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

体外活性：在 DU-145 Luc 和 MCF-7 Luc 细胞中观察到拓扑替康具有更强的药物活性。拓扑替康通过稳定拓扑异构酶 I 和 DNA 之间的共价复合物并防止酶联单链 DNA 断裂的重新连接，在 DNA 复制过程中引起细胞毒性。托泊替康可稳定抗辐射人 B 系急性淋巴细胞白血病 (ALL) 细胞中的拓扑异构酶 I/DNA 可裂解复合物，尽管 bcl-2 蛋白高水平表达，但仍会导致细胞快速凋亡，并在一定剂量下抑制 ALL 细胞克隆生长。依赖时尚。细胞测定：将拓扑替康溶解在无菌水中至储备浓度为 1 mg/mL，在培养基中稀释至 6 μg/mL，然后在不透明的白色组织培养处理的微孔板中按 1:4 连续稀释至最终体积 0.1毫升/孔。将MCF-7 Luc和DU-145 Luc细胞重悬于含有10% FBS和0.5 mg/mL Geneticin的高糖DMEM中，浓度为3×104 cells/mL；每孔中添加 100 μL 细胞。将板在 37°C、95% 湿度/5% CO2 下孵育 4 天。孵育后，向每个孔中添加 0.05 mL 含有 50 μg/mL D-荧光素的 0.1 M HEPES 缓冲液（pH 7.9）。在室温下孵育 10 分钟后，在微孔板发光计和分子光成像仪中测量培养微孔板。使用不含外源药物的无抑制对照孔和含有 ATP 抑制剂的最大抑制对照孔计算用微孔板发光计获得的结果。使用 5 分钟发光成像仪获得的值类似地计算分子光成像仪的结果。

动物皮下接种 DU-145 Luc 细胞，然后用拓扑替康治疗，通过卡尺和发光成像测量，显示出显着的肿瘤生长和消退。对照未治疗组的相关系数为 0.75，拓扑替康治疗组的相关系数为 0.93。类似地，对于腹腔注射 MCF-7 Luc 细胞的未治疗和拓扑替康治疗的小鼠，可以使用发光成像来测量肿瘤进展和消退。拓扑替康在人类预后不良 ALL 的严重联合免疫缺陷 (SCID) 小鼠模型中引发了有效的抗白血病活性。拓扑替康显着改善了在全身药物暴露水平下接受致命剂量的人类白血病细胞攻击的 SCID 小鼠的无事件存活率。神经胶质瘤优先表达 TRAIL R2，拓扑替康治疗显着上调其表达。

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[2]。

拓扑替康首先在培养基中稀释至 6 μg/mL，然后溶解在无菌水中至储备浓度为 1 mg/mL。每个不透明、白色组织培养处理的微孔板的最终体积是通过按 1:4 连续稀释溶液直至达到 0.1 mL/孔来获得的。每孔添加 100 μL 细胞。将 MCF-7 Luc 和 DU-145 Luc 细胞以 3×10⁴ cells/mL 重悬于含有 10% FBS 和 0.5 mg/mL Geneticin 的高葡萄糖 DMEM 中。将板在 37 °C、5% CO₂ 和 95% 湿度下孵育四天。孵育后，每个孔接受 0.05 mL 的 0.1 M HEPES 缓冲液（pH 7.9），其中含有 50 μg/mL D-荧光素。将培养微板在室温下孵育十分钟后，在分子光成像仪和微板发光计中进行测量。微孔板发光计的结果是使用含有 ATP 抑制剂的最大抑制对照孔和不含外源药物的无抑制对照孔计算的。使用 5 分钟发光成像仪获取的值以类似的方式计算分子光成像仪的结果。

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.

[1]. Anticancer Drugs . 2003 Aug;14(7):569-74.

[2]. Blood . 1995 May 15;85(10):2817-28.

[3]. J Neurooncol . 2005 Jan;71(1):19-25.

[4]. J Nucl Med . 2012 Jul;53(7):1146-54.

[5]. Cancer Chemother Pharmacol . 1998;41(5):385-90.

Topotecan Hydrochloride is the hydrochloride salt of a semisynthetic derivative of camptothecin with antineoplastic activity. During the S phase of the cell cycle, topotecan selectively stabilizes topoisomerase I-DNA covalent complexes, inhibiting religation of topoisomerase I-mediated single-strand DNA breaks and producing potentially lethal double-strand DNA breaks when complexes are encountered by the DNA replication machinery. Camptothecin is a cytotoxic quinoline-based alkaloid extracted from the Asian tree Camptotheca acuminata.
An antineoplastic agent used to treat ovarian cancer. It works by inhibiting DNA TOPOISOMERASES, TYPE I.
See also: Topotecan (has active moiety).

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Drug Indication
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.

C23H23N3O5.HCL

457.91

421.163

C, 60.33; H, 5.28; Cl, 7.74; N, 9.18; O, 17.47

119413-54-6

123948-87-8; 119413-54-6(HCl); 1044663-62-8 (Topotecan HCl hydrate)

60699

Yellow solid powder

1.5±0.1 g/cm3

782.9±60.0 °C at 760 mmHg

213-218ºC

427.3±32.9 °C

0.0±2.8 mmHg at 25°C

1.734

1.08

104.89

3

7

3

32

867

1

O1CC2C(N3CC4=CC5C(CN(C)C)=C(C=CC=5N=C4C3=CC=2[C@@](CC)(C1=O)O)O)=O

DGHHQBMTXTWTJV-BQAIUKQQSA-N

InChI=1S/C23H23N3O5.ClH/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;1H/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;hydrochloride

NSC609699; SKF-104864-A; NSC 609699; SKF 104864 A; NSC-609699; SKF S104864A; Nogitecan HCl; SKFS 104864A; SKF104864A; TOPO. Hycamtamine; Hycamtin Hydrochloride; Nogitecan Hydrochloride; Topotecan; Nogitecan Hydrochloride; Hycamtin; Nogitecan hydrochloride; Topotecan (Hydrochloride); Topotecan monohydrochloride; Evotopin; Trade name: Hycamtin

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

注意： 请将本产品存放在密封且受保护的环境中（例如氮气保护），避免吸湿/受潮和光照。

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

配方 1 中的溶解度: ≥ 2.5 mg/mL (5.46 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 25.0 mg/mL 澄清 DMSO 储备液加入900 μL 玉米油中，混合均匀。

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配方 2 中的溶解度: ≥ 2.08 mg/mL (4.54 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澄清的DMSO储备液加入到400 μL PEG300中，混匀；再向上述溶液中加入50 μL Tween-80，混匀；然后加入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 3 中的溶解度: ≥ 2.08 mg/mL (4.54 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 4 中的溶解度: Saline: 30 mg/mL

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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。