Valrubicin

Valrubicin is a chemotherapy agent, inhibits TPA- and PDBu-induced PKC activation with IC50s of 0.85 and 1.25 μM, respectively, and has antitumor and antiinflammatory activity.

In Vitro:Valrubicin (AD 32) is a chemotherapy agent, inhibits TPA- and PDBu-induced PKC activation with IC50s of 0.85 and 1.25 μM, respectively. Valrubicin inhibits the binding of [3H]PDBu to PKC. Therefore, Valrubicin competes with the tumor promoter for the PKC binding site and prevents the latter from both interacting with the phospholipid and binding to PKC[1]. Valrubicin shows cytotoxic activity against squamous cell carcinoma (SCC) cell line colony formation, with IC50s and IC90s of 8.24 ± 1.60 μM and 14.81 ± 2.82 μM for UMSCC5 cells, 15.90 ± 0.90 μM, 29.84 ± 0.84 μM for UMSCC5/CDDP‡ cells, and 10.50 ± 2.39 μM, 19.00 ± 3.91 μM for UMSCC10b cells, respectively. Moreover, Valrubicin in combination with radiation enhances the cytotoxicity[2].

In Vivo:Valrubicin (3, 6, or 9 mg) reduces tumor growth at week 3 by intratumoral jection in hamster. Valrubicin (6 mg) combined with minimally cytotoxic irradiation (150, 250, or 350 cGy) causes significant tumor shrinkage in hamster[2]. Valrubicin (0.1 μg/μL) significantly reduces the number of infiltrating neutrophils in biopsies challenged with TPA at 24 h and attenuates chronic inflammation in mice. Valrubicin also decreases the expression levels of inflammatory cytokines in the acute model[3].

References:
[1]. Chuang LF, et al. 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]. Wani MK, et al. Rationale for intralesional valrubicin in chemoradiation of squamous cell carcinoma of the head and neck. Laryngoscope. 2000 Dec;110(12):2026-32. [3]. Hauge E, et al. Topical valrubicin application reduces skin inflammation in murine models. Br J Dermatol. 2012 Aug;167(2):288-95.

Photophysical characterization of anticancer drug valrubicin in rHDL nanoparticles and its use as an imaging agent.[Pubmed:26735001]

J Photochem Photobiol B. 2016 Feb;155:60-5.

Nanoparticles are target-specific drug delivery agents that are increasingly used in cancer therapy to enhance bioavailability and to reduce off target toxicity of anti-cancer agents. Valrubicin is an anti-cancer drug, currently approved only for vesicular bladder cancer treatment because of its poor water solubility. On the other hand, Valrubicin carrying reconstituted high density lipoprotein (rHDL) nanoparticles appear ideally suited for extended applications, including systemic cancer chemotherapy. We determined selected fluorescence properties of the free (unencapsulated) drug vs. Valrubicin incorporated into rHDL nanoparticles. We have found that upon encapsulation into rHDL nanoparticles the quantum yield of Valrubicin fluorescence increased six fold while its fluorescence lifetime increased about 2 fold. Accordingly, these and potassium iodide (KI) quenching data suggest that upon incorporation, Valrubicin is localized deep in the interior of the nanoparticle, inside the lipid matrix. Fluorescence anisotropy of the rHDL Valrubicin nanoparticles was also found to be high along with extended rotational correlation time. The fluorescence of Valrubicin could also be utilized to assess its distribution upon delivery to prostate cancer (PC3) cells. Overall the fluorescence properties of the rHDL: Valrubicin complex reveal valuable novel characteristics of this drug delivery vehicle that may be particularly applicable when used in systemic (intravenous) therapy.

Fabrication of an electrochemical sensor based on carbon nanotubes modified with gold nanoparticles for determination of valrubicin as a chemotherapy drug: valrubicin-DNA interaction.[Pubmed:25687007]

Mater Sci Eng C Mater Biol Appl. 2015 Apr;49:769-775.

In this study, an electrochemical sensor was fabricated based on gold nanoparticles/ ethylenediamine/ multi-wall carbon-nanotubes modified gold electrode (AuNPs/en/MWCNTs/AuE) for determination of Valrubicin in biological samples. Valrubicin was effectively accumulated on the surface of AuNPs/en/MWCNTs/AuE and produced a pair of redox peaks at around 0.662 and 0.578V (vs. Ag/AgCl) in citrate buffer (pH4.0). The electrochemical parameters including pH, buffer, ionic strength, scan rate and size of AuNPs have been optimized. There was a good linear correlation between cathodic peak current and concentration of Valrubicin in the range of 0.5 to 80.0mumolL(-1) with the detection limit of 0.018mumolL(-1) in citrate buffer (pH4.0) and 0.1molL(-1) KCl. Finally, the constructed sensor was successfully applied for determination of Valrubicin in human urine and blood serum. In further studies, the different sequences of single stranded DNA probes have been immobilized on the surface of AuNPs decorated on MWCNTs to study the interaction of oligonucleotides with Valrubicin.

Use of intravesical valrubicin in clinical practice for treatment of nonmuscle-invasive bladder cancer, including carcinoma in situ of the bladder.[Pubmed:25276228]

Ther Adv Urol. 2014 Oct;6(5):181-91.

OBJECTIVES: The objective was to conduct a US multicenter, retrospective medical record study examining the effectiveness, safety, and patterns of use of Valrubicin for treatment of nonmuscle-invasive bladder cancer (NMIBC) by clinicians since the 2009 reintroduction of Valrubicin. METHODS: Patients >/= 18 years with NMIBC who received had one or more instillations of Valrubicin (October 2009- September 2011) were eligible. The primary endpoint was event-free survival (EFS). Safety and tolerability were also assessed. RESULTS: The medical records of 113 patients met the inclusion criteria; 100 patients (88.5%) completed Valrubicin treatment. The median age was 75 years (range 42-95 years). The median NMIBC duration was 31 months since diagnosis: 51.3% (58/113) had carcinoma in situ (CIS) alone, and 31.9% (36/113) had unspecified NMIBC. Most patients, 94.7% (107/113), had more than three Valrubicin instillations and 70.8% (80/113) completed a full course. The EFS rate (95% confidence interval) was 51.6% (40.9-61.3%), 30.4% (20.4-41.1%), and 16.4% (7.9-27.5%) at 3, 6, and 12 months, respectively. Median time to an event was 3.5 (2.5-4.0) months after the first Valrubicin instillation. Local adverse reactions (LARs) were experienced by 49.6% (56/113) of patients; most LARs were mild (93.6%). The most frequent LARs were hematuria, pollakiuria, micturition urgency, bladder spasm, and dysuria. In total, 4.4% (5/113) of patients discontinued Valrubicin because of adverse events or LARs. CONCLUSIONS: Data from the present retrospective study are consistent with previous prospective clinical trials that demonstrated Valrubicin effectiveness and tolerability for select patients with CIS, before considering cystectomy. Additional prospective studies are warranted to evaluate Valrubicin safety and efficacy in the broader patient population with NMIBC.

Valrubicin in refractory non-muscle invasive bladder cancer.[Pubmed:26569509]

Expert Rev Anticancer Ther. 2015;15(12):1379-87.

The most effective intravesical regimen for the treatment of non-muscle invasive bladder cancer (NMIBC) refractory to Bacillus Calmette-Guerin (BCG) has still not been identified or optimized to minimize recurrence-free survival and prevent progression reliably and consistently. Valrubicin, however, is a cytotoxic chemotherapeutic agent that is used as an intravesical agent for BCG-refractory carcinoma in situ (CIS) of the urinary bladder in patients for whom immediate cystectomy would be associated with unacceptable morbidity or mortality. Here we analyze the literature regarding the treatment of non-muscle invasive urothelial malignancies with intravesical Valrubicin for refractory bladder cancer, present our opinion on its current clinical impact and speculate on how its utilization will evolve in the near future.

Valrubicin is a chemotherapy agent, inhibits TPA- and PDBu-induced PKC activation with IC50s of 0.85 and 1.25 μM, respectively, and has antitumor and antiinflammatory activity.

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