Topoisomerase I (IC50 = 0.8 μM); Topoisomerase II (IC50 = 2.67 μM); Daunorubicins/Doxorubicins; HIV-1

体外活性：阿霉素是一种蒽环类抗生素，通常被认为在两个基本水平上发挥其抗肿瘤活性：改变 DNA 并产生自由基，通过 DNA 损伤引发癌细胞凋亡。阿霉素可以通过插入 DNA 链来阻断 DNA 的合成，并抑制 DNA 拓扑异构酶 II (TOP2)。当细胞快速增殖并表达高水平 TOP2 时，阿霉素最有效。此外，多柔比星还可以通过产生神经酰胺（通过激活 p53 或其他下游途径（例如 JNK）促进细胞凋亡）、丝氨酸苏氨酸蛋白酶降解 Akt、线粒体释放细胞色素 c、增加 FasL（死亡受体 Fas/CD95 配体）来触发细胞凋亡。 ) mRNA 的产生，以及自由基的产生。用 GSNO（亚硝基谷胱甘肽）预处理可抑制多柔比星耐药乳腺癌细胞系 MCF7/Dx 的耐药性，同时增强蛋白质谷胱甘肽化和多柔比星在细胞核中的积累。阿霉素诱导的 G2/M 检查点阻滞归因于细胞周期蛋白 G2 (CycG2) 表达升高以及共济失调毛细血管扩张突变 (ATM) 以及 ATM 和 Rad3 相关 (ATR) 信号通路中蛋白质的磷酸化修饰。阿霉素抑制 AMP 激活蛋白激酶 (AMPK)，导致 SIRT1 功能障碍、p53 积累以及小鼠胚胎成纤维细胞 (MEF) 和心肌细胞的细胞死亡增加，而 AMPK 的预抑制可进一步使其敏化。阿霉素引起显着的热休克反应，并且抑制或沉默热休克蛋白可增强阿霉素在神经母细胞瘤细胞中的凋亡作用。在没有可测量的蛋白酶体抑制的情况下，纳摩尔多柔比星治疗神经母细胞瘤细胞会导致一组特定蛋白质发生剂量依赖性过度泛素化，并导致泛素化酶（如乳酸脱氢酶和 α-烯醇酶）活性丧失，其蛋白质泛素化模式与蛋白酶体抑制剂硼替佐米相似，表明阿霉素也可能通过破坏蛋白质来发挥作用。细胞测定：用增加浓度的阿霉素（0.1、0.3、0.5和1.0 μg/ml，分别等于0.17、0.52、0.85和1.71 μM）处理H9c2细胞2小时，或用0.3 μg/ml（等于0.52μM）的阿霉素在不同的时间点。 Doxorubicin 以时间和剂量依赖性方式诱导 AMPKα (Thr 172) 及其下游乙酰辅酶 A 羧化酶 (ACC、Ser 79) 强烈磷酸化。 AMPKα 磷酸化在多柔比星处理 1 小时后变得明显，并进一步持续至少 6 小时。 LKB1（AMPK 可能的上游激酶）在 H9c2 细胞中也被阿霉素激活。

在体内，阿霉素与腺病毒 MnSOD (AdMnSOD) 加 1,3-双(2-氯乙基)-1-亚硝基脲 (BCNU) 联合使用，在减少 MB231 肿瘤体积和延长小鼠存活方面具有最大效果。尽管其使用受到其产生的慢性和急性毒副作用的限制，但阿霉素对于治疗乳腺癌和食道癌、儿童实体瘤、骨肉瘤、卡波西肉瘤、软组织肉瘤以及霍奇金和非霍奇金淋巴瘤至关重要。

纯化的人DNA拓扑异构酶I通过在0-2.0μM阿霉素存在下用超螺旋pHC624 DNA进行酶滴定来定量测定。在溴化乙锭存在下，通过琼脂糖凝胶电泳解析超螺旋和松弛的DNA，并通过扫描微密度测定法定量超螺旋DNA转化为松弛DNA的百分比。在不同浓度的阿霉素下测量DNA拓扑异构酶I活性的抑制作用。阿霉素在0.8微M的IC50值（抑制总活性的50%所需的浓度）下抑制酶活性。对结构相关的蒽环类抗肿瘤药物柔红霉素也观察到类似的抑制作用。这些结果表明，蒽环类药物在体内引起DNA损伤和细胞毒性的浓度下抑制人类DNA拓扑异构酶I活性[11]。

细胞培养[7]
LS141原代人细胞系来源于患有高级腹膜后去分化脂肪肉瘤的患者，MPNST细胞来源于患有大腿高级周围神经鞘肿瘤的患者。这些生长在补充有15%热灭活胎牛血清加青霉素和链霉素的RPMI1640中。[7]
菌落测定[7]
MPNST细胞依次用阿霉素、黄必利或这两种药物的组合处理。选择MPNST细胞是因为LS141（和其他CDK4依赖性）细胞在体外对CDK4抑制非常敏感，因此组合研究是不间断的。MPNST细胞以每板1000个细胞/100 mm2的密度进行三次接种。接种24小时后，用阿霉素（D，15nM）、黄必利（F，150nM）的IC50、无药物培养基（对照）或两种药物的组合同时或依次处理细胞24小时。处理后，去除含药物的培养基，并使细胞生长10天以形成集落。将所得菌落用0.01%结晶紫染色30分钟，并使用自动菌落计数器计数菌落。结果以未治疗对照的百分比表示，实验结果的统计学意义通过双侧t检验确定。

Female athymic nude mice injected s.c. with MB231 cells; 3 mg/kg/day; Delivered intratumorly
Female athymic nude mice injected s.c. with MB231 cells

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In vivo studies LS141 xenografts were established by directly implanting into severe combined immunodeficient (SCID) mice. Once tumors reached 100 mm3 , groups of five mice were treated with the maximum tolerated dose (MTD) of flavopiridol (9 mg/kg), doxorubicin (0.9 mg/kg), or doxorubicin (0.7 mg/kg) followed by flavopiridol (7 mg/kg) at selected time points (1, 4 and 7 hours). In addition, one set of animals was treated in reverse order of flavopiridol followed by doxorubicin, administered 7 hours apart. All treatments were administered in intraperitoneal fashion, twice weekly, for a total of 5 treatments. Tumors were measured every 2 to 3 days with calipers, and tumor volumes were calculated by the formula π/ 6 × (large diameter) × (small diameter)2. Tumor volume was compared between groups of mice at various points in time based on the experiment and the statistical significance of the experimental results was determined by the two-sided t test. Given the aggressive morbidity of the tumors, animal survival data could not be estimated. Toxicity was monitored by weight loss. These studies were done in accordance with the Principles of Laboratory Animal Care, under an IACUC-approved protocol.

Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Most sources consider breastfeeding to be contraindicated during maternal antineoplastic drug therapy, especially anthracyclines such as doxorubicin. It might be possible to breastfeed safely during intermittent therapy with an appropriate period of breastfeeding abstinence; however, the high levels and persistence of the active metabolite doxorubicinol in milk make defining an appropriate abstinence interval difficult. Some have suggested a breastfeeding abstinence period of 5 to 10 days after a dose. More recent pharmacokinetic modeling using a worst-case scenario suggests that 13 days would be required to minimize both systemic and gut toxicity after the colostral phase.
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
A woman was diagnosed with B-cell lymphoma at 27 weeks of pregnancy. Labor was induced at 34 4/7 weeks and treatment was begun with a standard regimen of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone in unspecified doses on a 21-day cycle, starting on day 2 postpartum. She pumped and discarded her milk and fed her infant donor milk for the first 10 days of each cycle and then breastfed her infant for the remaining 10 days before the next treatment cycle. The 10-day period of breastfeeding abstinence was determined by using about 3 half-lives of vincristine. After completion of 4 cycles of chemotherapy, her infant was reportedly healthy and developing without any complications.
◉ Effects on Lactation and Breastmilk
A study of adolescent males who had received chemotherapy for childhood malignancies found that having received doxorubicin was associated with elevated serum prolactin concentrations.
A woman diagnosed with Hodgkin's lymphoma during the second trimester of pregnancy received 3 rounds of chemotherapy during the third trimester of pregnancy and resumed chemotherapy 4 weeks postpartum. Milk samples were collected 15 to 30 minutes before and after chemotherapy for 16 weeks after restarting. The regimen consisted of doxorubicin 40 mg, bleomycin 16 units, vinblastine 9.6 mg and dacarbazine 600 mg, all given over a 2-hour period every 2 weeks. The microbial population and metabolic profile of her milk were compared to those of 8 healthy women who were not receiving chemotherapy. The breastmilk microbial population in the patient was markedly different from that of the healthy women, with increases in Acinetobacter sp., Xanthomonadacae and Stenotrophomonas sp. and decreases in Bifidobacterium sp. and Eubacterium sp. Marked differences were also found among numerous chemical components in the breastmilk of the treated woman, most notably DHA and inositol were decreased.
A telephone follow-up study was conducted on 74 women who received cancer chemotherapy at one center during the second or third trimester of pregnancy to determine if they were successful at breastfeeding postpartum. Only 34% of the women were able to exclusively breastfeed their infants, and 66% of the women reported experiencing breastfeeding difficulties. This was in comparison to a 91% breastfeeding success rate in 22 other mothers diagnosed during pregnancy, but not treated with chemotherapy. Other statistically significant correlations included: 1. mothers with breastfeeding difficulties had an average of 5.5 cycles of chemotherapy compared with 3.8 cycles among mothers who had no difficulties; and 2. mothers with breastfeeding difficulties received their first cycle of chemotherapy on average 3.4 weeks earlier in pregnancy. Of the 62 women who received a doxorubicin-containing regimen, 39 had breastfeeding difficulties.

[1]. Cancer Res . 2009 May 15;69(10):4294-300.

[2]. Food Chem Toxicol . 2010 Jun;48(6):1425-38.

[3]. Biochem J . 2011 Dec 1;440(2):175-83.

[4]. Br J Cancer . 2011 Mar 15;104(6):957-67.

[5]. J Biol Chem . 2012 Jun 29;287(27):22838-53.

[6]. J Biol Chem . 2012 Mar 9;287(11):8001-12.

[7]. Clin Cancer Res . 2012 May 1;18(9):2638-47.

[8]. FEBS J . 2012 Jun;279(12):2182-91.

[9]. Nat Rev Cancer . 2009 May;9(5):338-50.

[10]. Bioorg Med Chem . 2007 Feb 15;15(4):1651-8.

[11]. Cancer Chemother Pharmacol . 1992;30(2):123-5.

Doxorubicin Hydrochloride (Adriamycin) can cause cancer according to an independent committee of scientific and health experts. It can cause developmental toxicity and male reproductive toxicity according to state or federal government labeling requirements.
Adriamycin hydrochloride appears as orange-red thin needles. Aqueous solutions yellow-orange at acid pHs, orange-red at neutral pHs, and violet blue over pH 9. (NTP, 1992)
Doxorubicin hydrochloride is an anthracycline.
Doxorubicin hydrochloride (liposomal) is an antineoplastic prescription medicine approved by the U.S. Food and Drug Administration (FDA) for the treatment of certain types of cancer, including ovarian cancer, multiple myeloma, and AIDS-related Kaposi sarcoma.
Kaposi sarcoma is caused by infection with human herpesvirus-8 (HHV-8). HHV-8 infection can be an opportunistic infection (OI) of HIV.
Doxorubicin Hydrochloride is the hydrochloride salt of doxorubicin, an anthracycline antibiotic with antineoplastic activity. Doxorubicin, isolated from the bacterium Streptomyces peucetius var. caesius, is the hydroxylated congener of daunorubicin. Doxorubicin intercalates between base pairs in the DNA helix, thereby preventing DNA replication and ultimately inhibiting protein synthesis. Additionally, doxorubicin inhibits topoisomerase II which results in an increased and stabilized cleavable enzyme-DNA linked complex during DNA replication and subsequently prevents the ligation of the nucleotide strand after double-strand breakage. Doxorubicin also forms oxygen free radicals resulting in cytotoxicity secondary to lipid peroxidation of cell membrane lipids; the formation of oxygen free radicals also contributes to the toxicity of the anthracycline antibiotics, namely the cardiac and cutaneous vascular effects.
Antineoplastic antibiotic obtained from Streptomyces peucetius. It is a hydroxy derivative of DAUNORUBICIN.
See also: Doxorubicin (has active moiety).

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Drug Indication
Celdoxome pegylated liposomal is indicated in adults: as monotherapy for patients with metastatic breast cancer , where there is an increased cardiac risk. or treatment of advanced ovarian cancer in women who have failed a first-line platinum-based chemotherapy regimen. in combination with bortezomib for the treatment of progressive multiple myeloma in patients who have received at least one prior therapy and who have already undergone or are unsuitable for bone marrow transplant. for treatment of AIDS-related Kaposi's sarcoma (KS) in patients with low CD4 counts (< 200 CD4 lymphocytes/mm3) and extensive mucocutaneous or visceral disease. Celdoxome pegylated liposomal may be used as first-line systemic chemotherapy, or as second line chemotherapy in AIDS-KS patients with disease that has progressed with, or in patients intolerant to, prior combination systemic chemotherapy comprising at least two of the following agents: a vinca alkaloid, bleomycin and standard doxorubicin (or other anthracycline).
Caelyx pegylated liposomal is indicated: as monotherapy for patients with metastatic breast cancer , where there is an increased cardiac risk; for treatment of advanced ovarian cancer in women who have failed a first-line platinum-based chemotherapy regimen; in combination with bortezomib for the treatment of progressive multiple myeloma in patients who have received at least one prior therapy and who have already undergone or are unsuitable for bone marrow transplant; for treatment of AIDS-related Kaposi's sarcoma (KS) in patients with low CD4 counts (
Myocet liposomal, in combination with cyclophosphamide, is indicated for the first-line treatment of metastatic breast cancer in adult women.
Treatment of breast and ovarian cancer .
Treatment of hepatocellular carcinoma

C27H29NO11.HCL

579.98

579.15

C, 55.91; H, 5.21; Cl, 6.11; N, 2.42; O, 30.34

25316-40-9

25316-40-9 (Doxorubicin HCl); 23214-92-8

443939

Red to orange solid powder

810.3ºC at 760 mmHg

216ºC

443.8ºC

9.64E-28mmHg at 25°C

Streptomyces peucetius var. Caesius

1.503

206.07

7

12

5

40

977

6

Cl[H].O([C@@]1([H])C([H])([H])[C@@]([H])([C@@]([H])([C@]([H])(C([H])([H])[H])O1)O[H])N([H])[H])[C@]1([H])C2C(=C3C(C4C(=C([H])C([H])=C([H])C=4C(C3=C(C=2C([H])([H])[C@@](C(C([H])([H])O[H])=O)(C1([H])[H])O[H])O[H])=O)OC([H])([H])[H])=O)O[H]

MWWSFMDVAYGXBV-RUELKSSGSA-N

InChI=1S/C27H29NO11.ClH/c1-10-22(31)13(28)6-17(38-10)39-15-8-27(36,16(30)9-29)7-12-19(15)26(35)21-20(24(12)33)23(32)11-4-3-5-14(37-2)18(11)25(21)34;/h3-5,10,13,15,17,22,29,31,33,35-36H,6-9,28H2,1-2H3;1H/t10-,13-,15-,17-,22+,27-;/m0./s1

(7S,9S)-7-[(2R,4S,5S,6S)-4-amino-5-hydroxy-6-methyloxan-2-yl]oxy-6,9,11-trihydroxy-9-(2-hydroxyacetyl)-4-methoxy-8,10-dihydro-7H-tetracene-5,12-dione;hydrochloride

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture and light.

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: ≥ 2.75 mg/mL (4.74 mM) (饱和度未知) in 5% DMSO + 40% PEG300 + 5% Tween80 + 50% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
*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 (3.59 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 (3.59 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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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。