Anthracycline Analogues Research Articles

Structural Variance of Doxorubicin and Anthracycline Analogues as Topoisomerase Alpha and Beta (Top2a and Top2b) Inhibitors. Potential Design of Analogue Candidates of Less Side Effects on Cardiomyocytes.

Doxorubicin that is on WHO's list of essential medicines and other anthracycline analogues, in general, are natural metabolites isolated from Streptomycetaceae, or semi-synthetized derivatives stated as first-generation anticancer agents. The tetracyclic scaffold attached mostly to amino sugar is known to be effective against solid tumors compared to other anticancer agents. The mechanism had been stated as intercalating agent at the minor groove of DNA strands during the step of releasing supercoiled DNA. Along with their anticancer activity, anthracyclines possess antimicrobial effects of notable MIC values. Cardiotoxicity represents the main challenge for both of medical care for treatment of cancers and drug discoverers. This exertion deals with careful structural investigation of the three-dimensional, fully optimized drugs in use. Drug-candidates in clinical studies, and leads failed in last developments. The aim is to find a structural gate to guard against or reduce the cardiac side effects. It deals also, with the topological features differentiating between antibacterial and anticancer agents bearing the tetracyclic scaffold features as well as between the topoisomerases as target molecules.

Abstract 2013: Oxidized anthracycline payloads induce anti-tumor immunogenic cell-death and show linker-dependent tolerability when delivered as ADCs

Abstract Novel payloads with orthogonal mechanisms of action (MOAs) to established ADC technologies are important for expanding the utility of antibody-drug conjugates (ADCs) in cancer treatment. Anthracyclines, a class of cytotoxic small molecules that include important clinical chemotherapeutics such as doxorubicin, have long been of interest to the ADC field due to their high potency and unique MOA. Interest in anthracyclines has increased in recent years due to their status as canonical inducers of immunogenic-cell death (ICD), a feature that may lead to more durable tumor regressions and increased synergy with immune checkpoint blockade. In this work, we investigate several drug-linkers based on oxidized derivatives of the highly potent anthracycline analogue PNU-159682. Resultant ADCs are potent and immunologically specific with linker-dependent bystander activity in co-culture cytotoxicity assays displaying heterogeneous antigen (Ag+/Ag-) expression. Rodent in vivo anti-tumor activity and tolerability are shown with significant differences emerging between the toxicity profile of the cleavable and non-cleavable analogues. In vitro, tumor cells treated with anthracycline ADCs showed key hallmarks of ICD including markers of endoplasmic reticulum (ER) stress and the induction of ICD damage-associated molecular patterns (DAMPs) such as HMGB1 and ATP. In vivo mouse xenograft studies show increased tumoral F4/80+ macrophage infiltration by IHC in anthracycline ADC treated animals relative to controls. ADCs delivering monomethyl auristatin E (MMAE) show comparable activity in ICD assays, confirming MMAE as an ICD inducing ADC payload alongside canonical inducers such as anthracyclines. Our results indicate there is a therapeutic window in rodents alongside ICD induction by anthracycline ADCs, positioning anthracyclines as a potentially impactful class of ADC payloads. Citation Format: Joseph Z. Hamilton, Kerry Klussman, Rebecca Mahzereh, Jessica Simmons, Michelle Ulrich, Shyra J. Gardai, Peter D. Senter, Patrick J. Burke. Oxidized anthracycline payloads induce anti-tumor immunogenic cell-death and show linker-dependent tolerability when delivered as ADCs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2013.

A BioBricks Metabolic Engineering Platform for the Biosynthesis of Anthracyclinones in Streptomyces coelicolor.

Actinomycetes produce a variety of clinically indispensable molecules, such as antineoplastic anthracyclines. However, the actinomycetes are hindered in their further development as genetically engineered hosts for the synthesis of new anthracycline analogues due to their slow growth kinetics associated with their mycelial life cycle and the lack of a comprehensive genetic toolbox for combinatorial biosynthesis. In this report, we tackled both issues via the development of the BIOPOLYMER (BIOBricks POLYketide Metabolic EngineeRing) toolbox: a comprehensive synthetic biology toolbox consisting of engineered strains, promoters, vectors, and biosynthetic genes for the synthesis of anthracyclinones. An improved derivative of the production host Streptomyces coelicolor M1152 was created by deleting the matAB gene cluster that specifies extracellular poly-β-1,6-N-acetylglucosamine (PNAG). This resulted in a loss of mycelial aggregation, with improved biomass accumulation and anthracyclinone production. We then leveraged BIOPOLYMER to engineer four distinct anthracyclinone pathways, identifying optimal combinations of promoters, genes, and vectors to produce aklavinone, 9-epi-aklavinone, auramycinone, and nogalamycinone at titers between 15-20 mg/L. Optimization of nogalamycinone production strains resulted in titers of 103 mg/L. We structurally characterized six anthracyclinone products from fermentations, including new compounds 9,10-seco-7-deoxy-nogalamycinone and 4-O-β-d-glucosyl-nogalamycinone. Lastly, we tested the antiproliferative activity of the anthracyclinones in a mammalian cancer cell viability assay, in which nogalamycinone, auramycinone, and aklavinone exhibited moderate cytotoxicity against several cancer cell lines. We envision that BIOPOLYMER will serve as a foundational platform technology for the synthesis of designer anthracycline analogues.

Iron supplementation ameliorates aloin-induced iron deficiency anemia in rats

Aloin, an anthraquinone glycoside, is one of other C-glycosides found in the leaf exudate of Aloe plant. Aloin possesses several biologic activities, including antitumor activity in vitro and in vivo. However, aloin treatment has shown iron deficiency anemia and erythropoiesis in vivo. The present study was undertaken to verify if iron supplementation could alleviate these perturbations, compared to doxorubicin, an anthracycline analog. Oral iron supplementation (20.56 mg elemental Fe/kg bw) to aloin-treated rats normalized red blood corpuscles count, hemoglobin concentration, and serum levels of total iron binding capacity and saturated transferrin, as well as hepatic iron content, hepcidin level, and mRNA expression of ferritin heavy chain (Ferr-H) and transferrin receptor-1 (TfR-1) genes. Although, serum hyperferremia, and leukocytosis were maintained, yet the spleen iron overload was substantially modulated. However, combined aloin and iron treatment increased iron storage levels in the heart and bone marrow, compared to aloin treatment per se. On other hand, oral iron supplementation to rats treated with doxorubicin (15 mg/kg bw) lessened the increase in the spleen iron content concomitantly with hepatic hepcidin level, rebound hepatic iron content to normal level, and by contrast augmented serum levels of iron and transferrin saturation. Also, activated Ferr-H mRNA expression and repressed TfR-1 mRNA expression were recorded, compared to doxorubicin treatment per se. Histopathological examination of the major body iron stores in rats supplemented with iron along with aloin or doxorubicin showed an increase in extramedullary hematopoiesis. In conclusion, iron supplementation restores the disturbances in iron homeostasis and erythropoiesis induced by aloin treatment.

Free radical induced activity of an anthracycline analogue and its MnII complex on biological targets through in situ electrochemical generation of semiquinone

Cytotoxicity by anthracycline antibiotics is attributed to several pathways. Important among them are formation of free-radical intermediates. However, their generation makes anthracyclines cardiotoxic which is a concern on their use as anticancer agents. Hence, any change in redox behavior that address cardiotoxicity is welcome. Modulation of redox behavior raises the fear that cytotoxicity could be compromised. Regarding the generation of free radical intermediates on anthracyclines, a lot depends on the surrounding environment (oxic or anoxic), polarity and pH of the medium. In case of anthracyclines, one-electron reduction to semiquinone or two-electron reduction to quinone-dianion are crucial both for cytotoxicity and for cardiotoxic side effects. The disproportion-comproportionation equilibria at play between quinone-dianion, free quinone and semiquinone control biological activity. Whatever is the form of reduction, semiquinones are generated as a consequence of the presence of anthracyclines and these interact with a biological target. Alizarin, a simpler anthracycline analogue and its MnII complex were subjected to electrochemical reduction to realize what happens when anthracyclines are reduced by compounds present in cells as members of the electron transport chain. Glassy carbon electrode maintained at the pre-determined reduction potential of a compound was used for reduction of the compounds. Nucleobases and calf thymus DNA that were maintained in immediate vicinity of such radical generation were used as biological targets. Changes due to the generated species under aerated/de-aerated conditions on nucleobases and on DNA helps one to realize the process by which alizarin and its MnII complex might affect DNA. The study reveals alizarin was more effective on nucleobases than the complex in the free radical pathway. Difference in damage caused by alizarin and the MnII complex on DNA is comparatively less than that observed on nucleobases; the complex makes up for any inefficacy in the free radical pathway by its other attributes.

Co-loading of an anthracycline analogue Pirarubicin and Salinomycin in a 1:3 ratio into Quatramerbiodegradable polymeric nanoparticles synergistically inhibit growth of triple-negative breast cancer.

e15047 Background: Triple negative breast cancer (TNBC) accounts for about 10-15% of all breast cancers and differ from other types of invasive breast cancers in that they grow and spread faster. TNBCs have limited treatment options and a worse prognosis. Therapy with anthracyclines considered to be one of the most effective agents in the treatment. Unfortunately, resistance to anthracycline therapy is very common due to drug efflux mediated by overexpression of ABC transporter. Pirarubicin (PIRA), an analogue of doxorubicin (DOX), is approved in Japan, Korea and China and is shown to be less cardiotoxic than DOX. Recent studies suggest that cancer stem cells (CSCs) play an important role in tumorigenesis and biology of TNBC. Targeting CSCs may be a promising, novel strategy for the treatment of this aggressive disease. Recent studies have shown that salinomycin (SAL) preferentially targets the viability of CSCs. Methods: SAL and PIRA were co-encapsulated in polylactic acid (PLA)-based block copolymeric nanoparticles (NPs) to efficiently co-deliver these agents to treat TNBC cells. Results: Generated SAL-PIRA co-encapsulated dual drug-loaded NPs showed an average diameter of 110 ± 7 nm, zeta potential of -12.5 mV and PDI of less than 0.25. Both of these anti-cancer agents showed slow and sustained release profile in non-physiological buffer (PBS, pH 7.4) from these dual drug-encapsulated NPs. Additionally, multiple ratios (PIRA:SAL = 3:1, 1:1, 1:3) were encapsulated to generate diverse dual drug-loaded NPs. The results demonstrate that, in contrast to 1:1 and 3:1, treatment of TNBC cells with 1:3 ratio of PIRA:SAL dual drug-loaded NPs, was associated with significant inhibition of growth in vitro in multiple TNBC cell lines. Interestingly, PIRA:SAL (1:3) was synergistic as compared to either SAL- or PIRA single drug-loaded NPs. The IC50 of PIRA and SAL in single drug-encapsulated NPs is 150 nM and 700 nM respectively in MDA-MB-468. Importantly, the IC50 of PIRA in dual drug-encapsulated NPs dropped down to 30 nM (5-fold). Similar results were obtained in SUM-149 TNBC cell line. Studies are underway to evaluate in vivo biological activity of PIRA:SAL (1:3) on tumor growth in a TNBC xenograft mice model. Conclusions: These results demonstrate that a novel dual drug-loaded NP formulation of PIRA and SAL in a unique ratio of 1:3 represents an approach for successful targeting of CSCs and bulk tumor cells in TNBC and potentially other cancer types.

A Survey of Synthetic Routes and Antitumor Activities for Benzo[g]quinoxaline-5,10-diones

Anthracycline antibiotics play an important role in cancer chemotherapy. The need to improve their therapeutic index has stimulated an ongoing search for anthracycline analogs with enhanced properties. This review aims to summarize the common synthetic approaches to benzo[g]quinoxaline-5,10-diones and their uses in heterocyclic chemistry. Because of the valuable biological activities of the 1,4-diazaanthraquinone compounds, a summary of the most promising heterocyclic quinones is provided together with their antitumor properties.

Effect of Anticancer Quinones on Reactive Oxygen Production by Adult Rat Heart Myocytes.

This study investigated the effect of anthracycline antibiotics, mitomycin C, and menadione on oxygen consumption and hydrogen peroxide production by intact, beating, rat heart myocytes. Doxorubicin produced a dose-dependent increase in the rate of cyanide-resistant respiration by beating myocytes. The anthracycline analogs 4-demethoxydaunorubicin, 4′-epidoxorubicin, 4′-deoxydoxorubicin, and menogaril, as well as the anticancer quinones mitomycin C and menadione, also significantly increased oxygen consumption by cardiac myocytes. However, 5-iminodaunorubicin (which has a substituted quinone group) and mitoxantrone (which is not easily reduced by flavin dehydrogenases) had no effect on cardiac respiration. Both catalase (43%) and acetylated cytochrome c (19%) significantly decreased oxygen consumption that had been stimulated by doxorubicin; furthermore, extracellular hydrogen peroxide production was increased from undetectable control levels to 1.30 ± 0.02 nmol/min/107 myocytes (n = 4, P < 0.01) in the presence of 400 μM doxorubicin. These experiments suggest that the anthracycline antibiotics and other anticancer quinones stimulate cardiac oxygen radical production in intact heart myocytes; such a free radical cascade could contribute to the cardiac toxicity of these drugs.

New insights into the activities and toxicities of the old anticancer drug doxorubicin.

The anthracycline drug doxorubicin is among the most used-and useful-chemotherapeutics. While doxorubicin is highly effective in the treatment of various hematopoietic malignancies and solid tumours, its application is limited by severe adverse effects, including irreversible cardiotoxicity, therapy-related malignancies and gonadotoxicity. This continues to motivate investigation into the mechanisms of anthracycline activities and toxicities, with the aim to overcome the latter without sacrificing the former. It has long been appreciated that doxorubicin causes DNA double-strand breaks due to poisoning topoisomerase II. More recently, it became clear that doxorubicin also leads to chromatin damage achieved through eviction of histones from select sites in the genome. Evaluation of these activities in various anthracycline analogues has revealed that chromatin damage makes a major contribution to the efficacy of anthracycline drugs. Furthermore, the DNA-damaging effect conspires with chromatin damage to cause a number of adverse effects. Structure-activity relationships within the anthracycline family offer opportunities for chemical separation of these activities towards development of effective analogues with limited adverse effects. In this review, we elaborate on our current understanding of the different activities of doxorubicin and their contributions to drug efficacy and side effects. We then offer our perspective on how the activities of this old anticancer drug can be amended in new ways to benefit cancer patients, by providing effective treatment with improved quality of life.

Actinomycetes from the Red Sea Sponge Coscinoderma mathewsi: Isolation, Diversity, and Potential for Bioactive Compounds Discovery.

The diversity of actinomycetes associated with the marine sponge Coscinoderma mathewsi collected from Hurghada (Egypt) was studied. Twenty-three actinomycetes were separated and identified based on the 16S rDNA gene sequence analysis. Out of them, three isolates were classified as novel species of the genera Micromonospora, Nocardia, and Gordonia. Genome sequencing of actinomycete strains has revealed many silent biosynthetic gene clusters and has shown their exceptional capacity for the production of secondary metabolites, not observed under classical cultivation conditions. Therefore, the effect of mycolic-acid-containing bacteria or mycolic acid on the biosynthesis of cryptic natural products was investigated. Sponge-derived actinomycete Micromonospora sp. UA17 was co-cultured using liquid fermentation with two mycolic acid-containing actinomycetes (Gordonia sp. UA19 and Nocardia sp. UA 23), or supplemented with pure mycolic acid. LC-HRESIMS data were analyzed to compare natural production across all crude extracts. Micromonospora sp. UA17 was rich with isotetracenone, indolocarbazole, and anthracycline analogs. Some co-culture extracts showed metabolites such as a chlorocardicin, neocopiamycin A, and chicamycin B that were not found in the respective monocultures, suggesting a mycolic acid effect on the induction of cryptic natural product biosynthetic pathways. The antibacterial, antifungal, and antiparasitic activities for the different cultures extracts were also tested.

Effect of aloin on some gene biomarkers for epithelial-mesenchymal transition in breast cancer in vitro compared to an anthracycline analog (Doxorubicin)

Effect of aloin on some gene biomarkers for epithelial-mesenchymal transition in breast cancer in vitro compared to an anthracycline analog (Doxorubicin)

In situ reactivity of electrochemically generated semiquinone on Emodin and its CuII/MnII complexes with pyrimidine based nucleic acid bases and calf thymus DNA: Insight into free radical induced cytotoxicity of anthracyclines

There is enough proof to believe that free-radical intermediates of anthracycline based anticancer agents are involved in different stages of drug action. Subtle therapeutic differences observed in the actions of different anthracyclines largely influence the mechanism of action of the drugs that distinguish one member from another. Redox properties control biological responses related either to the one-electron quinone/semiquinone couple or the two-electron quinone/quinone-dianion couple. Comproportionation also leads to generation of semiquinone. Hence, whatever the form of reduction of the quinone moiety, a substantial amount of semiquinone is eventually formed in the system. Immediately after formation, there is competition between natural radical-decay pathways and one-electron transfer reactions that generate the superoxide-radical anion. Prototropic properties control rate of radical decay while redox properties control rate of electron transfer to molecular oxygen. In aerated medium, semiquinone-radical anion and superoxide-radical anion co-exist while in de-aerated medium semiquinone-radical anion predominates. All the radicals are damaging to the biological system. Through this study, attempt was made to detect changes induced by the radicals on pyrimidine based nucleic acid bases and calf thymus DNA in aerated and de-aerated (Ar saturated) medium to know the mechanism by which Emodin, its CuII/MnII complexes might affect DNA. Semiquinone-radical anion was generated electrochemically maintaining a glassy carbon electrode at the first reduction potential of each compound. Since the chosen compound (Emodin), its complexes are analogues of anthracyclines, findings on them can be extrapolated to understand the differences in anticancer activity or of adverse drug reactions reported in an innumerable number of clinical studies related to anthracyclines where the difference in structure of different members is due to differences in the relative positioning of hydroxy groups on the hydroxy-9, 10-anthraquinone moiety of anthracyclines. The study helps to realize action of compounds of this class as anticancer agents.

The Endogenous Lusitropic and Chronotropic Agent, B-Type Natriuretic Peptide, Limits Cardiac Troponin Release in Cancer Patients with an Early Impairment of Myocardial Relaxation Induced by Anthracyclines.

We have reported that cancer patients treated with anthracycline-based or nonanthracycline chemotherapy developed an early impairment of myocardial relaxation at echocardiography or persistent elevations of the cardiac hormone B-type natriuretic peptide (BNP). Post-hoc pharmacologic analyses showed that BNP elevations were induced by impaired relaxation and caused positive lusitropic effects that maintained normal relaxation. High BNP levels and impaired relaxation were therefore characterized as mutually exclusive manifestations of diastolic dysfunction, but high BNP levels resulted in positive chronotropism and inappropriate tachycardia. Some patients developed increased circulating levels of cardiac troponin I isoform (cTnI), a marker of cardiomyocyte necrosis. Here we have characterized whether cTnI elevations correlated with diastolic dysfunction that manifested as impaired relaxation or a high level of BNP. The effects of high BNP levels on cTnI elevations were also characterized. We show that impaired relaxation or high BNP levels were significantly more frequent in patients with cTnI elevations. High BNP levels diminished the plasma peak and area under the curve of cTnI, but this result was accompanied by inappropriate tachycardia. cTnI elevations occurred only in patients treated with anthracyclines; moreover, the association of impaired relaxation or high BNP levels with cTnI elevations was significantly more frequent in doxorubicin-treated patients compared with patients treated with its analog, epirubicin. These findings describe cause-and-effect relations between impaired relaxation and cardiomyocyte necrosis, illuminate the role of anthracycline analogs, denote that the beneficial effects of BNP in relieving impaired relaxation and cardiomyocyte necrosis are counterbalanced by inappropriate tachycardia. Patients showing troponin elevations and impaired relaxation or high BNP levels should be treated with lusitropic drugs that lack a positive chronotropism.

Novel oxazolinoanthracyclines as tumor cell growth inhibitors-Contribution of autophagy and apoptosis in solid tumor cells death.

Chemical modification of known, effective drugs are one method to improve the chemotherapy of tumors. We reported ability of oxazoline analogs of doxorubicin (O-DOX) and daunorubicin (O-DAU) to induce apoptosis and autophagy in ovarian and liver cancer cells. Reactive oxygen and nitrogen species (ROS and RNS, respectively), together with intracellular calcium-mediated downstream signaling, are essential for the anticancer effect of these new anthracycline analogs. The changes of mitochondrial membrane potential and induction of the ceramide pathway suggests that these compounds induce cell death by apoptosis. In addition, a significant increase of autophagosome formation was observed by fluorescence assay and acridine orange staining, indicating that the new analogs also induce autophagic cell death. Compared to free DOX- and DAU-treated cells, we observed inhibition of colony formation and migration, a time-dependency between ROS/RNS levels and a greater fall in mitochondrial membrane potential. Altogether, our research broadens the base of molecular oxazolinoanthracyclines targets and reveals that derivatives mediated oxidative stress, ceramide production and increase in intracellular calcium level by mitochondria. Furthermore, our data highlight the importance of mitochondria that simultaneously assume the role of activator of autophagy and apoptosis signals.

The importance of pKa in an analysis of the interaction of compounds with DNA

pKa of a compound is crucial for determining the contributions of different forms of it towards overall binding with DNA. Hence it is important to use correct pKa values in DNA interaction studies. This study takes a look at the importance of pKa values to realize binding of compounds with DNA. Since pKa of a compound determined in the presence of DNA is quite different from that determined in its absence hence, presence of different forms of a compound during interaction with DNA is different from that realized if the determination of pKa is done in normal aqueous solution in absence of DNA. Hence, calculations determining contributions of different forms of a compound interacting with DNA are affected accordingly. Two simple analogues of anthracyclines, alizarin and purpurin, were used to investigate the influence DNA has on pKa values. Indeed, they were different in presence of DNA than when determined in normal aqueous solution. pKa1 for alizarin and purpurin determined in the absence and presence of calf thymus DNA were used in equations that determine contributions of two forms (neutral and anionic) towards overall binding with DNA. The study concludes that correct pKa values, determined correctly i.e. under appropriate conditions, must be used for DNA binding experiments to evaluate contributions of individual forms.

Mass spectrometric approaches for the identification of anthracycline analogs produced by actinobacteria.

Anthracyclines are a well-known chemical class produced by actinobacteria used effectively in cancer treatment; however, these compounds are usually produced in few amounts because of being toxic against their producers. In this work, we successfully explored the mass spectrometry versatility to detect 18 anthracyclines in microbial crude extract. From collision-induced dissociation and nuclear magnetic resonance spectra, we proposed structures for five new and identified three more anthracyclines already described in the literature, nocardicyclins A and B and nothramicin. One new compound 8 (4-[4-(dimethylamino)-5-hydroxy-4,6-dimethyloxan-2-yl]oxy-2,5,7,12-tetrahydroxy-3,10-dimethoxy-2-methyl-3,4-dihydrotetracene-1,6,11-trione) was isolated and had its structure confirmed by (1) H nuclear magnetic resonance. The anthracyclines identified in this work show an interesting aminoglycoside, poorly found in natural products, 3-methyl-rhodosamine and derivatives. This fact encouraged to develop a focused method to identify compounds with aminoglycosides (rhodosamine, m/z 158; 3-methyl-rhodosamine, m/z 172; 4'-O-acethyl-3-C-methyl-rhodosamine, m/z 214). This method allowed the detection of four more anthracyclines. This focused method can also be applied in the search of these aminoglycosides in other microbial crude extracts. Additionally, it was observed that nocardicyclin A, nothramicin and compound 8 were able to interact to DNA through a DNA-binding study by mass spectrometry, showing its potential as anticancer drugs. Copyright © 2016 John Wiley & Sons, Ltd.

Curing Cancer, Saving the Heart: A Challenge That Cardioncology Should Not Miss.

Advances in oncologic therapies have led to considerable improvements in prognosis and survival. However, these improvements may ultimately be diminished by the increase of cardiovascular side effects. Typically, both conventional and new antitumoral therapies may induce asymptomatic or symptomatic left ventricular dysfunction. Its development still remains a major deterrent that may compromise clinical effectiveness of cancer treatment, independently of the oncologic prognosis, having a serious impact on the patient's survival and quality of life. Hence, prevention of cardiotoxicity remains a crucial topic both for cardiologists and oncologists. Many strategies to mitigate the risk of cardiotoxicity have been developed, including cardiac function monitoring, limitation of chemotherapy doses, use of anthracycline analogues and cardioprotectants, and early detection of cardiotoxicity by biomarkers, followed by prophylactic intervention in selected high risk patients. We reviewed the currently available approaches which have been demonstrated to be effective in preventing or limiting cancer drug-induced cardiotoxicity.

MP13-05 A RANDOMIZED TRIAL COMPARING TWO DIFFERENT RETENTION PERIODS OF INTRAVESICAL PIRARUBICIN INSTILLATION FOR INTERMEDIATE RISK NON-MUSCLE INVASIVE BLADDER CANCER (NMIBC) AFTER TRANSURETHRAL RESECTION.

You have accessJournal of UrologyBladder Cancer: Non-Invasive I1 Apr 2016MP13-05 A RANDOMIZED TRIAL COMPARING TWO DIFFERENT RETENTION PERIODS OF INTRAVESICAL PIRARUBICIN INSTILLATION FOR INTERMEDIATE RISK NON-MUSCLE INVASIVE BLADDER CANCER (NMIBC) AFTER TRANSURETHRAL RESECTION. Ryoma Kurahashi, Yutaka Kasejima, Yoshiaki Kawano, Wataru Takahashi, Takahiro Yamaguchi, Ken-ichiro Tanoue, Hiroshi Sakakida, Junji Yatsuda, Youji Murakami, Yutaka Sugiyama, and Masatoshi Eto Ryoma KurahashiRyoma Kurahashi More articles by this author , Yutaka KasejimaYutaka Kasejima More articles by this author , Yoshiaki KawanoYoshiaki Kawano More articles by this author , Wataru TakahashiWataru Takahashi More articles by this author , Takahiro YamaguchiTakahiro Yamaguchi More articles by this author , Ken-ichiro TanoueKen-ichiro Tanoue More articles by this author , Hiroshi SakakidaHiroshi Sakakida More articles by this author , Junji YatsudaJunji Yatsuda More articles by this author , Youji MurakamiYouji Murakami More articles by this author , Yutaka SugiyamaYutaka Sugiyama More articles by this author , and Masatoshi EtoMasatoshi Eto More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2016.02.2486AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Anthracyclines are recommended reagents for one immediate intravesical instillation after transurethral resection (TUR) and additional adjuvant instillation in intermediate risk non-muscle invasive bladder cancer (NMIBC) to reduce the risk of recurrence. Pirarubicin (THP), an anthracycline analogue, is widely used reagent for intravesical instillation chemotherapy. Several studies have showed that THP can rapidly penetrate tumor tissue after intravesical instillation. Therefore long instillation time (e.g. 120 min) may not be required for its prophylactic effect against recurrence since it may reduce the risk of adverse events such as cystitis and hematuria without compromising its efficacy. However, there is no high level evidence regarding optimized intravesical THP instillation time in terms of both toxicity and efficacy. METHODS This randomized, prospective, open-label trial intended to enroll 160 pts with primary NMIBC with intermediate risk based on EORTC criteria. All pts received initial THP instillation within 24 hr after TUR and then intended to continue weekly repetitive THP instillation for a total of 9 treatments. Pts who seemed likely to be at intermediate risk were provisionally registered and then randomized into two groups with different intravesical THP retention times before TUR, (a) 30 min versus (b) 120 min. Follow-up period is 4 years. Primary endpoint is change from baseline in quality of life (e.g. OABSS and I-PSS), which will be evaluated prior to THP intravesical instillation. Secondary endpoint is recurrence-free survival. RESULTS 126 pts were enrolled for provisional registration in this trial and randomized before TUR-B. After excluding pts due to the result of pathology by TUR-B such as benign disease, T1 G3 tumor and concomitance of CIS, 29 pts were assigned to group (a) (30 min), and 26 pts to group (b) (120 min). There is a trend that group (a) is less prone to increase in OABSS after 3rd instillation compared to group (b), which is not statistically significant. Log-rank test shows that there is no significant difference in recurrence-free survival between the groups during follow-up period (HR=2.161, 95% C.I.: 0.4317-10.82, p=0.3484). CONCLUSIONS Shortening intravesical instillation period to 30 min has little effect on reducing the adverse effect of THP. However, it does not compromise the prophylactic effect on recurrence in intermediate risk NMIBC pts. © 2016FiguresReferencesRelatedDetails Volume 195Issue 4SApril 2016Page: e135-e136 Advertisement Copyright & Permissions© 2016MetricsAuthor Information Ryoma Kurahashi More articles by this author Yutaka Kasejima More articles by this author Yoshiaki Kawano More articles by this author Wataru Takahashi More articles by this author Takahiro Yamaguchi More articles by this author Ken-ichiro Tanoue More articles by this author Hiroshi Sakakida More articles by this author Junji Yatsuda More articles by this author Youji Murakami More articles by this author Yutaka Sugiyama More articles by this author Masatoshi Eto More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Cardioprotection in women with neoplastic disease

Cardiotoxicity (CTX) is a serious adverse effect of anticancer drugs that impacts on quality of life and overall survival of cancer patients. Hypokinetic cardiomyopathy is the most typical form of CTX, and it is traditionally considered refractory to therapy. Prevention of CTX remains of paramount importance, and several measures, including serial cardiac function monitoring, reduction of cumulative anthracycline dose, use of anthracycline analogues and cardioprotective agents, have been proposed. Over the last decade, however, a new approach based on cardiac biomarkers has emerged as an effective alternative strategy for the early detection of subclinical cardiac injury. In particular, the role of troponin I in identifying patients at risk of CTX as well as of angiotensin-converting enzyme inhibitors in preventing left ventricular dysfunction and late cardiac events in high-risk patients, namely those with raised troponin I levels after chemotherapy, has been consistently demonstrated as an effective tool for CTX prevention.

A randomized trial comparing two different retention periods of intravesical pirarubicin instillation for intermediate risk non-muscule invasive bladder cancer (NMIBC) after transurethral resection.

384 Background: Anthracyclines are recommended reagents for one immediate intravesical instillation after transurethral resection (TUR) and additional adjuvant instillation in intermediate risk NMIBC to reduce the risk of recurrence. Several studies have showed that Pirarubicin (THP), an anthracycline analogue, can rapidly penetrate tumor tissue after intravesical instillation. Therefore long instillation time (e.g. 120 min) may not be required for its prophylactic effect against recurrence without compromising its efficacy. Methods: This randomised, prospective, open-label trial intended to enroll 160 pts with primary NMIBC with intermediate risk based on EORTC criteria. Pts who seemed likely to be at intermediate risk were provisionally registered and then randomised into two groups with different intravesical THP retention times before TUR, (a) 30 min versus (b) 120 min. The registration was finally confirmed by pathology results of TUR. All registered pts received initial THP instillation within 24 hr after TUR and then intended to continue weekly repetitive THP instillation for a total of 9 treatments. Follow-up period is 4 years. Primary endpoint is change from baseline in quality of life measurements (e.g. OABSS and I-PSS), which were evaluated prior to each THP intravesical instillation. Secondary endpoint is recurrence-free survival. Results: 126 pts were enrolled for provisional registration. After excluding pts due to the result of pathology by TUR, 29 pts were assigned to group (a), and 26 pts to group (b). Although not statistically significant, there is a trend that group (a) is less prone to increase in OABSS after 3rd instillation compared to group (b). Log-rank test shows that there is no significant difference in recurrence-free survival between the groups during follow-up period (HR = 2.161, 95% C.I.: 0.4317-10.82, p= 0.3484). Conclusions: Shortening intravesical instillation period to 30 min has little effect on reducing the adverse effect of THP. However, it does not compromise the prophylactic effect on recurrence in intermediate risk NMIBC pts. Clinical trial information: UMIN000006861.