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
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. ...

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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%

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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.

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

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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.

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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.

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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.

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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

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.)