-
Indian Journal of Urology : IJU :... 2015Non-muscle-invasive bladder cancer (NMIBC) is characterized by a tendency for recurrence and capacity for progression. Intravesical instillation therapy has been... (Review)
Review
Non-muscle-invasive bladder cancer (NMIBC) is characterized by a tendency for recurrence and capacity for progression. Intravesical instillation therapy has been employed in various clinical settings, which are summarized within this review. Several chemotherapeutic agents have shown clinical efficacy in reducing recurrence rates in the post-transurethral resection of bladder tumor (TURBT) setting, including mitomycin C (MMC), doxorubicin, and epirubicin. Mounting evidence also supports the use of intravesical MMC following nephroureterectomy to reduce later urothelial bladder recurrence. In the adjuvant setting, bacillus Calmette-Guérin (BCG) immunotherapy is an established first-line agent in the management of carcinoma in situ (CIS) and high-grade non muscle invasive urothelial carcinoma (UC). Among high and intermediate-risk patients (based on tumor grade, size, and focality) improvements in disease-free intervals have been seen with adjunctive administration of MMC prior to scheduled BCG dosing. Following failure of first-line intravesical therapy, gemcitabine and valrubicin have demonstrated modest activity, though valrubicin remains the only agent currently Food and Drug Administration (FDA)-approved for the treatment of BCG-refractory CIS. Techniques to optimize intravesical chemotherapy delivery have also been explored including pharmacokinetic methods such as urinary alkalization and voluntary dehydration. Chemohyperthermia and electromotive instillation have been associated with improved freedom from recurrence intervals but may be associated with increased urinary toxicity. Improvements in therapeutic selection may be heralded by novel opportunities for genomic profiling and refinements in clinical risk stratification.
PubMed: 26604440
DOI: 10.4103/0970-1591.166446 -
Journal of Inorganic Biochemistry Apr 2022Anthracycline chemotherapeutics are highly effective, but their clinical usefulness is hampered by adverse side effects such as cardiotoxicity. Cytochrome P450 2J2...
Anthracycline chemotherapeutics are highly effective, but their clinical usefulness is hampered by adverse side effects such as cardiotoxicity. Cytochrome P450 2J2 (CYP2J2) is a cytochrome P450 epoxygenase in human cardiomyocytes that converts arachidonic acid (AA) to cardioprotective epoxyeicosatrienoic acid (EET) regioisomers. Herein, we performed biochemical studies to understand the interaction of anthracycline derivatives (daunorubicin, doxorubicin, epirubicin, idarubicin, 5-iminodaunorubicin, zorubicin, valrubicin, and aclarubicin) with CYP2J2. We utilized fluorescence polarization (FP) to assess whether anthracyclines bind to CYP2J2. We found that aclarubicin bound the strongest to CYP2J2 despite it having large bulky groups. We determined that ebastine competitively inhibits anthracycline binding, suggesting that ebastine and anthracyclines may share the same binding site. Molecular dynamics and ensemble docking revealed electrostatic interactions between the anthracyclines and CYP2J2, contributing to binding stability. In particular, the glycosamine groups in anthracyclines are stabilized by binding to glutamate and aspartate residues in CYP2J2 forming salt bridge interactions. Furthermore, we used iterative ensemble docking schemes to gauge anthracycline influence on EET regioisomer production and anthracycline inhibition on AA metabolism. This was followed by experimental validation of CYP2J2-mediated metabolism of anthracycline derivatives using liquid chromatography tandem mass spectrometry fragmentation analysis and inhibition of CYP2J2-mediated AA metabolism by these derivatives. Taken together, we use both experimental and theoretical methodologies to unveil the interactions of anthracycline derivatives with CYP2J2. These studies will help identify alternative mechanisms of how anthracycline cardiotoxicity may be mediated through the inhibition of cardiac P450, which will aid in the design of new anthracycline derivatives with lower toxicity.
Topics: Anthracyclines; Arachidonic Acid; Cytochrome P-450 CYP2J2; Cytochrome P-450 Enzyme Inhibitors; Humans; Molecular Dynamics Simulation; Myocytes, Cardiac; Protein Binding; Static Electricity
PubMed: 35078036
DOI: 10.1016/j.jinorgbio.2022.111722 -
Dermatology Reports Dec 2015Acne is a common skin disease involving colonization with Propionibacterium acnes (P. acnes), hyperproliferation of the follicular epithelium and inflammatory events....
Acne is a common skin disease involving colonization with Propionibacterium acnes (P. acnes), hyperproliferation of the follicular epithelium and inflammatory events. Valrubicin is a second-generation anthracycline, non-toxic upon contact, and available in a topical formulation. Valrubicin's predecessor doxorubicin possesses antibacterial effects and previously we demonstrated that valrubicin inhibits keratinocyte proliferation and skin inflammation suggesting beneficial topical treatment of acne with valrubicin. This study aims to investigate valrubicin's possible use in acne treatment by testing valrubicin's antibacterial effects against P. acnes and P. acnes-induced skin inflammation in vitro and in vivo. Valrubicin was demonstrated not to possess antibacterial effects against P. acnes. Additionally, valrubicin was demonstrated not to reduce mRNA and protein expression levels of the inflammatory markers interleukin (IL)-1β, IL-8, and tumor necrosis factor (TNF)-α in vitro in human keratinocytes co-cultured with P. acnes. Moreover, in vivo, valrubicin, applied both topically and intra-dermally, was not able to reduce signs of inflammation in mouse ears intra-dermally injected with P. acnes. Taken together, this study does not support beneficial antibacterial and anti inflammatory effects of topical valrubicin treatment of acne.
PubMed: 26734122
DOI: 10.4081/dr.2015.6246 -
Cancer Medicine Dec 2023High-risk non-muscle-invasive bladder cancer (HR-NMIBC) presents a challenge to many physicians due to its ability to resist Bacillus Calmette-Guérin (BCG) intravesical... (Review)
Review
BACKGROUND
High-risk non-muscle-invasive bladder cancer (HR-NMIBC) presents a challenge to many physicians due to its ability to resist Bacillus Calmette-Guérin (BCG) intravesical therapy and the substantial rate of progression into muscle-invasive bladder cancer (MIBC). Patients who are BCG-unresponsive have worse prognosis and thus require further management including radical cystectomy (RC), which significantly impacts quality of life. Moreover, the ongoing worldwide shortage of BCG warrants the need for policies that prioritize drug use and utilize alternative treatment strategies. Hence, there is a significant unmet need for bladder preserving therapy in this subset of patients.
METHODS
To address this issue, we searched the relevant literature in PUBMED for articles published from 2019 through May of 2023 using appropriate keywords. All clinical trials of patients with HR-NMIBC treated with immune-related agents were retrieved from clinicaltrials.gov.
FINDINGS AND FUTURE PERSPECTIVES
Exploratory treatments for BCG-Unresponsive HR-NMIBC included immune checkpoint inhibitors (ICI), oncolytic viral therapy, cytokine agonists, and other immunomodulators targeting TLR, EpCaM, FGFR, MetAP2, and IDO1. Some combination therapies have been found to work synergistically and are preferred therapeutically over monotherapy. Three drugs-pembrolizumab, valrubicin, and most recently, nadofaragene firadenovec-vncg-have been FDA approved for the treatment of BCG-unresponsive NMIBC in patients who are ineligible for or decline RC. However, all explored treatment options tend to postpone RC rather than provide long-term disease control. Additional combination strategies need to be studied to enhance the effects of immunotherapy. Despite the challenges faced in finding effective therapies, many potential treatments are currently under investigation. Addressing the landscape of biomarkers, mechanisms of progression, BCG resistance, and trial design challenges in HR-NMIBC is essential for the discovery of new targets and the development of effective treatments.
Topics: Humans; BCG Vaccine; Non-Muscle Invasive Bladder Neoplasms; Quality of Life; Urinary Bladder Neoplasms; Immunotherapy; Neoplasm Invasiveness; Neoplasm Recurrence, Local
PubMed: 38037752
DOI: 10.1002/cam4.6768 -
Frontiers in Immunology 2022Bladder cancer (BCa) is one of the most common malignant tumors that cause death. Approximately 75%-85% of BCa develop into non-muscle-invasive bladder cancer (NMIBC).... (Review)
Review
Bladder cancer (BCa) is one of the most common malignant tumors that cause death. Approximately 75%-85% of BCa develop into non-muscle-invasive bladder cancer (NMIBC). Bacillus Calmette-Guérin (BCG) is the gold standard for avoiding cystectomy in the treatment of NMIBC. Unfortunately, up to 30% of patients do not respond to BCG treatment, and up to 70% of BCG responders relapse. The United States Food and Drug Administration (FDA) approved valrubicin (1998) and pembrolizumab (2020) for the treatment of BCG-unresponsive (BCGu) NMBIC. However, the complete remission rate for valrubicin and pembrolizumab was only 16% and 40.6%, respectively. ALT-803 (N-803) is an IL-15 superagonist and reduces tumor burden by promoting the proliferation and activation of NK cells and CD8 T cells. The FDA received (23 May 2022) and accepted to review (28 July 2022) the marketing submission of ALT-803 plus BCG for the treatment of BCGu NMIBC. However, the FDA previously rejected the application for oportuzumab monatox (OM) due to a lack of data comparing it with pembrolizumab on August 20, 2021. Interestingly, the clinical efficacy and safety of ALT-803 were higher than that of pembrolizumab and OM, suggesting that ALT-803 may be approved by FDA. This review aims to further knowledge of the preclinical and clinical evidence of ALT-803 in the treatment of NMIBC and discuss its translational potential.
Topics: United States; Humans; Urinary Bladder Neoplasms; CD8-Positive T-Lymphocytes; BCG Vaccine; Neoplasm Recurrence, Local; Mycobacterium bovis
PubMed: 36439125
DOI: 10.3389/fimmu.2022.1040669 -
International Journal of Nanomedicine 2017Current cancer chemotherapy is frequently associated with short- and long-term side effects, affecting the quality of life of cancer survivors. Because malignant cells...
Current cancer chemotherapy is frequently associated with short- and long-term side effects, affecting the quality of life of cancer survivors. Because malignant cells are known to overexpress specific surface antigens, including receptors, targeted drug delivery is often utilized to reduce or overcome side effects. The current study involves a novel targeting approach using specifically designed nanoparticles, including encapsulation of the anti-cancer drug valrubicin into superparamagnetic iron oxide nanoparticle (SPION) containing reconstituted high-density lipoprotein (rHDL) nanoparticles. Specifically, rHDL-SPION-valrubicin hybrid nanoparticles were assembled and characterized with respect to their physical and chemical properties, drug entrapment efficiency and receptor-mediated release of the drug valrubicin from the nanoparticles to prostate cancer (PC-3) cells. Prussian blue staining was used to assess nanoparticle movement in a magnetic field. Measurements of cytotoxicity toward PC-3 cells showed that rHDL-SPION-valrubicin nanoparticles were up to 4.6 and 31 times more effective at the respective valrubicin concentrations of 42.4 µg/mL and 85 µg/mL than the drug valrubicin alone. These studies showed, for the first time, that lipoprotein drug delivery enhanced via magnetic targeting could be an effective chemotherapeutic strategy for prostate cancer.
Topics: Antineoplastic Agents; Cell Line, Tumor; Dextrans; Dose-Response Relationship, Drug; Doxorubicin; Drug Delivery Systems; Humans; Iron; Lipoproteins, HDL; Magnetite Nanoparticles; Male; Prostatic Neoplasms; Scavenger Receptors, Class B
PubMed: 28260891
DOI: 10.2147/IJN.S122036 -
Journal of Photochemistry and... Feb 2016Nanoparticles are target-specific drug delivery agents that are increasingly used in cancer therapy to enhance bioavailability and to reduce off target toxicity of...
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.
Topics: Antineoplastic Agents; Apolipoprotein A-I; Cell Line, Tumor; Contrast Media; Doxorubicin; Humans; Lipoproteins, HDL; Microscopy, Confocal; Nanoparticles; Spectrometry, Fluorescence; Temperature
PubMed: 26735001
DOI: 10.1016/j.jphotobiol.2015.12.007 -
Journal of Pharmaceutical Analysis Jun 2017In this study, the molecular interactions between valrubicin, an anticancer drug, and fish sperm DNA have been studied in phosphate buffer solution (pH 7.4) using UV-Vis...
In this study, the molecular interactions between valrubicin, an anticancer drug, and fish sperm DNA have been studied in phosphate buffer solution (pH 7.4) using UV-Vis spectrophotometry and cyclic voltammetry techniques. Valrubicin intercalated into double stranded DNA under a weak displacement reaction with methylene blue (MB) molecule in a competitive reaction. The binding constant () of valrubicin-DNA was determined as 1.75×10 L/mol by spectrophotometric titration. The value of non-electrostatic binding constant ([Formula: see text]) was almost constant at different ionic strengths while the ratio of [Formula: see text]/ increased from 4.51% to 23.77%. These results indicate that valrubicin binds to ds-DNA via electrostatic and intercalation modes. Thermodynamic parameters including ΔH, ΔS and ΔG for valrubicin-DNA interaction were determined as -25.21×10 kJ/mol, 1.55×10 kJ/mol K and -22.03 kJ/mol, respectively. Cyclic voltammetry study shows a pair of redox peaks for valrubicin at 0.45 V and 0.36 V (vs. Ag/AgCl). The peak currents decreased and peak positions shifted to positive direction in the presence of DNA, showing intercalation mechanism due to the variation in formal potential.
PubMed: 29404035
DOI: 10.1016/j.jpha.2017.01.003 -
Therapeutic Advances in Urology Oct 2014The objective was to conduct a US multicenter, retrospective medical record study examining the effectiveness, safety, and patterns of use of valrubicin for treatment of...
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.
PubMed: 25276228
DOI: 10.1177/1756287214541798