Valrubicin   中文名称: 戊柔比星

调节剂 valrubicin (AD 32) 的 IC50 分别为 0.85 μM 和 1.25 μM，抑制 TPA 和 PDBu 产生的 PKC 激活。 Valrubicin 可防止 [3H]PDBu 附着在 PKC 上。结果，肿瘤促进剂和戊柔比星竞争 PKC 结合。 Valrubicin 对鳞状细胞癌 (SCC) 细胞系集落表现出细胞毒性作用，其对 UMSCC5 细胞的 IC50 和 IC90 值分别为 8.24 ± 1.60 μM 和 14.81 ± 2.82 μM。 /CDDP细胞的浓度分别为15.90±0.90μM和29.84±0.84μM，而UMSCC10b细胞的浓度为10.50±2.39μM和19.00±3.91μM。此外，戊柔比星联合放射治疗可增加细胞毒性[2]。

通过腹膜内给药，戊柔比星（3、6或9毫克）在第三周抑制了仓鼠的肿瘤生长。在仓鼠中，戊柔比星 (6 mg) 与低剂量的细胞毒性辐射（150、250 或 350 cGy）相结合，导致正在发育的肿瘤显着减少 [2]。在接受 24 小时 TPA 挑战活检的小鼠中，戊柔比星 (0.1 μg/μL) 显着降低了活性中性粒细胞的数量，并减少了慢性炎症。在急性情况下，戊柔比星还可以降低炎症细胞因子的表达量[3]。

Absorption, Distribution and Excretion
Following intravesical administration of 800 mg valrubicin and retention in the bladder for a period of 2-hours in patients with carcinoma in situ (CIS) of the bladder ... minimal amounts of the drug are absorbed into the plasma; metabolites of valrubicin also have been detected in plasma. Following intravesical administration of 200 to 900 mg valrubicin once weekly in patients with CIS of the bladder or stage Ta, T1, or T2 bladder cancer low plasma concentrations of valrubicin and its metabolites, ... were detected within 6 hours after administration of the first, third and sixth doses of the drug.
Elimination: Almost entirely by voiding the instillate.
Valrubicin penetrates easily into the bladder cell wall after intravesical administration. The degree of any systemic absorption depends on the condition of the bladder wall. Serum concentration usually are very low (nanogram quantities), even after extensive transurethral resection, although a case has been reported in which concentrations after administration to a patient with a perforated bladder were similar to those achieved after intravenous administration.
It is not known whether valrubicin is distributed in breast milk.
... Valrubicin entered individual cells more rapidly than doxorubicin in vitro. When valrubicin was administered intravesically to patients with bladder cancer, cytotoxic concentrations of the drug penetrated the superficial muscle layer of the bladder. ...

---

Metabolism / Metabolites
Valrubicin is metabolized to two primary metabolites: N-trifluoroacetyladriamycin and N-trifluoroacetyladriamycinol.
Following intravesical instillation of valrubicin, conversion of the drug to its major metabolites, N-trifluoroacetyladriamycin and N-trifluoroacetyladriamycinol, is minimal during the 2 hr retention period. Voiding of the instillate after the 2-hour retention period results in almost complete excretion of the drug. About 98.6% of an intravesical dose of the drug is excreted in the urine unchanged; N-trifluoroacetyladriamycin and total anthracyclines account for 0.4 and 99.0%, respectively, of an administered dose.
Major metabolites are N-trifluoroacetyladriamycin and N-trifluoroacetyladriamycinol, which have been measured in blood.

Protein Binding
>99%

---

Interactions
In an in vivo study, the activity of valrubicin against a resistant line of human bladder tumor cells was enhanced by the calcium-channel blocking agent verapamil.

[1]. Activation of human leukemia protein kinase C by tumor promoters and its inhibition by N-trifluoroacetyladriamycin-14-valerate (AD 32). Biochem Pharmacol. 1992 Feb 18;43(4):865-72.

[2]. Rationale for intralesional valrubicin in chemoradiation of squamous cell carcinoma of the head and neck. Laryngoscope. 2000 Dec;110(12):2026-32.

[3]. Topical valrubicin application reduces skin inflammation in murine models. Br J Dermatol. 2012 Aug;167(2):288-95.

Valrubicin is an anthracycline and a trifluoroacetamide.
Valrubicin (N-trifluoroacetyladriamycin-14-valerate) is a chemotherapy drug commonly marketed under the trade name VALSTAR. It is a semisynthetic analog of the [doxorubicin], which is an anthracycline drug. Used in the treatment of the bladder cancer, valrubicin is administered by direct infusion into the bladder.
Valrubicin is a semisynthetic derivative of the antineoplastic anthracycline antibiotic doxorubicin. With a mechanism of action that appears to differ from doxorubicin, valrubicin is converted intracytoplasmically into N-trifluoroacetyladriamycin, which interacts with topoisomerase II, stabilizing the complex between the enzyme and DNA; consequently, DNA replication and repair and RNA and protein synthesis are inhibited and the cell cycle is arrested in the G2 phase. In addition, this agent accumulates in the cell cytoplasm where it inhibits protein kinase C (PKC). Valrubicin is less cardiotoxic than doxorubicin when administered systemically; applied topically, this agent shows excellent tissue penetration. Structurally, the trifluoro-acetyl moiety on the amino group of the glycoside and the valerate moiety appear to result in a lipophilicity that is greater than of doxorubicin, resulting in increased intracytoplasmic concentrations.

---

Drug Indication
For the treatment of cancer of the bladder.
FDA Label

---

Mechanism of Action
Valrubicin is an anthracycline that affects a variety of inter-related biological functions, most of which involve nucleic acid metabolism. It readily penetrates into cells, where after DNA intercalation, it inhibits the incorporation of nucleosides into nucleic acids, causes extensive chromosomal damage, and arrests cell cycle in G2. Although valrubicin does not bind strongly to DNA, a principal mechanism of its action, mediated by valrubicin metabolites, is interference with the normal DNA breaking-resealing action of DNA topoisomerase II.
Valrubicin (AD-32) is an N-trifluoroacetyl, 14-valerate derivative of the anthracycline doxorubicin. It has antineoplastic activity which probably results from interference with nucleic acid metabolism by the drug. Valrubicin entered individual cells more rapidly than doxorubicin in vitro. ...
Valrubicin is an anthracycline glycoside that affects a number of biological functions involving nucleic acid metabolism. After penetration into cells, it inhibits incorporation of nucleosides into nucleic acids, causes extensive chromosomal damage, and arrests cells in the G2 phase of cell division. Although it does not bind strongly to DNA, its metabolites interfere with the normal DNA breaking-resealing action of DNA topoisomerase II.

---

Therapeutic Uses
Antineoplastic
Intravesical valrubicin is indicated for treatment of carcinoma in situ of the urinary bladder that is refractory to Bacillus Calmette-Guerin (BCG), in patients for whom immediate cystectomy would be associated with unacceptable morbidity or mortality. /Included in US product labeling/
To assess the effect and tolerance of a 6-week course of intravesical valrubicin on a tumor intentionally left in the bladder (marker lesion) following incomplete transurethral resection of the bladder tumor (TURBT). In a prospective phase II study, 40 patients with refractory superficial transitional cell carcinoma (TCC), with or without carcinoma in situ, underwent TURBT at which a tumor <1 cm in diameter was deliberately left in the bladder. They were then treated with six instillations of 800 mg valrubicin at weekly intervals. Patients were assessed three months after the initial TURBT by cystoscopy and biopsy. Patients remaining clear of disease underwent repeat cystoscopies at 3-monthly intervals until recurrence or for up 2 years. 21/39 (54%) of patients were found to be clinically clear of disease upon cystoscopic examination at 3 months. 18/39 (46%) of patients were considered histologically clear of bladder disease. The current estimate of the mean time to recurrence is 248 days. A 6-week course of intravesical valrubicin has proved effective in ablating a marker tumor left in the bladder after incomplete TURBT and in preventing or delaying recurrence of further tumors in a group of patients with previously treated superficial TCC.
We assess the efficacy and safety of intravesical valrubicin for the treatment of carcinoma in situ in patients with failure or recurrence after bacillus Calmette-Guerin (BCG) and who otherwise would have undergone cystectomy. Total anthracycline recovery in urine samples obtained within 24 hours of valrubicin administration was assessed in a subset of patients. A total of 90 patients with recurrent carcinoma in situ after failed multiple prior courses of intravesical therapy, including at least 1 course of BCG, participated in this open label, noncomparative study. Each patient received 6 weekly instillations of 800 mg. intravesical valrubicin. Disease evaluations were made at baseline and 3-month intervals following treatment. Evaluations included cystoscopy with biopsy and urine cytology. Toxicity was noted throughout treatment and followup. No evidence of disease recurrence for 6 months or greater was considered a complete response. Of 90 patients 19 (21%) had a complete response, including 7 who remained disease-free at the last evaluation, with a median followup of 30 months. Additionally, 14 patients who did not meet the strict protocol definition of complete response had superficial Ta disease only. Median time to failure and/or last followup for complete responders was greater than 18 months. Recurrence has been noted in 79 patients to date, including only 2 with clinically advanced disease (stage T2). Of these 79 patients 44 (56%, 4 responders and 40 nonresponders) underwent radical cystectomy. Of the 41 patients with known pathological stage 6 (15%) had stage pT3 or greater at cystectomy. Four patients died of bladder cancer during the median followup of 30 months, none of whom was a complete responder or underwent cystectomy following valrubicin. The main side effects of valrubicin therapy were reversible local bladder symptoms. Valrubicin was effective and well tolerated in patients with carcinoma in situ of the bladder refractory to BCG therapy. Delaying cystectomy while attempting salvage therapy with valrubicin does not pose an undue risk to most patients.
... Twenty-two patients with recurrent or newly diagnosed Stage Ta or T1 transitional cell tumors received a single dose of 400 mg, 600 mg, or 800 mg of intravesical valrubicin immediately after transurethral resection of bladder tumors (TURBT). Four patients thought to be at high risk of recurrence were followed up with five additional doses of 800 mg valrubicin, given weekly. The use of valrubicin after TURBT was generally well tolerated. Little evidence was found to suggest a direct relationship among the dose of valrubicin, the time between the end of TURBT and drug instillation, and the occurrence of most bladder symptoms. The most commonly reported adverse events included dysuria (77%), hematuria (59%), and urgency/frequency (23%). Pharmacokinetic analyses revealed that the mean systemic exposure to valrubicin and its metabolites depended on the extent of the TURBT and the damage to the bladder wall. The results of this study indicated that administration of valrubicin immediately after TURBT is feasible.

---

Drug Warnings
The risk of developing metastatic disease must be considered in patients with refractory carcinoma in situ (CIS) of the urinary bladder who delay cystectomy. Among 90 patients with BCG-refractory CIS of the bladder receiving intravesical valrubicin in a clinical trial, 11% (10 patients) subsequently developed metastatic or deeply invasive bladder cancer during follow-up, including 4 patients (none of whom underwent cystectomy) who died of metastatic bladder cancer.
Myelosuppression has been reported in patients exposed systemically to valrubicin (e.g., inadvertent systemic administration of the drug, intravesical administration of the drug in a patient with bladder rupture or perforation). Myelosuppression, manifested by severe leukopenia and neutropenia approximately 2 weeks following valrubicin administration, was observed in a single patient who received 800 mg valrubicin by intravesical instillation within 1 hour following transurethral resection of the bladder (TURB) and immediately after experiencing a perforated bladder (as a complication of TURB).
FDA Pregnancy Risk Category: C /RISK CANNOT BE RULED OUT. Adequate, well controlled human studies are lacking, and animal studies have shown risk to the fetus or are lacking as well. There is a chance of fetal harm if the drug is given during pregnancy; but the potential benefits may outweigh the potential risk./
It is not known whether valrubicin is distributed in breast milk. However, because the medication is highly lipophilic, there is the potential for exposure of and harm to breast-fed infants. Breast-feeding is not recommended during valrubicin therapy.
For more Drug Warnings (Complete) data for VALRUBICIN (17 total), please visit the HSDB record page.

---

Pharmacodynamics
Valrubicin is an anticancer agent.

C34H36F3NO13

723.64

723.213

56124-62-0

56124-62-0;

454216

Orange to red solid powder

1.5±0.1 g/cm3

867.7±65.0 °C at 760 mmHg

116-117ºC

478.6±34.3 °C

0.0±0.3 mmHg at 25°C

1.619

6.31

215.22

5

16

11

51

1350

6

CCCCC(=O)OCC(=O)[C@]1(C[C@@H](C2=C(C1)C(=C3C(=C2O)C(=O)C4=C(C3=O)C=CC=C4OC)O)O[C@H]5C[C@@H]([C@@H]([C@@H](O5)C)O)NC(=O)C(F)(F)F)O

ZOCKGBMQLCSHFP-KQRAQHLDSA-N

InChI=1S/C34H36F3NO13/c1-4-5-9-21(40)49-13-20(39)33(47)11-16-24(19(12-33)51-22-10-17(27(41)14(2)50-22)38-32(46)34(35,36)37)31(45)26-25(29(16)43)28(42)15-7-6-8-18(48-3)23(15)30(26)44/h6-8,14,17,19,22,27,41,43,45,47H,4-5,9-13H2,1-3H3,(H,38,46)/t14-,17-,19-,22-,27+,33-/m0/s1

[2-oxo-2-[(2S,4S)-2,5,12-trihydroxy-4-[(2R,4S,5S,6S)-5-hydroxy-6-methyl-4-[(2,2,2-trifluoroacetyl)amino]oxan-2-yl]oxy-7-methoxy-6,11-dioxo-3,4-dihydro-1H-tetracen-2-yl]ethyl] pentanoate

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)

DMSO : ~125 mg/mL (~172.74 mM)

配方 1 中的溶解度: ≥ 2.17 mg/mL (3.00 mM) (饱和度未知) in 10% DMSO + 40% PEG300 +5% Tween-80 + 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 21.7 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。

---

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。