Topo I (DU-145 Luc cells) ( IC50 = 2 nM ); Topo I (MCF-7 Luc cells) ( IC50 = 13 nM )

拓扑替康以剂量和时间依赖性方式强烈抑制人胶质瘤细胞以及胶质瘤干细胞 (GSC) 的生长 [1]。与对照组相比，拓扑替康 (0–40 μM) 以剂量依赖性方式显着降低细胞活力 [1]。对于 U251、U87、GSCs-U251 和 GSCs-U87 细胞，拓扑替康具有抗增殖作用，IC50 值依次为 2.73±0.25、2.95±0.23、5.46±0.41 和 5.95±0.24 μM [1]。

治疗14天后，NUB-7移植模型4组动物全部屠宰。用低剂量节拍（LDM）拓扑替康（TP）和TP+帕唑帕尼（PZ）治疗的动物的肝脏重量明显低于对照组。除TP+PZ外，所有小鼠组的肝脏均出现微肿瘤，证明TP+PZ具有预防肝转移的能力[2]。在卵巢癌模型中，拓扑替康（0.5、1.0 和 1.5 mg/kg；每日口服）显着降低微血管密度；然而，口服给予 1.5 mg/kg 的小鼠，当剂量降低时，抗肿瘤作用同样减弱[2]。

拓扑替康[（S）-9-二甲氨基甲基-10-羟基喜树碱盐酸盐；SK&F 104864-A，NSC 609699]是喜树碱的水溶性半合成类似物，是一种强效的拓扑异构酶I抑制剂。在这里，我们表明拓扑替康稳定了抗辐射的人类B系急性淋巴细胞白血病（ALL）细胞中的拓扑异构酶I/DNA可切割复合物，尽管bcl-2蛋白表达水平很高，但仍会导致快速凋亡细胞死亡，并以剂量依赖的方式抑制ALL细胞的体外克隆生长。此外，拓扑替康在三种不同的人类预后不良ALL的严重联合免疫缺陷（SCID）小鼠模型中引发了强效的抗白血病活性，并显著提高了SCID小鼠在全身药物暴露水平下用致命剂量的人类白血病细胞攻击的无事件生存率，这在白血病儿童中很容易实现[Blood. 1995 May 15;85(10):2817-28]。

胶质瘤是最恶性的脑肿瘤，含有一小部分胶质瘤干细胞（GSCs），与治疗耐药性和肿瘤复发有关。拓扑异构酶I抑制剂紫草素和拓扑替康在抗癌治疗中发挥着至关重要的作用。成功分离和鉴定胶质瘤细胞中的GSCs后，在不同时间点用不同浓度的紫草素或拓扑替康给药U251、U87、GSCs-U251和GSCs-U87细胞，以寻求最佳给药浓度和时间点。采用细胞计数试剂盒-8和流式细胞仪检测细胞活力、细胞周期和凋亡，观察对胶质瘤细胞和GSCs的抑制作用。我们证明，紫草素和拓扑替康不仅明显抑制人脑胶质瘤细胞的增殖，而且以剂量和时间依赖的方式抑制GSCs的增殖。根据24小时的IC50值，选择2μmol/L的紫草素和3μmol/L的拓扑替康作为最佳给药浓度。此外，紫草素和拓扑替康诱导细胞周期阻滞在G0/G1期和S期，并促进细胞凋亡。Bcl-2表达的下调与胱天蛋白酶9/3依赖途径的激活有关。因此，上述结果表明，拓扑异构酶I抑制剂紫草素和拓扑替康抑制了GSCs和胶质瘤细胞的生长并诱导了它们的凋亡，这表明它们可能是靶向胶质瘤的潜在抗癌药物，从而提供了一种新的治疗策略[1]。

In vivo antitumor efficacies of the LDM topotecan and pazopanib as single agents and in combination were tested on 4 subcutaneous xenograft models and on 2 neuroblastoma metastatic models. Circulating angiogenic factors such as circulating endothelial cells (CEC), circulating endothelial pro genitor cells (CEP), and microvessel densities were used as surrogate biomarker markers of antiangiogenic activity.[2]

Absorption, Distribution and Excretion
Renal clearance is an important determinant of topotecan elimination. In a mass balance/excretion study in 4 patients with solid tumors, the overall recovery of total topotecan and its N-desmethyl metabolite in urine and feces over 9 days averaged 73.4 ± 2.3% of the administered IV dose. Fecal elimination of total topotecan accounted for 9 ± 3.6% while fecal elimination of N-desmethyl topotecan was 1.7 ± 0.6%.
The pharmacokinetics of topotecan have been extensively studied in patients with normal renal function and there is one study of patients with mild to moderate renal insufficiency. However, the effect of hemodialysis on topotecan disposition has not been reported. The objective of this study was to characterize the disposition of topotecan in a patient with severe renal insufficiency receiving hemodialysis. Topotecan lactone disposition was characterized in a patient on and off hemodialysis. The topotecan lactone clearance determined after administration of topotecan alone and with hemodialysis was 5.3 L/hr per sq m vs 20.1 L/hr per sq m respectively. At 30 min after the completion of hemodialysis, the topotecan plasma concentration obtained was greater than that measured at the end of hemodialysis (i.e. 8.0 ng/mL vs 4.9 ng/mL), suggesting a rebound effect. The topotecan terminal half-life off dialysis was 13.6 hr, compared with an apparent half-life determined during hemodialysis of 3.0 hr. These results demonstrate that topotecan plasma clearance while on hemodialysis increased approximately fourfold. Hemodialysis may be an effective systemic clearance process for topotecan and should be considered in selected clinical situations (e.g. inadvertent overdose, severe renal dysfunction).
In lactating rats receiving IV topotecan at a dosage of 4.72 mg/sq m, high concentrations of the drug (i.e., up to 48 times higher than plasma concentrations) were distributed into milk. It is not known whether topotecan is distributed into human milk.
Following oral administration, about 57% of topotecan (administered daily for 5 days) is excreted in urine as unchanged drug (20%) and as the N-desmethyl metabolite (2%).47 Approximately 33% of the oral dose of topotecan was eliminated in feces as total topotecan and approximately 2% as N-desmethyl topotecan. Following IV administration, about 74% of a topotecan dose is excreted, mostly unchanged in urine (51%) and feces (18%) within 9 days; excretion of N-desmethyl topotecan in urine is approximately 3% and in feces is approximately 2%. O-Glucuronide metabolites of topotecan and N-desmethyl topotecan also have been detected in urine following oral and IV (less than 2% of the administered IV dose) administration of the drug.
No substantial gender-related differences in pharmacokinetics were reported in patients receiving oral topotecan. The average plasma clearance of IV topotecan was 24% higher in males than in females, mainly because of difference in body size.
For more Absorption, Distribution and Excretion (Complete) data for Topotecan (6 total), please visit the HSDB record page.

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Metabolism / Metabolites
Topotecan undergoes a reversible pH dependent hydrolysis of its lactone moiety; it is the lactone form that is pharmacologically active.
Topotecan undergoes a reversible pH-dependent hydrolysis of its lactone moiety; it is the lactone form that is pharmacologically active. At pH =4, the lactone is exclusively present, whereas the ring-opened hydroxy-acid form predominates at physiologic pH. In vitro studies in human liver microsomes indicate topotecan is metabolized to an N-demethylated metabolite. The mean metabolite:parent AUC ratio was about 3% for total topotecan and topotecan lactone following IV administration.

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Biological Half-Life
2-3 hours
The pharmacokinetics of topotecan have been evaluated in cancer patients following doses of 0.5 to 1.5 mg/sq m administered as a 30-minute infusion. Topotecan exhibits multiexponential pharmacokinetics with a terminal half-life of 2 to 3 hours.
Topotecan has a terminal half-life of 3-6 hours following oral administration and 2-3 hours following IV administration of the drug.
... The objective of this study was to characterize the disposition of topotecan in a patient with severe renal insufficiency receiving hemodialysis. ... The topotecan terminal half-life off dialysis was 13.6 hr, compared with an apparent half-life determined during hemodialysis of 3.0 hr. ...

Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Most sources consider breastfeeding to be contraindicated during maternal high-dose antineoplastic drug therapy. The manufacturer recommends that women not breastfeed during treatment with topotecan and for 1 week after the last dose. Chemotherapy may adversely affect the normal microbiome and chemical makeup of breastmilk. Women who receive chemotherapy during pregnancy are more likely to have difficulty nursing their infant.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

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Protein Binding
35%

[1]. PLoS One. 2013 Nov 26;8(11):e81815.Topoisomerase I inhibitors, Shikonin and Topotecan, inhibit growth and induce apoptosis of glioma cells andglioma stem cells.

[2]. Metronomic oral topotecan with pazopanib is an active antiangiogenic regimen in mouse models of aggressive pediatric solid tumor. Clin Cancer Res. 2011 Sep 1;17(17):5656-67.

Topotecan is a pyranoindolizinoquinoline used as an antineoplastic agent. It is a derivative of camptothecin and works by binding to the topoisomerase I-DNA complex and preventing religation of these 328 single strand breaks. It has a role as an EC 5.99.1.2 (DNA topoisomerase) inhibitor and an antineoplastic agent.
An antineoplastic agent used to treat ovarian cancer. It works by inhibiting DNA topoisomerases, type I.
Topotecan is a Topoisomerase Inhibitor. The mechanism of action of topotecan is as a Topoisomerase Inhibitor.
Topotecan is a semisynthetic derivative of camptothecin, a cytotoxic, quinoline-based alkaloid extracted from the Asian tree Camptotheca acuminata. Topotecan inhibits topoisomerase I activity by stabilizing the topoisomerase I-DNA covalent complexes during S phase of cell cycle, thereby inhibiting religation of topoisomerase I-mediated single-strand DNA breaks and producing potentially lethal double-strand DNA breaks when encountered by the DNA replication machinery.
An antineoplastic agent used to treat ovarian cancer. It works by inhibiting DNA TOPOISOMERASES, TYPE I.
See also: Topotecan Hydrochloride (has salt form); Topotecan Hydrochloride (1:1.25) (is active moiety of).

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Drug Indication
For the treatment of advanced ovarian cancer in patients with disease that has recurred or progressed following therapy with platinum-based regimens. Also used as a second-line therapy for treatment-sensitive small cell lung cancer, as well as in combination with cisplatin for the treatment of stage IV-B, recurrent, or persistent cervical cancer not amenable to curative treatment with surgery and/or radiation therapy.
FDA Label
Hycamtin capsules are indicated as monotherapy for the treatment of adult patients with relapsed small cell lung cancer (SCLC) for whom re-treatment with the first-line regimen is not considered appropriate. Topotecan is indicated for the treatment of patients with metastatic carcinoma of the ovary after failure of first-line or subsequent therapy. Hycamtin capsules are indicated as monotherapy for the treatment of adult patients with relapsed small cell lung cancer (SCLC) for whom re-treatment with the first-line regimen is not considered appropriate.
Topotecan monotherapy is indicated for the treatment of: - patients with metastatic carcinoma of the ovary after failure of first-line or subsequent therapy- patients with relapsed small cell lung cancer (SCLC) for whom re-treatment with the first-line regimen is not considered appropriate (see section 5. 1). Topotecan in combination with cisplatin is indicated for patients with carcinoma of the cervix recurrent after radiotherapy and for patients with Stage IVB disease. Patients with prior exposure to cisplatin require a sustained treatment free interval to justify treatment with the combination (see section 5. 1).
Topotecan monotherapy is indicated for the treatment of patients with relapsed small-cell lung cancer (SCLC) for whom re-treatment with the first-line regimen is not considered appropriate. , , Topotecan in combination with cisplatin is indicated for patients with carcinoma of the cervix recurrent after radiotherapy and for patients with stage IVB disease. Patients with prior exposure to cisplatin require a sustained treatment-free interval to justify treatment with the combination. ,
Topotecan monotherapy is indicated for the treatment of patients with relapsed small cell lung cancer [SCLC] for whom re-treatment with the first-line regimen is not considered appropriate. , , Topotecan in combination with cisplatin is indicated for patients with carcinoma of the cervix recurrent after radiotherapy and for patients with Stage IVB disease. Patients with prior exposure to cisplatin require a sustained treatment free interval to justify treatment with the combination. ,
Topotecan monotherapy is indicated for the treatment of: , , , patients with metastatic carcinoma of the ovary after failure of first line or subsequent therapy; , patients with relapsed small cell lung cancer [SCLC] for whom re-treatment with the first-line regimen is not considered appropriate. , , , Topotecan in combination with cisplatin is indicated for patients with carcinoma of the cervix recurrent after radiotherapy and for patients with Stage IVB disease. Patients with prior exposure to cisplatin require a sustained treatment free interval to justify treatment with the combination. ,
Topotecan monotherapy is indicated for the treatment of patients with relapsed small cell lung cancer (SCLC) for whom re-treatment with the first-line regimen is not considered appropriate. Topotecan in combination with cisplatin is indicated for patients with carcinoma of the cervix recurrent after radiotherapy and for patients with Stage IVB disease. Patients with prior exposure to cisplatin require a sustained treatment free interval to justify treatment with the combination.
Topotecan is indicated for the treatment of patients with metastatic carcinoma of the ovary after failure of first-line or subsequent therapy.

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Mechanism of Action
Topotecan has the same mechanism of action as irinotecan and is believed to exert its cytotoxic effects during the S-phase of DNA synthesis. Topoisomerase I relieves torsional strain in DNA by inducing reversible single strand breaks. Topotecan binds to the topoisomerase I-DNA complex and prevents religation of these single strand breaks. This ternary complex interferes with the moving replication fork, which leads to the induction of replication arrest and lethal double-stranded breaks in DNA. As mammalian cells cannot efficiently repair these double strand breaks, the formation of this ternary complex eventually leads to apoptosis (programmed cell death). Topotecan mimics a DNA base pair and binds at the site of DNA cleavage by intercalating between the upstream (−1) and downstream (+1) base pairs. Intercalation displaces the downstream DNA, thus preventing religation of the cleaved strand. By specifically binding to the enzyme–substrate complex, Topotecan acts as an uncompetitive inhibitor.
Topoisomerase I relieves torsional strain in DNA by inducing reversible single-strand breaks. Topotecan binds to the topoisomerase I-DNA complex and prevents religation of these single-strand breaks. The cytotoxicity of topotecan is thought to be due to double-strand DNA damage produced during DNA synthesis, when replication enzymes interact with the ternary complex formed by topotecan, topoisomerase I, and DNA. Mammalian cells cannot efficiently repair these double strand breaks.

C23H23N3O5

421.453

421.163

C, 65.55; H, 5.50; N, 9.97; O, 18.98

123948-87-8

Topotecan hydrochloride;119413-54-6; Topotecan hydrochloride hydrate;1044663-62-8; Topotecan-d6;1044904-10-0; 123948-87-8

60700

Typically exists as solid at room temperature

1.5±0.1 g/cm3

782.9±60.0 °C at 760 mmHg

−114 °C(lit.)

427.3±32.9 °C

0.0±2.8 mmHg at 25°C

1.734

1.08

104.89

2

7

3

31

867

1

O=C1[C@](O)(CC)C2=C(CO1)C(N3CC4=CC5=C(CN(C)C)C(O)=CC=C5N=C4C3=C2)=O

UCFGDBYHRUNTLO-QHCPKHFHSA-N

InChI=1S/C23H23N3O5/c1-4-23(30)16-8-18-20-12(9-26(18)21(28)15(16)11-31-22(23)29)7-13-14(10-25(2)3)19(27)6-5-17(13)24-20/h5-8,27,30H,4,9-11H2,1-3H3/t23-/m0/s1

(19S)-8-[(dimethylamino)methyl]-19-ethyl-7,19-dihydroxy-17-oxa-3,13-diazapentacyclo[11.8.0.02,11.04,9.015,20]henicosa-1(21),2,4(9),5,7,10,15(20)-heptaene-14,18-dione

NSC 609699; NSC-609699; NSC609699; SKF S104864A; SKF 104864 A; SKF-104864-A; SKF104864A; TOPO. Hycamtamine; Topotecan lactone; Hycamptamine; Hycamptin; (S)-Topotecan; Topotecane; Topotecanum; Nogitecan; Topotecan

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)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

注意: 如下所列的是一些常用的体内动物实验溶解配方，主要用于溶解难溶或不溶于水的产品（水溶度<1 mg/mL）。 建议您先取少量样品进行尝试，如该配方可行，再根据实验需求增加样品量。

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注射用配方1: DMSO : Tween 80： Saline = 10 : 5 : 85 (如： 100 μL DMSO → 50 μL Tween 80 → 850 μL Saline)
*生理盐水/Saline的制备：将0.9g氯化钠/NaCl溶解在100 mL ddH ₂ O中，得到澄清溶液。
注射用配方 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (如： 100 μL DMSO → 400 μL PEG300 → 50 μL Tween 80 → 450 μL Saline)
注射用配方 3: DMSO : Corn oil = 10 : 90 (如： 100 μL DMSO → 900 μL Corn oil)
示例: 以注射用配方 3 (DMSO : Corn oil = 10 : 90) 为例说明, 如果要配制 1 mL 2.5 mg/mL的工作液, 您可以取 100 μL 25 mg/mL 澄清的 DMSO 储备液，加到 900 μL Corn oil/玉米油中, 混合均匀。

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注射用配方 4: DMSO : 20% SBE-β-CD in Saline = 10 : 90 [如：100 μL DMSO → 900 μL (20% SBE-β-CD in Saline)]
*20% SBE-β-CD in Saline的制备（4°C，储存1周）：将2g SBE-β-CD (磺丁基-β-环糊精) 溶解于10mL生理盐水中，得到澄清溶液。
注射用配方 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (如： 500 μL 2-Hydroxypropyl-β-cyclodextrin (羟丙基环胡精)→ 500 μL Saline)
注射用配方 6: DMSO : PEG300 : Castor oil : Saline = 5 : 10 : 20 : 65 (如： 50 μL DMSO → 100 μL PEG300 → 200 μL Castor oil → 650 μL Saline)
注射用配方 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (如： 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
注射用配方 8: 溶解于Cremophor/Ethanol (50 : 50), 然后用生理盐水稀释。
注射用配方 9: EtOH : Corn oil = 10 : 90 (如： 100 μL EtOH → 900 μL Corn oil)
注射用配方 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (如： 100 μL EtOH → 400 μL PEG300 → 50 μL Tween 80 → 450 μL Saline)

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口服配方 1: 悬浮于0.5% CMC Na (羧甲基纤维素钠)
口服配方 2: 悬浮于0.5% Carboxymethyl cellulose (羧甲基纤维素)
示例: 以口服配方 1 (悬浮于 0.5% CMC Na)为例说明, 如果要配制 100 mL 2.5 mg/mL 的工作液, 您可以先取0.5g CMC Na并将其溶解于100mL ddH2O中，得到0.5%CMC-Na澄清溶液；然后将250 mg待测化合物加到100 mL前述 0.5%CMC Na溶液中，得到悬浮液。

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口服配方 3: 溶解于 PEG400 (聚乙二醇400)
口服配方 4: 悬浮于0.2% Carboxymethyl cellulose (羧甲基纤维素)
口服配方 5: 溶解于0.25% Tween 80 and 0.5% Carboxymethyl cellulose (羧甲基纤维素)
口服配方 6: 做成粉末与食物混合

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注意: 以上为较为常见方法，仅供参考， InvivoChem并未独立验证这些配方的准确性。具体溶剂的选择首先应参照文献已报道溶解方法、配方或剂型，对于某些尚未有文献报道溶解方法的化合物，需通过前期实验来确定（建议先取少量样品进行尝试），包括产品的溶解情况、梯度设置、动物的耐受性等。

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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;
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7、 以上所有助溶剂都可在 Invivochem.cn网站购买。