVHD的积极影响[1]。

DLA-nonidentical marrow grafts [1]
All recipient dogs were conditioned for transplantation by 920 cGy TBI at 7 cGy/minute using a linear accelerator. Dogs in group A1 received ECP administered on days −2 and −1 with TBI on day 0 and dogs in group A2 received ECP on days −6 and −5, intravenous (IV) infusion of pentostatin at a dose of 4mg/m2 on days −4 and −3, and TBI on day 0 (Table 1). Donor marrow cells from DLA-nonidentical donors were aspirated under general anesthesia through needles inserted into humeri and femora and stored in heparinized tissue culture medium at 4°C for no more than 6 hours.22 Within 4 hours of TBI, harvested marrow cells were infused IV into recipients at a median dose of 2.9 (range, 1.9 to 6.1) ×108 total nucleated cells (TNC)/kg. The day of marrow grafting was designated as day 0. In addition to marrow graft, recipients were given IV infusions of peripheral blood buffy coat cells obtained by leukapheresis from the marrow donor on days 1 and 2, at a median dose of 2.3 (range, 1.2 to 6.9) ×108 TNC/kg to ensure consistent hematopoietic engraftment. MTX, at a dose of 0.4 mg/kg intravenously was used as postgrafting immunosuppression and administered on days +1, +3, +6 and +11, then weekly thereafter until day 102.

Absorption, Distribution and Excretion
Not absorbed orally, crosses blood brain barrier.
In man, following a single dose of 4 mg/m2 of pentostatin infused over 5 minutes, approximately 90% of the dose was excreted in the urine as unchanged pentostatin and/or metabolites as measured by adenosine deaminase inhibitory activity.
68 mL/min/m2
Plasma concentrations of pentostatin following direct iv injection of 0.25 mg/kg daily for 4 or 5 days in a limited number of patients with advanced, refractory cancer ranged from approximately 3.2-9.7 ng/ml. Plasma concentrations appear to increase linearly with dose; in a study in patients with leukemia, plasma pentostatin concentrations determined 1 hour after administration of 0.25 or 1 mg/kg of the drug as a 30 min iv infusion averaged approximately 0.4 or 1.26 ug/ml, respectively.
No apparent correlation has been documented between mean or absolute plasma adenosine or deoxyadenosine concentrations and therapeutic or toxic responses to pentostatin; however, limited data suggest that there may be a correlation between response to the drug and the ratio of deoxyadenosine triphosphate to adenosine triphosphate in lymphoblasts. In addition, increases in plasma deoxyadenosine reportedly parallel the accumulation of deoxyadenosine triphosphate in erythrocytes and lymphoblasts, and there appears to be a correlation between toxicity and the ratio of deoxyadenosine triphosphate to adenosine triphosphate in erythrocytes.
Studies in animals indicate that pentostatin distributes rapidly to all body tissues, but the extent of drug accumulation in different tissues appears to vary among species. Following intraperitoneal injection in mice, the highest concentrations of the drug were found in the kidneys, liver, and spleen. In dogs, pentostatin tissue concentrations following iv administration were proportional to tissue adenosine deaminase activity, with the highest concentrations in the lungs, spleen, pancreas, heart, liver, and jejunum. Pentostatin reportedly enters erythrocytes via a facilitated transport system common to other nucleosides or by simple diffusion; efflux of the drug from cells has not been characterized, although the time course of pentostatin's effects (eg, adenosine deaminase inhibition) varies among different types of cells (eg, lymphocytes, erythrocytes).
Limited data in animals and humans indicate that pentostatin distributes relatively poorly into CSF, with peak CSF concentrations averaging approximately 10% of concurrent plasma concentrations. In a 6 yr old leukemia patient receiving pentostatin 0.25 mg/kg daily for 3 successive days by direct iv injection, serum and CSF (via lumbar puncture) pentostatin concentrations 4 hr after the initial dose were approximately 147 and 19 ng/ml, respectively, using an enzyme-inhibition titration assay; one hour after the third dose, corresponding serum and CSF concentrations were approximately 241 and 35 ng/ml, respectively.
For more Absorption, Distribution and Excretion (Complete) data for PENTOSTATIN (7 total), please visit the HSDB record page.

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Metabolism / Metabolites
Primarily hepatic, but only small amounts are metabolized.
Primarily hepatic, but only small amounts are metabolized.
Route of Elimination: In man, following a single dose of 4 mg/m2 of pentostatin infused over 5 minutes, approximately 90% of the dose was excreted in the urine as unchanged pentostatin and/or metabolites as measured by adenosine deaminase inhibitory activity.
Half Life: 5.7 hours (with a range between 2.6 and 16 hrs)

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Biological Half-Life
5.7 hours (with a range between 2.6 and 16 hrs)
Following iv administration of 4 mg/sq m of pentostatin as a single dose over 5 min in healthy individuals, the distribution half-life and terminal elimination half-life reportedly averaged 11 min and 5.7 hr, respectively. In a multiple dose study in a limited number of patients receiving 36 courses of pentostatin at a dosage of 4 mg/sq m iv, distribution half-life and terminal elimination half-life reportedly averaged 9.6 min (range: 3.1-48.5 min) and 4.9 hr, respectively. In other studies in a limited number of patients with advanced cancer, the distribution half-life averaged 17-85 min and the terminal elimination half-life averaged 2.6-15 hr following single iv doses of 0.1 or 0.25 mg/kg of pentostatin.
In patients with renal impairment (creatinine clearance less than 60 ml/min),the half-life of pentostatin averages approximately 18 hr.

Hepatotoxicity
In clinical trials, serum enzymes elevations occurred in up to 25% of patients receiving pentostatin, but the abnormalities were generally mild and transient and rarely required dose modification. Clinically apparent liver injury from pentostatin is rare, but striking instances of severe liver injury leading rapidly to multiorgan failure and death have been described both in adults and children. The time to onset varied from a few days to six months. The possible role of shock, ischemia, opportunistic infections and sepsis in these cases has not always been well defined. Both hepatocellular and cholestatic patterns of enzyme elevations have been described. Immunoallergic features and autoantibodies were not typical.
Likelihood score: D (possible rare cause of clinically apparent liver disease).

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Protein Binding
4%

[1]. Extracorporeal photopheresis combined with pentostatin in the conditioning regimen for canine hematopoietic cell transplantation does not prevent GVHD. Bone Marrow Transplant. 2014 Sep;49(9):1198-204.

[2]. Cordycepin (3'-deoxyadenosine) pentostatin (deoxycoformycin) combination treatment of mice experimentally infected with Trypanosoma evansi. Parasitology. 2013 Apr;140(5):663-71.

Pentostatin can cause developmental toxicity according to state or federal government labeling requirements.
Pentostatin is a member of the class of coformycins that is coformycin in which the hydroxy group at position 2' is replaced with a hydrogen. It is a drug used for the treatment of hairy cell leukaemia. It has a role as an EC 3.5.4.4 (adenosine deaminase) inhibitor, an antineoplastic agent, an antimetabolite, a bacterial metabolite and an Aspergillus metabolite. It is a conjugate base of a pentostatin(1+).
A potent inhibitor of adenosine deaminase. The drug is effective in the treatment of many lymphoproliferative malignancies, particularly hairy-cell leukemia. It is also synergistic with some other antineoplastic agents and has immunosuppressive activity.
Pentostatin is a Nucleoside Metabolic Inhibitor. The mechanism of action of pentostatin is as a Nucleic Acid Synthesis Inhibitor.
Pentostatin is a purine analogue and antineoplastic agent used in the therapy of hairy cell leukemia and T cell lymphomas. Pentostatin is associated with a low rate of serum enzyme elevations during therapy and has been linked to rare instances of severe acute liver injury with jaundice.
Pentostatin has been reported in Streptomyces antibioticus with data available.
Pentostatin is a purine nucleotide analogue antibiotic isolated from the bacterium Streptomyces antibioticus. Also known as 2'-deoxycoformycin, pentostatin binds to and inhibits adenine deaminase (ADA), an enzyme essential to purine metabolism; ADA activity is greatest in cells of the lymphoid system with T-cells having higher activity than B-cells and T-cell malignancies higher ADA activity than B-cell malignancies. Pentostatin inhibition of ADA appears to result in elevated intracellular levels of dATP which may block DNA synthesis through the inhibition of ribonucleotide reductase. This agent may also inhibit RNA synthesis and may selectively deplete CD26+ lymphocytes. (NCI04)
Pentostatin is only found in individuals that have used or taken this drug. It is a potent inhibitor of adenosine deaminase. The drug is effective in the treatment of many lymphoproliferative malignancies, particularly hairy-cell leukemia. It is also synergistic with some other antineoplastic agents and has immunosuppressive activity. Pentostatin is a potent transition state inhibitor of adenosine deaminase (ADA), the greatest activity of which is found in cells of the lymphoid system. T-cells have higher ADA activity than B-cells, and T-cell malignancies have higher activity than B-cell malignancies. The cytotoxicity that results from prevention of catabolism of adenosine or deoxyadenosine is thought to be due to elevated intracellular levels of dATP, which can block DNA synthesis through inhibition of ribonucleotide reductase. Intracellular activation results in incorporation into DNA as a false purine base. An additional cytotoxic effect is related to its incorporation into RNA. Cytotoxicity is cell cycle phase-specific (S-phase).
A potent inhibitor of ADENOSINE DEAMINASE. The drug induces APOPTOSIS of LYMPHOCYTES, and is used in the treatment of many lymphoproliferative malignancies, particularly HAIRY CELL LEUKEMIA. It is also synergistic with some other antineoplastic agents and has immunosuppressive activity.

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Drug Indication
For the treatment of hairy cell leukaemia refractory to alpha interferon.

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Mechanism of Action
Pentostatin is a potent transition state inhibitor of adenosine deaminase (ADA), the greatest activity of which is found in cells of the lymphoid system. T-cells have higher ADA activity than B-cells, and T-cell malignancies have higher activity than B-cell malignancies. The cytotoxicity that results from prevention of catabolism of adenosine or deoxyadenosine is thought to be due to elevated intracellular levels of dATP, which can block DNA synthesis through inhibition of ribonucleotide reductase. Intracellular activation results in incorporation into DNA as a false purine base. An additional cytotoxic effect is related to its incorporation into RNA. Cytotoxicity is cell cycle phase-specific (S-phase).
... Adenosine deaminase inhibitor
The precise mechanism(s) of action of pentostatin in hairy cell leukemia and other lymphoid malignancies has not been fully elucidated. Pentostatin is a potent transition state (tight binding) inhibitor of adenosine deaminase, an enzyme involved in purine metabolism. This enzyme appears to regulate intracellular adenosine concentrations via irreversible deamination of adenosine and deoxyadenosine. Although adenosine deaminase is widely distributed in mammalian tissues, highest levels are found in lymphoid tissue: levels in circulating T cells (particularly in T cell lymphoblastic leukemia) are higher than those in B cells. While the level of enzyme activity is low in healthy bone marrow, it is high in myeloid leukemic blast cells. ... Inhibition of adenosine deaminase by pentostatin results in intracellular accumulation of toxic levels of adenine deoxynucleotides (eg, deoxyadenosine triphosphate), which in the presence of deoxyadenosine can lead to cell death. Pentostatin alone, even in concentrations high enough to inhibit adenosine deaminase completely, is not cytotoxic to lymphoid cells cultured in the absence of cytotoxic nucleosides (eg, deoxyadenosine). Thus, unlike many other nucleoside-analog antineoplastic agents, the cytoxic effects of pentostatin do not appear to be attributable directly to the drug or its metabolites but instead appear to result indirectly from the effects of the substrates for adenosine deaminase (adenosine and deoxyadenosine) and/or their metabolites. Although elevated deoxyadenosine triphosphate concentrations in the cell can block DNA synthesis via inhibition of ribonucleotide reductase, the precise role of high deoxyadenosine triphosphate concentrations in pentostatin-induced cytotoxicity is controversial. Pentostatin also can inhibit RNA synthesis, cause DNA strand breaks, disrupt ATP-dependent cellular processes, and inhibit adenosylhomocysteinase (S-adenosylhomocysteine hydrolase), all of which also may contribute to the drug's lymphocytotoxic effects.
The degree to which pentostatin inhibits adenosine deaminase varies among cell types, possibly because of differences in enzyme inhibitor dissociation constants in different cells as well as differences in cellular accumulation of the drug. There generally has been no clear relation between adenosine deaminase inhibition and pentostatin induced cytotoxicity in clinical studies. However, the cytotoxic and growth inhibitory effects of adenosine deaminase inhibition appear to be greater in T cells than in B cells. Although conflicting data exist, some evidence suggests that T cells accumulate more deoxyadenosine triphosphate than B cells and thus may be more susceptible to the effects of adenosine deaminase inhibition; deoxyadenosine triphosphate concentrations in B cells may be lower because these cells possess higher membrane associated ecto-5'-nucleotidase activity, which promotes the hydrolysis of higher phosphate compounds to more freely diffusible nucleosides. Differences in the sensitivity of B and T cells to pentostatin's effects also may be artifactual as a result of testing procedure variables (eg, cell source, culture media conditions). The time course of adenosine deaminase inhibition appears to differ in erythrocytes and lymphocytes and depends on the intrinsic activity of the enzyme in the cell as well as cell specific pharmacodynamics (eg, protein synthesis, rate of cellular proliferation). In some cells, inhibition by a single dose of pentostatin may persist for 1 week or longer. It is not known whether recovery from adenosine deaminase inhibition occurs as a result of slow efflux of pentostatin from the cell or regeneration of adenosine deaminase; however, recovery of blood adenosine deaminase activity may result from replenishment of enzyme from newly formed erythrocytes in that such recovery in animals has been reported to coincide with the life span of erythrocytes in circulation (eg, 40-60 days). ... Response to pentostatin varies according to the type and sensitivity of the neoplasm being treated. Conditions associated with relatively low adenosine deaminase activity (eg, hairy cell and chronic lymphocytic leukemias) manifest prolonged and complete adenosine deaminase inhibition in response to relatively low dosages of pentostatin, whereas conditions associated with high adenosine deaminase activity (eg, acute leukemias) are less sensitive to the drug, requiring higher doses that produce relatively incomplete inhibition of adenosine deaminase activity.

C11H16N4O4

268.2691

268.117

C, 49.25; H, 6.01; N, 20.88; O, 23.86

53910-25-1

439693

White crystals from methanol/water
White to off-white solid

1.8±0.1 g/cm3

673.1±65.0 °C at 760 mmHg

220-225ºC

360.9±34.3 °C

0.0±2.2 mmHg at 25°C

1.793

-2.16

112.13

4

6

2

19

356

4

O1[C@]([H])(C([H])([H])O[H])[C@]([H])(C([H])([H])[C@]1([H])N1C([H])=NC2[C@@]([H])(C([H])([H])N=C([H])N([H])C1=2)O[H])O[H]

FPVKHBSQESCIEP-KDXUFGMBSA-N

InChI=1S/C11H16N4O4/c16-3-8-6(17)1-9(19-8)15-5-14-10-7(18)2-12-4-13-11(10)15/h4-9,16-18H,1-3H2,(H,12,13)/t6-,7+,8+,9-/m0/s1

(R)-3-((2S,4S,5R)-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-3,6,7,8-tetrahydroimidazo[4,5-d][1,3]diazepin-8-ol

Deoxycoformycin; CI825; CI-825; Deoxycoformycin; Nipent; 53910-25-1; 2'-Deoxycoformycin; PD-ADI; Pentostatina; Pentostatine; CI 825; PD81565; PD-81565; PD 81565; covidarabine; deoxycoformycin; pentostatine. brand name: Nipent.

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

H2O : ~100 mg/mL (~372.76 mM)
DMSO : ≥ 50 mg/mL (~186.38 mM)

配方 1 中的溶解度: ≥ 2.08 mg/mL (7.75 mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 20.8 mg/mL澄清DMSO储备液加入400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；加入450 μL生理盐水定容至1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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配方 2 中的溶解度: ≥ 2.08 mg/mL (7.75 mM) (饱和度未知) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 20.8 mg/mL澄清DMSO储备液加入900 μL 20% SBE-β-CD生理盐水溶液中，混匀。
*20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。

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配方 3 中的溶解度: ≥ 2.08 mg/mL (7.75 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 20.8 mg/mL 澄清 DMSO 储备液加入到 900 μL 玉米油中并混合均匀。

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。