The modulator valrubicin (AD 32) has an IC50 of 0.85 μM and 1.25 μM, respectively, and inhibits PKC activation produced by TPA and PDBu. Valrubicin prevents [3H]PDBu from attaching itself to PKC. As a result, tumor promoters and valrubicin compete for PKC binding. Valrubicin exhibits cytotoxic effect against colonies of squamous cell carcinoma (SCC) cell line, as seen by its IC50 and IC90 values for UMSCC5 cells, which are 8.24 ± 1.60 μM and 14.81 ± 2.82 μM, respectively. /CDDP The cells had respective concentrations of 15.90 ± 0.90 μM and 29.84 ± 0.84 μM, while the UMSCC10b cells had concentrations of 10.50 ± 2.39 μM and 19.00 ± 3.91 μM. Furthermore, valrubicin plus radiation therapy can increase cytotoxicity [2].

By intraperitoneal administration, valrubicin (3, 6, or 9 mg) inhibited tumor growth in hamsters at week three. In hamsters, valrubicin (6 mg) in combination with low doses of cytotoxic radiation (150, 250, or 350 cGy) caused developing tumors to significantly decrease [2]. In mice with 24-hour TPA-challenged biopsies, valrubicin (0.1 μg/μL) dramatically lowers the amount of active neutrophils and decreases chronic inflammation. In acute settings, valrubicin can also lower the amounts of inflammatory cytokine expression [3].

Absorption, Distribution and Excretion
In patients with bladder carcinoma in situ (CIS), after intravesical instillation of 800 mg valrubicin and retention for 2 hours, only a small amount of drug was absorbed into the plasma; valrubicin metabolites were also detected in the plasma. In patients with bladder carcinoma in situ or Ta, T1, or T2 stage bladder cancer, after weekly intravesical instillation of 200 to 900 mg valrubicin, low plasma concentrations of valrubicin and its metabolites were detected within 6 hours after the first, third, and sixth doses. Excretion: The instillation fluid is almost entirely eliminated through urination. Following intravesical administration, valrubicin readily penetrates the bladder cell wall. Systemic absorption depends on the condition of the bladder wall. Even after extensive transurethral resection, serum concentrations are typically low (nanograms), but there have been reports of drug concentrations similar to those achieved after intravenous administration in patients with bladder perforation. It is currently unknown whether valrubicin is distributed into breast milk.
...In vitro studies have shown that valrubicin enters single cells more rapidly than doxorubicin. When valrubicin is instilled intravesically into bladder cancer patients, the cytotoxic concentration of the drug can penetrate the superficial muscular layer of the bladder. ...

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Metabolism/Metabolites
Valrubicin is metabolized into two major metabolites: N-trifluoroacetyl doxorubicin and N-trifluoroacetyl doxorubicin alcohol.
After intravesical instillation of valrubicin, very little of the drug is converted to its major metabolites, N-trifluoroacetyl doxorubicin and N-trifluoroacetyl doxorubicin alcohol, during the 2-hour retention period. After the 2-hour retention period, the instillation fluid is emptied, and the drug is almost completely excreted. Approximately 98.6% of the intravesical dose is excreted unchanged in the urine; N-trifluoroacetyl doxorubicin and total anthracyclines account for 0.4% and 99.0% of the administered dose, respectively.
The major metabolites are N-trifluoroacetyl doxorubicin and N-trifluoroacetyl doxorubicin alcohol, which have been detected in the blood.

Protein Binding
99% Interaction In an in vivo study, the calcium channel blocker verapamil enhanced the activity of valrubicine against drug-resistant human bladder tumor cell lines.

[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 trifluoroacetamide antibiotic. Valrubicin (N-trifluoroacetyl-14-valerate) is a chemotherapy drug, usually marketed under the brand name VALSTAR. It is a semi-synthetic analogue of the anthracycline drug doxorubicin. Valrubicin is used to treat bladder cancer and is administered via direct intravesical infusion. Valrubicin is a semi-synthetic derivative of the antitumor anthracycline antibiotic doxorubicin. Its mechanism of action appears to differ from doxorubicin; valrubicin is converted to N-trifluoroacetyl-14-valerate in the cytoplasm, which interacts with topoisomerase II, stabilizing the complex between this enzyme and DNA; therefore, DNA replication and repair, as well as RNA and protein synthesis, are inhibited, and the cell cycle arrests in the G2 phase. Furthermore, the drug accumulates in the cytoplasm and inhibits protein kinase C (PKC). When administered systemically, valrubicin has lower cardiotoxicity than doxorubicin; when applied topically, it has excellent tissue penetration. Structurally, the trifluoroacetyl and valerate groups on the glycoside amino group appear to make it more lipophilic than doxorubicin, leading to increased intracellular concentration. Drug Indications: For the treatment of bladder cancer. FDA Label: Mechanism of Action: Valrabicin is an anthracycline antibiotic that affects a variety of interrelated biological functions, most of which involve nucleic acid metabolism. It readily penetrates cells, inhibiting nucleoside incorporation into nucleic acids after DNA intercalation, causing widespread chromosomal damage and arresting the cell cycle in the G2 phase. Although valrabicin has a weak binding affinity to DNA, its primary mechanism of action (mediated by valrabicin metabolites) is to interfere with the normal DNA break-rejoining process of DNA topoisomerase II. Valrabicin (AD-32) is an N-trifluoroacetyl-14-valerate derivative of the anthracycline antibiotic doxorubicin. It possesses antitumor activity, likely due to its interference with nucleic acid metabolism. In vitro studies have shown that valrabicin enters single cells faster than doxorubicin. ...
Valorubicin is an anthracyclic glycoside that affects a variety of biological functions involved in nucleic acid metabolism. Once inside the cell, it inhibits nucleoside incorporation into nucleic acids, causing widespread chromosomal damage and arresting cells in the G2 phase of cell division. Although it has a weak binding affinity for DNA, its metabolites interfere with the normal DNA break-rejoining process of DNA topoisomerase II.

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Therapeutic Use
Anti-tumor
Intravesical instillation of valorubicin is indicated for the treatment of BCG-resistant bladder carcinoma in situ, particularly in patients for whom immediate cystectomy would result in unacceptable complications or mortality. /US product label includes/
This study aimed to evaluate the efficacy and tolerability of intravesical instillation of valorubicin for 6 weeks in patients with intact tumors (marked lesions) after incomplete transurethral resection of bladder tumors (TURBT). In a prospective phase II study, 40 patients with refractory superficial transitional cell carcinoma (TCC) (with or without carcinoma in situ) underwent transurethral resection of the bladder (TURBT), during which a tumor less than 1 cm in diameter was intentionally preserved within the bladder. Patients subsequently received 6 weeks of valrubicin intravesical instillation at 800 mg weekly. Three months after the initial TURBT, patients were evaluated by cystoscopy and biopsy. Patients without recurrence underwent repeat cystoscopy every 3 months until recurrence or were followed up for up to 2 years. Of the 39 patients, 21 (54%) were clinically recurrent at 3 months via cystoscopy. Of the 39 patients, 18 (46%) were considered histologically recurrent in the bladder. The estimated mean time to recurrence is currently 248 days. A 6-week intravesical instillation of valrubicin has been shown to effectively clear marker tumors remaining in the bladder after incomplete transurethral resection of bladder tumor (TURBT) and to prevent or delay tumor recurrence in patients with previously treated superficial transitional cell carcinoma (TCC). We evaluated the efficacy and safety of intravesical valrubicin in treating patients with recurrent or failed BCG therapy who would otherwise have undergone cystectomy. In some patients, we assessed the overall recovery rate of anthracyclines in urine samples within 24 hours after valrubicin administration. This open-label, non-controlled study included 90 patients with recurrent TCC who had failed multiple previous intravesical therapies (including at least one cycle of BCG). Each patient received 800 mg of valrubicin intravesical instillation once weekly for a total of 6 weeks. Disease assessments were performed at baseline and every 3 months after treatment. Assessments included cystoscopy and biopsy, and urine cytology. Toxicity was recorded throughout treatment and follow-up. Complete remission was defined as disease-free for 6 months or longer. Of the 90 patients, 19 (21%) achieved complete remission, with 7 remaining disease-free at the last assessment. The median follow-up was 30 months. Additionally, 14 patients who did not achieve a strictly defined complete remission had only superficial Ta stage lesions. The median time to treatment failure and/or time to last follow-up for patients with complete remission both exceeded 18 months. To date, 79 patients have experienced recurrence, with only 2 being clinically advanced (T2 stage). Of these 79 patients, 44 (56%, 4 responders, 40 failures) underwent radical cystectomy. Of the 41 patients with known pathological stages, 6 (15%) had a pT3 or higher pathological stage at the time of cystectomy. The median follow-up was 30 months. During this period, 4 patients died of bladder cancer; none of these patients achieved complete remission and none had undergone cystectomy after receiving varubicin treatment. The main side effect of valrubicin treatment is reversible local bladder symptoms. Valrubicin is significantly effective and well-tolerated in patients with bladder carcinoma in situ that is unresponsive to BCG. Delaying cystectomy while attempting salvage therapy with valrubicin does not pose an excessive risk to most patients. ...Twenty-two patients with recurrent or newly diagnosed Ta or T1 stage transitional cell tumors received a single intravesical instillation of 400 mg, 600 mg, or 800 mg of valrubicin immediately after transurethral resection of bladder tumor (TURBT). Four patients considered at high risk of recurrence received follow-up treatment, five times weekly at 800 mg valrubicin per dose. Valrubicin was generally well-tolerated after TURBT. There is little evidence to suggest a direct relationship between valrubicin dose, the time interval between the end of TURBT and drug instillation, and the occurrence of most bladder symptoms. The most common adverse events included dysuria (77%), hematuria (59%), and urinary urgency/frequency (23%). Pharmacokinetic analysis showed that the mean systemic exposure to valrubicin and its metabolites depended on the extent of transurethral resection of bladder tumor (TURBT) and the degree of bladder wall injury. The results of this study indicate that immediate administration of valrubicin after TURBT is feasible.
Drug Warnings

The risk of metastatic disease must be considered in patients with refractory orthotopic bladder cancer (CIS) who have delayed cystectomy.
In a clinical trial, among 90 patients with BCG-refractory CIS treated with intravesical valrubicin, 11% (10 patients) developed metastatic or deep invasive bladder cancer during follow-up, and 4 of these patients (none of whom underwent cystectomy) died from metastatic bladder cancer.
Bone marrow suppression has been reported in patients with systemic exposure to valrubicin (e.g., accidental systemic administration, or intravesical administration in patients with bladder rupture or perforation). A patient developed bone marrow suppression, manifested as severe leukopenia and neutropenia, approximately 2 weeks after receiving varrubicin treatment. This patient received an intravesical instillation of 800 mg varrubicin within 1 hour following transurethral resection of bladder tumor (TURB) and immediately subsequently developed bladder perforation (a complication of TURB). FDA Pregnancy Risk Classification: Category C/Risk cannot be ruled out. There is a lack of adequate, well-controlled clinical studies, and animal studies have not shown any risk to the fetus. Use of this drug during pregnancy may cause harm to the fetus; however, the potential benefits may outweigh the potential risks. It is unknown whether varrubicin is excreted into breast milk. However, due to the drug's high lipophilicity, there is a possibility that breastfed infants may be exposed to the drug and harmed. Breastfeeding is not recommended while taking varrubicin. For more complete data on drug warnings for varrubicin (17 total), please visit the HSDB record page. Pharmacodynamics: Varrubicin is an anticancer drug.

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

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)

Solubility in Formulation 1: ≥ 2.17 mg/mL (3.00 mM) (saturation unknown) in 10% DMSO + 40% PEG300 +5% Tween-80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 21.7 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 + to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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 (Please use freshly prepared in vivo formulations for optimal results.)