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Journal articles on the topic 'Antineoplastic Anthracyclines Anthracyclines Crystallography'
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1
Zucchi, Riccardo, and Romano Danesi. "Cardiac Toxicity of Antineoplastic Anthracyclines." Current Medicinal Chemistry-Anti-Cancer Agents 3, no. 2 (March 1, 2003): 151–71. http://dx.doi.org/10.2174/1568011033353434.
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Luo, Dasan, and Steven R. Vincent. "Inhibition of nitric oxide synthase by antineoplastic anthracyclines." Biochemical Pharmacology 47, no. 11 (June 1994): 2111–12. http://dx.doi.org/10.1016/0006-2952(94)90088-4.
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Brunetti, Luigi, Giustino Orlando, Barbara Michelotto, Lucia Recinella, Enzo Ragazzoni, and Michele Vacca. "A possible prolactin-related adverse effect of certain antineoplastic anthracyclines." Toxicology Letters 116, no. 3 (August 2000): 231–36. http://dx.doi.org/10.1016/s0378-4274(00)00223-x.
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Creutzig, Ursula, Sylke Diekamp, Martin Zimmermann, and Dirk Reinhardt. "Long Term Data on Anthracycline Cardiotoxicity in 547 Children with AML." Blood 108, no. 11 (November 1, 2006): 2014. http://dx.doi.org/10.1182/blood.v108.11.2014.2014.
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Abstract Anthracyclines are effective antineoplastic drugs in acute mylogenous leukemia (AML) and dose intensity and cumulative doses are especially important. However, the use of anthracyclines is limited by cardiotoxicity, which occurs already at 300 mg/m2 cumulative doses (given as daunorubicin dosage) in children. To evaluate anthracycline-associated cardiomyopathy in pediatric AML-patients, the incidence of late clinical and subclinical cardiotoxicity (using echocardiography) was analysed in studies AML-BFM 93 and 98. Out of a total of 1,207 patients under 18 years, 547 (45%) patients were eligible for the analysis of late cardiotoxicity - de novo AML: 470 of 1,010 (46%), AML-Down syndrome: 69 of 121 (57%), secondary AML 8 of 76 (11%) -, median follow-up 5.3 years (0.8–11.7 years) after diagnosis. The cumulative dose of anthracyclines was risk-adapted between 300 and 450 mg/m2 or even higher in patients with secondary AML. Results: Late cardiomyopathy was seen in 16 patients, cumulative incidence (CI) after 11 years 5±1% (de novo patients: 4±1%), including 4 of 38 patients (10.5%) who suffered already from early cardiomyopathy. Nine of these 16 patients (CI 2.5±1%) showed clinical symptoms, with persistent abnormal shortening fraction in 5 of them, which led to death in one AML-Down syndrome patient. Late subclinical cardiomyopathy occurred temporarily in 7 patients. Late clinical cardiomyopathy mainly effected patients with a second anthracycline therapy (3 of 8 with AML as secondary malignancy) and those with early cardiotoxicity. Using anthracyclines risk-adapted or administering long-term infusion might have contributed to the low rate of cardiomyopathy in AML de novo patients.
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Dolinsky, Vernon W. "The role of sirtuins in mitochondrial function and doxorubicin-induced cardiac dysfunction." Biological Chemistry 398, no. 9 (August 28, 2017): 955–74. http://dx.doi.org/10.1515/hsz-2016-0316.
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Abstract Anthracycline chemotherapeutics such as doxorubicin continue to be important treatments for many cancers. Through improved screening and therapy, more patients are surviving and living longer after the diagnosis of their cancer. However, anthracyclines are associated with both short- and long-term cardiotoxic effects. Doxorubicin-induced mitochondrial dysfunction is a central mechanism in the cardiotoxic effects of doxorubicin that contributes to impaired cardiac energy levels, increased reactive oxygen species production, cardiomyocyte apoptosis and the decline in cardiac function. Sirtuins are protein deacetylases that are activated by low energy levels and stimulate energy production through their activation of transcription factors and enzymatic regulators of cardiac energy metabolism. In addition, sirtuins activate oxidative stress resistance pathways. SIRT1 and SIRT3 are expressed at high levels in the cardiomyocyte. This review examines the function of sirtuins in the regulation of cardiac mitochondrial function, with a focus on their role in heart failure and an emphasis on their effects on doxorubicin-induced cardiotoxicity. We discuss the potential for sirtuin activation in combination with anthracycline chemotherapy in order to mitigate its cardiotoxic side-effects without reducing the antineoplastic activity of anthracyclines.
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Vermorken, J. B. "The role of anthracyclines in second-line therapy of ovarian cancer." International Journal of Gynecologic Cancer 13, Suppl 2 (2003): 178–84. http://dx.doi.org/10.1136/ijgc-00009577-200311001-00009.
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Anthracyclines (ANTs) have been in clinical practice since the 1960s and represent one of the most commonly used classes of anticancer drugs. In the 1990s, meta-analyses showed a favorable impact of doxorubicin (DOX/A) on the survival of patients with advanced ovarian cancer, when it was combined with cyclophosphamide and cisplatin (CAP) and compared to CP alone. With the acceptance of paclitaxel-carboplatin (TCb) as the new reference arm for first-line treatment, testing the addition of ANTs to TCb seems a logic next step. Trials presently testing this, make use of either epirubicin (EPI) or pegylated liposomal doxorubicin (PLD: Doxil®/Caelyx®). These are the two most favorable ANTs, based on data obtained with various ANTs in ovarian cancer failing platinum-based chemotherapy. EPI has not been evaluated in direct comparison with other antineoplastic agents. PLD has been compared with both paclitaxel and topotecan. No difference in efficacy parameters could be observed, but the toxicity profile of PLD scored favorably against those of the comparator in both trials, despite the fact that palmar-plantar erythrodysesthesia can be troublesome, and sometimes lead to treatment discontinuation. Data from four randomized trials evaluating the role of ANT combinations in patients with relapsed ovarian cancer suggest that the addition of EPI or DOX to paclitaxel does not lead to better outcomes in patients with platinum-refractory or resistant disease. In platinum-sensitive disease, any benefit of EPI-platinum or DOX-platinum combinations over platinum alone is uncertain. There are no randomized trials with PLD combinations in the second-line setting. It is concluded that both EPI and PLD can be recommended as a reasonable single-agent treatment option for relapsed patients, with a preference for PLD taking into account its more favorable toxicity profile.
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Sartor, Lauren, Charmaine Ibarra, Ahmad Al-Mestarihi, Brian O. Bachmann, and Jessica L. Vey. "Structure of DnmZ, a nitrososynthase in the Streptomyces peucetius anthracycline biosynthetic pathway." Acta Crystallographica Section F Structural Biology Communications 71, no. 10 (September 23, 2015): 1205–14. http://dx.doi.org/10.1107/s2053230x15014272.
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The anthracyclines are a class of highly effective natural product chemotherapeutics and are used to treat a range of cancers, including leukemia. The toxicity of the anthracyclines has stimulated efforts to further diversify the scaffold of the natural product, which has led to renewed interest in the biosynthetic pathway responsible for the formation and modification of this family of molecules. DnmZ is an N-hydroxylating flavin monooxygenase (a nitrososynthase) that catalyzes the oxidation of the exocyclic amine of the sugar nucleotide dTDP-L-epi-vancosamine to its nitroso form. Its specific role in the anthracycline biosynthetic pathway involves the synthesis of the seven-carbon acetal moiety attached to C4 of L-daunosamine observed in the anthracycline baumycin. Here, X-ray crystallography was used to elucidate the three-dimensional structure of DnmZ. Two crystal structures of DnmZ were yielded: that of the enzyme alone, solved to 3.00 Å resolution, and that of the enzyme in complex with thymidine diphosphate, the nucleotide carrier portion of the substrate, solved to 2.74 Å resolution. These models add insights into the structural features involved in substrate specificity and conformational changes involved in thymidine diphosphate binding by the nitrososynthases.
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Hashizume, Makoto. "Experimental Studies on the Effect of Antineoplastic Drugs, Especially of Anthracyclines, and Coenzyme Q10 on Human Platelets." Journal of Kansai Medical University 37, no. 4 (1985): 534–59. http://dx.doi.org/10.5361/jkmu1956.37.4_534.
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Aceves, Carmen, Yunuen Alfaro-Hernandez, and Guadalupe Delgado. "Abstract B38: Iodine supplement exerts antineoplastic adjuvancy, chemoresistance inhibition and cardioprotection in mammary cancer treatment with anthracyclines." Cancer Prevention Research 5, no. 11 Supplement (November 2012): B38. http://dx.doi.org/10.1158/1940-6207.prev-12-b38.
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Kulyova, Svetlana A., Tatiana Yu Semiglazova, Daria A. Zvyagintseva, Margarita B. Belogurova, Svetlana V. Ivanova, and Irina V. Okisheva. "Cardiovascular complications of antineoplastic therapy in children." Pediatrician (St. Petersburg) 8, no. 3 (May 15, 2017): 130–41. http://dx.doi.org/10.17816/ped83130-141.
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The improvement of long-term survival in children with malignant tumors is noted in the last five decades. Serious late consequences of the applied therapy including early death, the second tumors, different organ dysfunctions (heart, gonads, liver, lungs) began to come to light with increase in number of cured and follow-up. The article discusses the emergence of cardiotoxicity in children treated with cytostatic and radiation therapy for malignant tumors. Particular attention is paid to the influence of anthracycline antibiotics on the state of the heart muscle. Anthracycline and similar medicines - doxorubicin, rubomycin, idarubicin, mitoxantrone - are an important component of most regimen of chemotherapy in children. Briefly describes the history of the application of this group of drugs in oncology and the study of their effects on heart function. The attention to the pathogenesis of anthracycline cardiotoxicity risk factors for its development, display options, how to identify and mitigate. We describe the clinical manifestations of early and late cardiotoxicity arising after the application of antitumor antibiotics anthracyclines. The article defines the role of chemotherapeutic agents other groups in the development and worsening cardiotoxicity. No less important role in the development of long-term effects of the heart and blood vessels plays radiotherapy. The paper paid attention to cardiovascular dysfunctions that arise in different periods of observation after irradiation of the mediastinum. Finally, recommendations for practitioners on screening, monitoring and treatment of identified diseases of the cardiovascular system in patients cured of childhood malignancies are presented.
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Maurea, Nicola, Carmela Coppola, Domenica Rea, Giovanna Piscopo, Gennaro Riccio, Antonio Barbieri, Giuseppe Palma, et al. "Inhibition of cardiomyocytes late INa with ranolazine blunts anthracyclines-cardiotoxicity in experimental models in vitro and in vivo." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): e13539-e13539. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.e13539.
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e13539 Background: Anthracyclines produce a well-known cardiomyopathy through multiple mechanisms, which also include, among many, Ca2+ overload due to reduced SERCA2a activity and inappropriate opening of the RyR2, and impaired myocardial energetics. Anthracyclines generate Reactive Oxigen and Nitrogen Species (ROS and RNS), posing the heart at increased demand for oxygen, thus setting the stage for a metabolic ischemia that also activates late INa, the target of ranolazine (RAN). Here, we aim at assessing whether RAN, diminishing intracellular Ca2+ through its inhibition of late INa, and enhancing myocardial glucose utilization (and/or reverting impairment of glucose utilization caused by chemotherapy) blunts anthracyclines cardiotoxicity. Methods: To assess for toxicity in vitro, rat H9C2 cardiomyoblasts were pretreated with RAN (0.1-1mM) for 72 hours and then treated with doxorubicin (DOX, 0.1 mM) for additional 24 hours. Cells counts were assessed by Trypan exclusion test. To evaluate cardiac function in vivo, fractional shortening (FS) and ejection fraction (EF) were measured by echocardiography in C57BL6 mice, 2-4 mo old, pretreated with RAN (370mg/kg/day, a dose comparable to the one used in humans) per os for 3 days. RAN was then administered for additional 7 days, together with DOX (2.17mg/kg/day ip), according to our well established protocol. Results: After DOX, only 68% of the cells were viable. RAN alone did not affect cell survival, but blunted DOX toxicity, rescuing % cell survival to 87% (p=.01 vs DOX alone). In our in vivo studies, after 7 days with DOX, FS decreased to 50±2%, p=.002 vs 60±1% (sham), and EF to 81±2%, p=0.0001 vs 91±1% (sham). RAN alone did not change FS (59±2%) nor EF (89±1%). Interestingly, in mice treated with RAN and DOX, the reduction in cardiac function was milder: FS was 57±1%, EF was 89±1%, p=0.01 and 0.0009 respectively, vs DOX alone. Conclusions: RAN blunts DOX cardiotoxic effects in 2 different models, in vitro and in vivo. We plan to test RAN as a cardioprotective agent with other antineoplastic cardiotoxic drugs in our experimental models, and to better characterize the cardioprotective mechanisms of RAN in all these settings.
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Maurea, Nicola, Carmela Coppola, Giovanna Piscopo, Clemente Cipresso, Domenica Rea, Carlo G. Tocchetti, Michelino De Laurentiis, Claudio Arra, and Rosario Vincenz Iaffaioli. "Inhibition of cardiomyocytes late INa with ranolazine to prevent anthracyclines cardiotoxicity in experimental models in vitro and in vivo." Journal of Clinical Oncology 31, no. 26_suppl (September 10, 2013): 170. http://dx.doi.org/10.1200/jco.2013.31.26_suppl.170.
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170 Background: Anthracyclines are first line drugs against cancer, but produce a well-known cardiomyopathy through multiple mechanisms, which also include Ca2+ overload due to reduced SERCA2a activity and inappropriate opening of the RyR2, and impaired myocardial energetics. Anthracyclines generate Reactive Oxigen and Nitrogen Species, posing the heart at increased demand for oxygen, thus setting the stage for a metabolic ischemia that also activates late INa, the target of ranolazine (RAN). Here, we aim at assessing whether RAN, diminishing intracellular Ca2+ through its inhibition of late INa, and enhancing myocardial glucose utilization (and/or reverting impairment of glucose utilization caused by chemotherapy) blunts anthracyclines cardiotoxicity. Methods: To assess for cardiotoxicity in vitro, rat H9C2 cardiomyoblasts were pretreated with RAN (0.1-1µM) for 72 hours and then treated with doxorubicin (DOX, 0.1 µM)for additional 24 hours. Cells counts were assessed by Trypan exclusion test. To evaluate cardiac function in vivo, fractional shortening (FS) and ejection fraction (EF) were measured by echocardiography in C57BL6 mice, 2-4 mo old, pretreated with RAN (370mg/kg/day, a dose comparable to the one used in humans) per os for 3 days. RAN was then administered for additional 7 days, alone and together with DOX (2.17mg/kg/day ip), according to our well established protocol. Results: After DOX, only 68% of the cells were viable. RAN alone did not affected cell survival, but blunted DOX toxicity, rescuing % cell survival to 87% (p=.01 vs DOX alone). In our in vivo studies, after 7 days with DOX, FS decreased to 50±2%, p=.002 vs 60±1% (sham), and EF to 81+2%, p=0.0001 vs 91+1% (sham). RAN alone did not change FS (59±2%) nor EF 89+1%. Interestingly, in mice treated with RAN and DOX, the reduction in cardiac function was milder: FS was 57±1%, EF was 89+1%, p=0.01 and 0.0009, vs DOX alone. Conclusions: RAN blunts DOX cardiotoxic effects in 2 different models, in vitro and in vivo. We plan to test RAN as a cardioprotective agent with other antineoplastic cardiotoxic drugs in our experimental models, and to better characterize the cardioprotective mechanisms of RAN in all these settings.
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Deidda, Martino, Valentina Mercurio, Alessandra Cuomo, Antonio Noto, Giuseppe Mercuro, and Christian Cadeddu Dessalvi. "Metabolomic Perspectives in Antiblastic Cardiotoxicity and Cardioprotection." International Journal of Molecular Sciences 20, no. 19 (October 4, 2019): 4928. http://dx.doi.org/10.3390/ijms20194928.
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Despite advances in supportive and protective therapy for myocardial function, cardiovascular diseases due to antineoplastic therapy—primarily cardiomyopathy associated with contractile dysfunction—remain a major cause of morbidity and mortality. Because of the limitations associated with current therapies, investigators are searching for alternative strategies that can timely recognise cardiovascular damage—thus permitting a quick therapeutic approach—or prevent the development of the disease. Damage to the heart can result from both traditional chemotherapeutic agents, such as anthracyclines, and new targeted therapies, such as tyrosine kinase inhibitors. In recent years, metabolomics has proved to be a practical tool to highlight fundamental changes in the metabolic state in several pathological conditions. In this article, we present the state-of-the-art technology with regard to the metabolic mechanisms underlying cardiotoxicity and cardioprotection.
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Pawłowska, Natalia, Anna Czajkowska, Anna Bielawska, and Krzysztof Bielawski. "Ecteinascidins – new antineoplastic drugs from the depths of the seas." Postępy Higieny i Medycyny Doświadczalnej 72 (December 13, 2018): 1062–72. http://dx.doi.org/10.5604/01.3001.0012.7873.
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Trabectedin, also known as ecteinascidin 743 (Et-743), is a tetrahydroisoquinoline alkaloid that was originally isolated from the Caribbean sea squirt Ecteinascidia turbinata. Trabectedin is one of the first anticancer drugs of marine origin that has been approved in the European Union. The compound is used to treat patients with advanced soft tissue sarcoma in case of failure of conventional anthracyclines and ifosfamide therapy and in the treatment of recurrent platinum-sensitive ovarian cancer in combination with pegylated liposomal doxorubicin. The mechanism of action of trabectedin is based on interaction with the minor groove of DNA double helix. It triggers a cascade of events that interfere with several transcription factors, DNA binding proteins and DNA repair pathways, resulting in G2/M cell cycle arrest and ultimately apoptosis. Moreover, emerging evidence indicates that Et-743 has dual effects. In addition to induce direct growth inhibition, cell death and differentiation of malignant cells it also affects the tumor microenvironment by reducing the production of key inflammatory mediators. A multifaceted mechanism of action may explain positive results when trabectedin is used in the treatment of cancer that exhibits resistance to conventional chemotherapeutics. The widespread use of ecteinascidins in therapy as well as in clinical trials is, however, limited by the high price of these compounds. Therefore, intensive work is being carried out on the search for synthetic analogues of ecteinascidins with equally high activity against tumor cells.
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Becker, Torben K., and Sai-Ching J. Yeung. "Drug-induced QT interval prolongation in cancer patients." Oncology Reviews 4, no. 4 (December 14, 2011): 223. http://dx.doi.org/10.4081/oncol.2010.223.
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Cancer patients are at an increased risk for QT interval prolongation and subsequent potentially fatal Torsade de pointes tachycardia due to the multiple drugs used for treatment of malignancies and the associated symptoms and complications. Based on a systematic review of the literature, this article analyzes the risk for prolongation of the QT interval with antineoplastic agents and commonly used concomitant drugs. This includes anthracyclines, fluorouracil, alkylating agents, and new molecularly targeted therapeutics, such as vascular disruption agents. Medications used in the supportive care can also prolong QT intervals, such as methadone, 5-HT3-antagonists and antihistamines, some antibiotics, antifungals, and antivirals. We describe the presumed mechanism of QT interval prolongation, drug-specific considerations, as well as important clinical interactions. Multiple risk factors and drug–drug interactions increase this risk for dangerous arrhythmias. We propose a systematic approach to evaluate cancer patients for the risk of QT interval prolongation and how to prevent adverse effects.
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Merkel, D. E., S. A. Fuqua, A. K. Tandon, S. M. Hill, A. U. Buzdar, and W. L. McGuire. "Electrophoretic analysis of 248 clinical breast cancer specimens for P-glycoprotein overexpression or gene amplification." Journal of Clinical Oncology 7, no. 8 (August 1989): 1129–36. http://dx.doi.org/10.1200/jco.1989.7.8.1129.
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Multiple drug resistance (MDR), consisting of acquired cross resistance to anthracyclines, vinca alkyloids, and other antineoplastic antibiotics, has been described in a variety of cell lines. This MDR phenotype is associated with overexpression and sometimes amplification of a gene coding for a 170 kDa glycoprotein, termed P-glycoprotein. To understand the role of this mechanism in clinical breast cancer, 248 breast cancer specimens representing both untreated primary and refractory relapsing disease were probed for evidence of P-glycoprotein gene amplification or overexpression using Southern, Northern, or Western blot techniques. In no case was an increase in P-glycoprotein gene copy number or expression detected. Though these findings do not necessarily rule out a role for P-glycoprotein in mediating drug resistance in breast cancer, electrophoretic analysis of clinical specimens is unlikely to provide useful predictive information. More sensitive assays must be developed to overcome the difficulties inherent in analyzing heterogenous tissue samples.
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Ocadlikova, Darina, Clara Iannarone, Anna Rita Redavid, Michele Cavo, and Antonio Curti. "A Screening of Antineoplastic Drugs for Acute Myeloid Leukemia Reveals Contrasting Immunogenic Effects of Etoposide and Fludarabine." International Journal of Molecular Sciences 21, no. 18 (September 16, 2020): 6802. http://dx.doi.org/10.3390/ijms21186802.
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Background: Recent evidence demonstrated that the treatment of acute myeloid leukemia (AML) cells with daunorubicin (DNR) but not cytarabine (Ara-C) results in immunogenic cell death (ICD). In the clinical setting, chemotherapy including anthracyclines and Ara-C remains a gold standard for AML treatment. In the last decade, etoposide (Eto) and fludarabine (Flu) have been added to the standard treatment for AML to potentiate its therapeutic effect and have been tested in many trials. Very little data are available about the ability of these drugs to induce ICD. Methods: AML cells were treated with all four drugs. Calreticulin and heat shock protein 70/90 translocation, non-histone chromatin-binding protein high mobility group box 1 and adenosine triphosphate release were evaluated. The treated cells were pulsed into dendritic cells (DCs) and used for in vitro immunological tests. Results: Flu and Ara-C had no capacity to induce ICD-related events. Interestingly, Eto was comparable to DNR in inducing all ICD events, resulting in DC maturation. Moreover, Flu was significantly more potent in inducing suppressive T regulatory cells compared to other drugs. Conclusions: Our results indicate a novel and until now poorly investigated feature of antineoplastic drugs commonly used for AML treatment, based on their different immunogenic potential.
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Turci, Roberta, Claudio Minoia, Cristina Sottani, Raffaella Coghi, Paolo Severi, Cecilia Castriotta, Massimo Del Bianco, and Marcello Imbriani. "Occupational exposure to antineoplastic drugs in seven Italian hospitals: The effect of quality assurance and adherence to guidelines." Journal of Oncology Pharmacy Practice 17, no. 4 (September 7, 2010): 320–32. http://dx.doi.org/10.1177/1078155210381931.
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In health care facilities, dermal contact and inhalation are considered to be the main routes of exposure to cytotoxic antineoplastic drugs (ADs). Hand-to-mouth contamination or accidental needle sticks as well as events due to inadequate disposal may also contribute to exposure. In order to measure the extent of contamination, biological and environmental monitoring are essential tools for routine testing. Moreover, reliable sampling and analytical procedures are required. During the last decade, several methods have been developed and validated. The appropriate analytical techniques were used to quantify even very low levels of some of the more commonly used ADs, such as cyclophosphamide, 5-fluoruracil, taxol, anthracyclines, and platinum-compounds. The main objective of this study is to assess the adherence to existing standards of practice through an effective monitoring program, including environmental and biological measurements. In seven hospitals located in Northern-Central Italy, periodic surveys were scheduled to verify continuing compliance with guidelines over a 5-year period. All biological samples were found to be below detection limits and a progressive, significant decrease in workplace contamination was observed. Our results confirm that a cost-effective monitoring regime, including fast and simple sample pre-treatment procedures, simultaneous determination of the analytes and their metabolites, validated procedures including uncertainty evaluation, and periodic surveys, is the adequate approach for the collection of reliable exposure data and hence for effective intervention.
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Thakur, Devendra Singh. "Topoisomerase II Inhibitors in Cancer Treatment." International Journal of Pharmaceutical Sciences and Nanotechnology 3, no. 4 (February 28, 2011): 1173–81. http://dx.doi.org/10.37285/ijpsn.2010.3.4.2.
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Topoisomerase II constitutes a family of nuclear enzymes essential to all living cells. These enzymes are capable of transferring one DNA double helix through a transient break in another DNA double helix. Type II topoisomerases play important roles in DNA metabolic processes, in which they are involved in DNA replication, transcription, chromosome condensation and de-condensation. Topoisomerase II is also the cellular target for a number of widely used anticancer agents currently in clinical use, such as the anthracyclines (daunorubicin and doxorubicin), the epipodophyllotoxins (etoposide and teniposide), and the aminoacridines. These agents stimulate the topoisomerase II-cleavable complex, which is a transient configuration of topoisomerase II on DNA in which topoisomerase II is covalently attached to DNA. This causes the accumulation of cytotoxic nonreversible DNA double-strand breaks generated by the processing of such complexes by DNA metabolic processes. As of present, the clinical use of catalytic topoisomerase inhibitors as antineoplastic agents is limited to aclarubicin and MST-16. Both of these compounds are preferentially active toward hematological malignancies and show limited activity toward solid tumors. This review explains the role of topoisomerase inhibitors in cancer therapy.
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Semiglazova, T. Y., M. L. Gershanovich, D. H. Latipova, L. V. Filatova, V. A. Chubenko, V. F. Semiglazov, V. V. Semiglazov, P. V. Krivorotko, D. E. Matsko, and V. V. Klimenko. "Low Doses of Gemcitabine (G) with Cisplatin (C) in Treatment of Metastatic Breast Cancer (MBC) Progressing after Anthracyclines, Taxanes, Capecitabine and Other Antineoplastic Agents." Annals of Oncology 23 (September 2012): ix139. http://dx.doi.org/10.1016/s0923-7534(20)32963-x.
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Carroll, Michael P., Olin Feuerbacher, Andrew M. Yeager, and Terry H. Landowski. "Bortezomib Induces Rapid Upregulation of Topoisomerase IIα and Demonstrates Schedule-Dependent Synergistic Cytotoxicity with Anthracyclines and Etoposide in Acute Myeloid Leukemia and Myeloma Cell Lines." Blood 106, no. 11 (November 16, 2005): 2478. http://dx.doi.org/10.1182/blood.v106.11.2478.2478.
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Abstract The proteasome inhibitor bortezomib (BZ) has significant antineoplastic activity in multiple myeloma, lymphoma and acute leukemia. Recently, it has been shown that BZ can potentiate the activity of other antitumor agents in vitro. Topoisomerase IIα (topo IIα) is known to be regulated by proteasomal degradation, suggesting that proteasomal inhibition might increase intracellular topo IIα levels and thereby enhance sensitivity to topo IIα-targeted agents, including etoposide, daunorubicin and mitoxantrone. Incubation with sublethal concentrations of BZ led to rapid upregulation of topo IIα protein levels in the human TF-1 AML cell line, the human 8226 myeloma cell line and the 8226-derived, topo IIα-deficient, anthracycline-resistant Dox1V line (kindly provided by William S. Dalton), as measured by Western blot assay. Enhanced topo IIα expression was evident at 3 hrs, peaked at 6 hrs and fell off markedly 24 hrs after BZ addition. Maximal upregulation was 25–90 fold as measured by optical densitometry. BZ induced a shift in the apparent molecular weight of topo IIα, suggesting that upregulation resulted, at least in part, from the stabilization of the ubiquitinated form(s) of the enzyme following proteasomal inhibition. The kinetics of topo IIα upregulation inversely correlated with measured 20S proteasomal activity, further supporting a post-translational mechanism. Nuclear extracts prepared from BZ-treated cells showed a corresponding 36-fold increase in topo IIα enzymatic activity. The cytotoxicity of BZ in combination with other antineoplastic agents was evaluated by MTT assay. Synergistic cytotoxicity was observed for BZ plus mitoxantrone, etoposide or daunorubicin, but no significant augmentation was observed in this system for BZ plus cytarabine, melphalan, camptothecin, dexamethasone, vincristine or fludarabine. In TF-1 AML cells, sublethal doses of BZ reduced the IC50 for daunorubicin, mitoxantrone and etoposide 16-, 52- and 22-fold, respectively. In 8226 myeloma cells, BZ enhanced sensitivity to daunorubicin and etoposide 11- and 4-fold, respectively. Importantly, BZ treatment overcame chemoresistance in topo IIα-deficient Dox1V myeloma cells, enhancing the sensitivity to daunorubicin and etoposide 110- and 7- fold, respectively. The observed synergy was sequence-dependent and correlated with BZ-induced upregulation of topo IIα. Maximal synergy occurred within 3–6 hrs of BZ pretreatment and diminished after 24 hrs. Minimal synergy occurred when topo IIα-targeted agents preceded BZ by ≥ 6 hrs. These findings demonstrate that BZ has synergistic cytotoxic effects with topo IIα-targeted agents in AML and myeloma cell lines, which correlate with BZ-induced upregulation of topo IIα protein and nuclear enzymatic activity. Furthermore, these data provide a rationale for timed-sequential cytotoxic therapy in patients with hematologic malignancies.
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Mealey, Katrina L., Rola Barhoumi, Robert C. Burghardt, Stephen Safe, and Deborah T. Kochevar. "Doxycycline Induces Expression of P Glycoprotein in MCF-7 Breast Carcinoma Cells." Antimicrobial Agents and Chemotherapy 46, no. 3 (March 2002): 755–61. http://dx.doi.org/10.1128/aac.46.3.755-761.2002.
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ABSTRACT P-glycoprotein (P-gp) overexpression by tumor cells imparts resistance to multiple antineoplastic chemotherapeutic agents (multiple drug resistance). Treatment of tumor cells with chemotherapeutic agents such as anthracyclines, epipodophyllotoxins, and Vinca alkaloids results in induction of P-gp expression. This study was performed to determine if clinically relevant antimicrobial drugs (i.e., drugs that are used to treat bacterial infections in cancer patients) other than antineoplastic agents can induce expression of P-gp in MCF-7 breast carcinoma cells. Expression of P-gp and MDR1 mRNA was determined in samples from MCF-7 cells that were treated in culture with doxorubicin (positive control) and the antimicrobial drugs doxycycline, piperacillin, and cefoperazone. The functional status of P-gp was assessed using laser cytometry to determine intracellular doxorubicin concentrations. The MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) assay was used to determine if the cytotoxicity of experimental drugs was related to their ability to induce P-gp expression. MCF-7 cells treated with doxycycline (MCF-7/doxy) were stimulated to overexpress P-gp, whereas cells treated with piperacillin and cefoperazone did not overexpress P-gp. MCF-7/doxy cells were compared to a positive-control subline, MCF-7/Adr, previously selected for doxorubicin resistance, and to MCF-7 cells treated with doxorubicin (MCF-7/doxo). All three sublines overexpressed P-gp and MDR1 mRNA and accumulated less intracellular doxorubicin than did control MCF-7 cells. P-gp expression was induced only by experimental drugs that were cytotoxic (doxorubicin and doxycycline). Doxycycline, a drug that has been used for treatment of bacterial infections in cancer patients, can induce functional P-gp expression in cancer cells, resulting in multidrug resistance.
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Chan, Brandon Y. H., Andrej Roczkowsky, Nils Moser, Mathieu Poirier, Bryan G. Hughes, Ramses Ilarraza, and Richard Schulz. "Doxorubicin induces de novo expression of N-terminal-truncated matrix metalloproteinase-2 in cardiac myocytes." Canadian Journal of Physiology and Pharmacology 96, no. 12 (December 2018): 1238–45. http://dx.doi.org/10.1139/cjpp-2018-0275.
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Anthracyclines, such as doxorubicin, are commonly prescribed antineoplastic agents that cause irreversible cardiac injury. Doxorubicin cardiotoxicity is initiated by increased oxidative stress in cardiomyocytes. Oxidative stress enhances intracellular matrix metalloproteinase-2 (MMP-2) by direct activation of its full-length isoform and (or) de novo expression of an N-terminal-truncated isoform (NTT-MMP-2). As MMP-2 is localized to the sarcomere, we tested whether doxorubicin activates intracellular MMP-2 in neonatal rat ventricular myocytes (NRVM) and whether it thereby proteolyzes two of its identified sarcomeric targets, α-actinin and troponin I. Doxorubicin increased oxidative stress within 12 h as indicated by reduced aconitase activity. This was associated with a twofold increase in MMP-2 protein levels and threefold higher gelatinolytic activity. MMP inhibitors ARP-100 or ONO-4817 (1 μM) prevented doxorubicin-induced MMP-2 activation. Doxorubicin also increased the levels and activity of MMP-2 secreted into the conditioned media. Doxorubicin upregulated the mRNA expression of both full-length MMP-2 and NTT-MMP-2. α-Actinin levels remained unchanged, whereas doxorubicin downregulated troponin I in an MMP-independent manner. Doxorubicin induces oxidative stress and stimulates a robust increase in MMP-2 expression and activity in NRVM, including NTT-MMP-2. The sarcomeric proteins α-actinin and troponin I are, however, not targeted by MMP-2 under these conditions.
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Tkaczuk, Katherine H. Rak. "Ixabepilone as Monotherapy or in Combination with Capecitabine for the Treatment of Advanced Breast Cancer." Breast Cancer: Basic and Clinical Research 5 (January 2011): BCBCR.S5331. http://dx.doi.org/10.4137/bcbcr.s5331.
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Breast Cancer is the most prevalent cancer in the world with 4.4 million survivors up to 5 years following the diagnosis. 1 In the US alone approximately forty thousand women die annually of metastatic breast cancer (MBC). Despite many effective systemic treatment options approximately 50% of women with MBC succumb to the disease within 24 months of the diagnosis. 2 Ixabepilone is a novel, first in class member of the epothilone class of antineoplastic agents. Ixabepilone is indicated as monotherapy for the treatment of metastatic or locally advanced breast cancer in patients whose tumors are resistant or refractory to anthracyclines, taxanes, and Capecitabine. Ixabepilone is also indicated in combination with Capecitabine for the treatment of patients with metastatic or locally advanced breast cancer resistant to treatment with an anthracycline and a taxane, or whose cancer is taxane resistant and for whom further anthracycline therapy is contraindicated. Ixabepilone was extensively studied as a single agent in patients with MBC and was found to be effective and well tolerated with a predictable and manageable safety profile. Not surprisingly prior exposure to anthracyclines and taxanes affects significantly the potential for response to therapy with single agent Ixabepilone in metastatic setting. MBC patients with taxane resistant MBC have objective response rate (RR) of 12%, patients with prior low exposure to taxanes and/or resistance RR = 22%, Ixabepilone treatment after adjuvant anthracycline therapy exposure renders RR = 42% and in Taxane naïve patients RR = 57%. In two large phase III studies of Ixabepilone + Capecitabine versus Capecitabine alone, progression free survival (PFS) and overall response rates (RR) were higher in the combination treatment arms, but no survival advantage was seen overall. Treatment with Ixabepilone + Capecitabine in a phase II study resulted in an overall response rate (ORR) of 23% in ER/PR/HER2 negative, triple-negative breast cancer patients (TNBC) while ORR of 31% was seen in a preplanned pooled analysis of TNBC in the phase III trials of Ixabepilone + Capecitabine. Significantly prolonged median PFS was seen for TNBC treated with the combination of Ixabepilone + Capecitabine compared to Capecitabine alone 4.2 vs. 1.7 months respectively. Ixabepilone as single agent appears to show excellent antitumor activity in patients with TNBC MBC. Addition of Ixabepilone to Capecitabine results in approximately doubling in median PFS for TNBC versus Capecitabine alone. Single agent Ixabepilone is generally well tolerated, and its toxicity profile does not overlap with that of Capecitabine and therefore depending on prior exposure to chemotherapy both single agent Ixabepilone or in combination with Capecitabine can be used safely and effectively for treatment of advanced breast cancer.
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Błasiak, Janusz, Ewa Gloc, and Mariusz Warszawski. "A comparison of the in vitro genotoxicity of anticancer drugs idarubicin and mitoxantrone." Acta Biochimica Polonica 49, no. 1 (March 31, 2002): 145–55. http://dx.doi.org/10.18388/abp.2002_3831.
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Idarubicin is an anthracycline antibiotic used in cancer therapy. Mitoxantrone is an anthracycline analog with presumed better antineoplastic activity and lesser toxicity. Using the alkaline comet assaywe showed that the drugs at 0.01-10 microM induced DNA damage in normal human lymphocytes. The effect induced by idarubicin was more pronounced than by mitoxantrone (P < 0.001). The cells treated with mitoxantrone at 1 microM were able to repair damage to their DNA within a 30-min incubation, whereas the lymphocytes exposed to idarubicin needed 180 min. Since anthracyclines are known to produce free radicals, we checked whether reactive oxygen species might be involved in the observed DNA damage. Catalase, an enzyme inactivating hydrogen peroxide, decreased the extent of DNA damage induced by idarubicin, but did not affect the extent evoked by mitoxantrone. Lymphocytes exposed to the drugs and treated with endonuclease III or formamidopyrimidine-DNA glycosylase (Fpg), enzymes recognizing and nicking oxidized bases, displayed a higher level of DNA damage than the untreated ones. 3-Methyladenine-DNA glycosylase II (AlkA), an enzyme recognizing and nicking mainly methylated bases in DNA, increased the extent of DNA damage caused by idarubicin, but not that induced by mitoxantrone. Our results indicate that the induction of secondary malignancies should be taken into account as side effects of the two drugs. Direct strand breaks, oxidation and methylation of the DNA bases can underlie the DNA-damaging effect of idarubicin, whereas mitoxantrone can induce strand breaks and modification of the bases, including oxidation. The observed in normal lymphocytes much lesser genotoxicity of mitoxantrone compared to idarubicin should be taken into account in planning chemotherapeutic strategies.
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Schachter, Levanto, Irene M. Hutchins, Jill Waalen, Carol Burian, Darren Finlay, Kristiina Vuori, Giovanni Paternostro, et al. "Drug Sensitivity Across Acute Myeloid Leukemia Subtypes Using an in Vitro Assay." Blood 128, no. 22 (December 2, 2016): 5208. http://dx.doi.org/10.1182/blood.v128.22.5208.5208.
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Abstract Introduction: Acute myeloid leukemia (AML) remains a challenging malignancy to treat, with high mortality despite recent advances in cancer care. The mainstay of therapy is intensive chemotherapy including anthracyclines and antimetabolites, with or without allogeneic bone marrow transplant. The standard of care has not changed significantly in decades, and treatment options are limited for patients who do not respond to induction, or who relapse. Although the genetic and molecular diversity of AML is well recognized, the effective integration of targeted therapies into treatment regimens has been difficult. The current study evaluates the in vitro activity of an array of antineoplastic agents in AML, with the goal of identifying drug sensitivity patterns that may help guide therapies based on mutational and cytogenetic profiling. Methods: 51 patients with AML were enrolled in the study from September 2013 to July 2016 under an IRB approved consenting process at Scripps Health. Samples were collected at both diagnosis and relapse if available. Both bone marrow and peripheral blood were accepted, with a requirement of significant circulating blasts if peripheral blood was used. Samples were tested for common biomarkers and cytogenetic abnormalities. 2,500 cells per well were transferred onto tissue culture treated plates. Drugs with potential antileukemic activity were added to each well in concentrations of 0.1, 1.0, and 10.0 μM. The cells were incubated with the drugs for 96 hours at 37oC. Cell viability was measured and reported as a percentage of plate-specific controls incubated with dimethylsulfoxide alone. Results: Drugs were grouped by therapeutic class. In vitro responses to anthracyclines and antimetabolites were noted across all mutational subtypes of AML. BCL-2 inhibitors and the histone deacetylase inhibitor romidepsin showed significant in vitro antileukemic activity across all subtypes. Proteasome inhibitors almost universally showed robust in vitro activity, even at the lowest drug concentration. The drug pevonedistat, a selective small-molecule inhibitor of NEDD8-activating enzyme, had significant differential activity depending on mutational status. FLT3-ITD mutations conferred sensitivity to the molecule, while mutations in NPM1 appeared to confer resistance. For the 10.0 μM concentration of pevonedistat, the average cell viability was 149.8% vs 37.3% (P=0.02) for the NPM1 mutated samples vs the FLT3-ITD mutated samples respectively. Conclusion: This in vitro assay demonstrates the ability to rapidly determine sensitivity of human AML cells to a wide variety of antileukemic drugs. Limitations include the fixed concentrations used across all medications which allowed comparisons between patients, but limits comparison of drug efficacy for an individual patient. The mechanism of some medications, such as hypomethylating agents and tretinoin, may require longer duration of exposure, thus confounding interpretation of the 96-hour viability results. Despite these limitations, we were able to find interesting patterns of responses across a wide spectrum of AML types. Anticipated applications of the assay include experimentation with novel drug combinations, directing in vivo clinical studies, and informing individualized treatment decisions in AML. Disclosures No relevant conflicts of interest to declare.
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Paridaens, R., J. C. Heuson, J. P. Julien, C. Veyret, J. Van Zyl, J. G. Klijn, R. Sylvester, and F. Mignolet. "Assessment of estrogenic recruitment before chemotherapy in advanced breast cancer: a double-blind randomized study. European Organization for Research and Treatment of Cancer Breast Cancer Cooperative Group." Journal of Clinical Oncology 11, no. 9 (September 1993): 1723–28. http://dx.doi.org/10.1200/jco.1993.11.9.1723.
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PURPOSE In the present phase III study, the specific effect of estrogenic recruitment was assessed by comparing two groups of patients with advanced breast cancer receiving either ethinylestradiol (EE2) or placebo (PL) before chemotherapy (CT). PATIENTS AND METHODS The therapeutic regimen consisted of (1) estrogen suppression by aminoglutethimide (AGL) 1 g/d plus hydrocortisone (HC) 40 mg/d, with surgical castration performed on premenopausal patients; (2) fluorouracil (5-FU) 500 mg/m2, doxorubicin 50 mg/m2, and cyclophosphamide (CPA) 500 mg/m2 (FAC) intravenously (IV) every 3 weeks; (3) following randomization, patients were double-blinded to receive either PL or EE2 50 micrograms exactly 24 hours before receiving FAC. All patients had advanced breast cancer presumably sensitive to endocrine therapy (estrogen receptor-positive [ER+] and/or progesterone receptor-positive [PgR+] status) with measurable lesions; none had received prior systemic antineoplastic therapy for metastatic disease; prior adjuvant hormonal therapy (HT) or CT (without anthracyclines) was allowed if interval since completion was longer than 1 year. RESULTS Among 154 patients treated according to the protocol, tolerance, response rates, time to progression, and median survival duration were identical in the PL and EE2 groups. Only performance status, dominant metastatic site, and menopausal status seemed to influence response (overall response, 64%), with the highest levels of partial remission (PR) and complete remission (CR) being achieved in premenopausal women (CR plus PR, 26% plus 55%) and in those with dominant soft tissue lesions (CR plus PR, 45% plus 28%). CONCLUSION We conclude that the validity of the hormonal recruitment concept has not yet been established in clinical practice so that this approach remains experimental. The results achieved by combining (near) complete estrogenic suppression and cyclical FAC chemotherapy are not significantly different from those to be expected with the more conventional use of HT followed by CT in presumably hormone-responsive (ER+) patients.
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Treshalin, Michael I., and E. V. Neborak. "TOPOISOMERASES: FEATURES OF THE ACTION, CLASSIFICATION, CELL FUNCTIONS, INHIBITION, ANTHRAFURANDION." Russian Journal of Oncology 23, no. 2 (April 15, 2018): 60–70. http://dx.doi.org/10.18821/1028-9984-2018-23-2-60-70.
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Introduction. Topoisomerases influence on DNA topology and are capable of running down their super spiraling molecules by importation of one- or two-chained ruptures with the subsequent restitution and also the negative super rounds or catenae’s. Topoisomerases are known to be targets for antineoplastic therapy. Inhibitors of these enzymes of various nature and chemical structure are widely used for the suppression of tumor Topoisomerase I and/or II activity with the blocking cells in the phase G2 and a delay of their introduction in mitosis. Such difficult curable tumors as colorectal cancer, carcinoma of the stomach, non-small cell lung cancer and so forth are the most sensitive to these drugs. The search of perspective antineoplastic inhibitors is implemented generally in ranks of the non-camptothecin agents among which heterocyclic condensed nitrogenous compounds, in particular, anthrafurandiones show the most significant results. The review of thematic literature from 2011 to 2018 is devoted to the description of properties of topoisomerase as targets and their inhibitors from perspective classes. Objectives: 1. The analysis of signal characteristics of topoisomerases as targets for anticancer non-camptothecin inhibitors. 2. Identification of structure-activity relationship in the ranks of potential inhibitors of topoisomerases. 3. The choice of the most perspective non-camptothecin topoisomerase inhibitors among heterocyclic condensed nitrogenous compounds on the basis of the comparative analysis of structure and properties. Material and methods. Materials of 79 scientific articles published in the leading biological, biochemical and chemical journals of the different countries within the 8 last years are subjected to the analysis. The structure of the review meets the purpose and tasks of the scientific analysis. Results. The analysis of the thematic literature showed topoisomerases to be relevant targets for antineoplastic therapy of severe oncological pathology. In this regard, intensive search of various pharmaceuticals among topoisomerase inhibitors is performed in recent years. Researchers modify the known basic structures as well as synthesize new compounds. The discovery of a top-directional effect of the known medicines expands the data on their mechanism of the action. To identify the topoisomerase inhibitory activity of the drug the methods with the use of plasmid DNA is applied. The cytotoxic activity, apoptosis induction, including the caspases activation, modification of mitochondrial potential, influence on p53 and others are examined in parallel studies. The research directed on the identification of new effective non-camptothecin oral topoisomerase inhibitors among the anthracyclines derivatives are of undoubted relevance. Such agents, in contrast to Doxorubicin (anthracycline antibiotic widely used for tumor therapy), have moderate toxicity and allow to control the growth of solid tumors and leukemia in mono-therapy mode. Conclusion. In terms of searching of original antineoplastic agents, a class of heterocyclic condensed nitrogenous compounds, first of all, the anthraquinones showing properties of topoisomerase inhibitors is one of the most promising. The results of chemical and biological research of the compounds of this series were laid in a basis of the design of medicinal substances and their drug formulations. Prognostically significant data obtained in preclinical testing allow us to hope that obtained antitumor agents will be highly effective on a clinical stage of trials.
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Kampmann, Eric, Dominique Harnicek, Ana Sofia Cardoso Martins, Berina Eppink, Eike Gallmeier, Lars Lindner, Roland Kanaar, and Rolf D. Issels. "Heat-shock (H-S) and trabectedin efficacy in human soft-tissue sarcoma (STS) cells in vitro." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): e13540-e13540. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.e13540.
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e13540 Background: Regional hyperthermia improves response and survival when combined with chemotherapy in patients with high-risk STSs (Issels, R.D. Lancet Oncol 2010). Trabectedin is the first marine-derived antineoplastic drug approved in Europe for the treatment of advanced STS after failure of anthracyclines and ifosfamide, or for patients who are unsuited to receive these drugs. Trabectedin’s cytotoxicity is associated with the induction of lethal DNA double-strand breaks (DSB). The rationale to combine trabectedin with H-S is that heat-exposure sensitizes tumor cells by inhibiting the repair of induced DSBs (Krawczyk, P.M. PNAS 2011). Methods: Combinations of trabectedin and H-S at clinically relevant temperatures were examined in 3 different human cell lines: Osteosarcoma (U2Os), liposarcoma (SW872) and synovial sarcoma (SW982). Cells were treated with trabectedin at the dose of 500-4000 pM for 3 hours. H-S was applied in an incubator at 41.8°C and 43°C for 90 or 150 min before, during or after trabectedin incubation. Cytotoxicity was assessed measuring clonogenic survival of cells. Expression of BRCA2, which recruits homologous recombination repair recombinase Rad 51 to DSBs, was measured by Western Blot (WB). Recruitment of Rad 51 and the amount of gH2AX positive DSB-repair-foci were analysed by immunocytochemistry (ICC). Results: All cell lines showed reduced viability after increasing doses of trabectedin at 37°C. Combined treatment with trabectedin and H-S additionally enhanced cytotoxicity of trabectedin with strongest effects observed after simultaneous administration of both. WB-analysis showed strong heat-dependent reduction of BRCA2 expression. ICC revealed that recruitment of Rad 51 to DSBs was reduced after heat exposure at 41.8°C and abolished after exposure at 43°C. Accordingly, combined treatment significantly increased the amount of cells with severe DNA damage (>50 DSBs). Conclusions: Combined treatment with trabectedin and H-S in vitro resulted in significantly enhanced cytotoxicity that was accompanied by elevated DNA-damage in term of DSB-accumulation. The mechanisms of interaction between trabectedin and H-S concerning DNA repair are under investigation.
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Le Cesne, Axel, Isabelle Ray-Coquard, Florence Duffaud, Christine Chevreau, Nicolas Penel, Binh Bui, Sophie Piperno-Neumann, et al. "A large retrospective analysis of trabectedin in 885 patients with advanced soft tissue sarcoma." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): 10563. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.10563.
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10563 Background: Trabectedin (Yondelis) is the first marine-derived antineoplastic drug approved in Europe for the treatment of patients with recurrent ASTS or for patients unsuited to receive anthracyclines and ifosfamide. We retrospectively analyzed the RetrospectYon database with patients’ data treated with trabectedin between Jan 2008 - Dec 2011. Methods: Trabectedin was given at the approved dose of 1.5 mg/m2 as a 24-h infusion every 3 weeks. Patients who achieved partial response (PR) or stable disease (SD) after 6 cycles could receive maintaining trabectedin treatment. Uni- and multivariate analyses of prognostic factors were performed. Results: 885 patients (486 women) from 26 centers in France with ASTS with a median age of 54 years (range 12-84) were included. Most had leiomyosarcoma (36%), liposarcoma (18%) or synovial STS (11%). At baseline, performance status (PS) was 0 in 26%, 1 in 47% and >1 in 27% of patients. A median of 4 trabectedin cycles (range 1-28) was given as a 2nd (41%), 3rd (39%) or ≥4th (20% of patients) treatment line. Toxic death and unscheduled re-hospitalization occurred in 0.5% and 8% of patients, respectively.The objective response rate was 15% (6 complete and 127 PR), and SD rate was 45.5% (n=403). After a median follow-up of 22.6 months (range 0.03-51.2), the patients who received trabectedin as 2nd, 3rd or ≥4th line had the median PFS of 4.3, 4.2 and 3.4 months, respectively, and the median OS of 12.9, 12.3 and 9.5 months. Multivariate analysis identified liposarcoma, leiomyosarcoma, angiosarcoma, undifferentiated pleomorphic sarcoma (UPS) and trabectedin line as independent prognostic factors for PFS, and UPS, angiosarcoma, rhabdomyosarcoma, gender, PS and trabectedin line for OS. After 6 cycles, 205 of the 273 patients with non-progressive disease received trabectedin as maintenance treatment and obtained a superior PFS (median 11 vs. 7.2 months, p=0.0001) and OS (median 25.1 vs. 16.9 months, p<0.0001) that those who stopped trabectedin after 6 cycles. Conclusions: Patients with ASTS treated with trabectedin had PFS and OS comparable or better to those observed in phase II/III trials. Trabectedin maintenance beyond 6 cycles is associated with improved OS and warrants further exploration.
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Martinez-Trufero, Javier, Isabel Pajares, Alba Hernandez Garcia, Ana Cebollero, Lourdes Calera, and Antonio Anton. "Efficacy of trabectedin for advanced soft tissue sarcoma (ASTS): A retrospective single center analysis." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): e21509-e21509. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.e21509.
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e21509 Background: Trabectedin (Yondelis) is the first marine-derived antineoplastic drug approved in Europe for the treatment of patients with recurrent ASTS or for patients unsuited to receive anthracyclines and ifosfamide. We retrospectively analyzed patients with ASTS treated with trabectedin from Nov. 2006 to April 2012. Methods: Trabectedin was given at the approved dose of 1.5 mg/m2as a 24-h infusion every 3 weeks. An analysis of response rate, time to progression (TTP) and overall survival (OS) and univariate analyses of prognostic factors were performed. Results: Overall,39 patients (24 men) with mostly high-grade (n=29) ASTS with a median age of 57 years (range 20-81) were analyzed. Most had L-type STS (leiomyosarcoma n=10; liposarcoma n=3), undifferentiated pleomorphic sarcoma (n=11), sarcoma NOS (n=5), or synovial STS (n=2). Eight had one of 6 very rare STS. At baseline patients had metastatic (n=21), bulky (n=4) or metastatic/bulky (n=14) disease and were pretreated with a median of 2 prior chemotherapy lines (range: 0-3; 4 patients received adjuvant chemotherapy only), including anthracycline-based chemotherapy (n=30), gemcitabine plus dacarbazine (GEM-DTIC; n=18), other (n=20). Patients received a median of 4 trabectedin cycles (range 1-34). Among 37 evaluable patients best responses as per RECIST were partial response (PR, n=7), stable disease (SD >3 months, n=9, 5 had SD >6 months) and disease progression (n=19), and 5 patients had a decrease in tumor density. Responses to trabectedin and GEM-DTIC did not exclude responses to the other regimen suggesting the feasibility of sequential treatment. After a median follow-up of 9.37 months, median TTP and OS were 4.4 months (95% CI: 3.5-5.4) and 9.7 months (95% CI: 4.5-14.9), respectively. Univariate analyses identified low/medium-grade STS and growth modulation index >1.13 as favorable prognostic factors for TTP, and retroperitoneal/visceral localization, L-type and rare STS and low/medium-grade STS for OS. Conclusions: The results of this real-life retrospective analysis confirmed the findings of previous trials showing that trabectedin is active drug for ASTS.
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Ocadlikova, Darina, Clara Iannarone, Anna Rita Redavid, Michele Cavo, and Antonio Curti. "A Screening of Antineoplastic Drugs for Acute Myeloid Leukemia Reveals That Fludarabine Has Weak Immunogenic Capacity and Induces T Regulatory Cells." Blood 136, Supplement 1 (November 5, 2020): 5. http://dx.doi.org/10.1182/blood-2020-137455.
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INTRODUCTION: Recent evidence demonstrated that the treatment of acute myeloid leukemia (AML) cells with Daunorubicin (DNR) but not Cytarabine (Ara-C), results in efficient activation of anti-leukemia T cells. This process, named as immunogenic cell death (ICD), is characterized by some specific events. In the clinical setting, chemotherapy including anthracyclines and Ara-C remains a gold standard for AML treatment. However, the probability of relapse remains elevated, particularly in elderly or prognostically "high risk" patients In the last decade, Etoposide (Eto) and Fludarabine (Flu) have been added to the standard treatment for AML to potentiate its therapeutic effect, and tested in many trials. Regarding the immunogenicity of these two drugs, too few studies are reported in recent literature, and even fewer regarding AML. We therefore studied the immunogenic potential of Eto and Flu as compared to DNR and Ara-C. METHODS: AML cell lines HL-60 and KG-1, and primary AML cells were treated with all four drugs. Calreticulin and heat shock proteins 70/90 translocation, non-histone chromatin-binding protein high mobility group box 1 and adenosine triphosphate release were evaluated. The treated cells were then pulsed into dendritic cells and used forin vitroimmunological tests, in particular for T-cell proliferation and T regulatory cells (Tregs) induction. RESULTS: Collectively, our data indicate that, among the drugs that have been proposed to increase the efficacy of the conventional chemotherapy backbone including DNR and Ara-C, Eto has a similar and comparable capacity to DNR in inducing both early and late ICD events. On the contrary, Flu has a low if any effect, proving similar to Ara-C. Moreover, Eto treatment was the most powerful among the tested drugs in stimulating T-cell proliferation, thus suggesting a significant capacity to activate the immune response. On the contrary, Flu had weak immunogenic potential and can be considered a non-immunogenic chemotherapy drug. Interestingly, Flu was significantly more potent in inducing suppressive T regulatory cells compared to other drugs. CONCLUSIONS: Taken together, the present investigation expands the knowledge on the immunogenic and tolerogenic potential of the chemotherapy drugs commonly used in the therapy of AML. Among these, important differences have been observed, indicating that, particularly in an era when immunotherapy is being included in the clinical stage of AML treatment, the immunological perspective of chemotherapy should be taken into consideration in therapy decision-making. This research was funded by AIRC (Associazione Italiana per la Ricerca sul Cancro) 2017 IG20654. Bologna AIL (Associazione Italiana contro le Leucemie)/ Bologna Section. FATRO/Foundation Corrado and Bruno Maria Zaini-Bologna. Disclosures Cavo: Sanofi:Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Janssen:Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel accomodations, Speakers Bureau;GlaxoSmithKline:Honoraria, Speakers Bureau;Karyopharm:Honoraria;Novartis:Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Celgene:Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel accomodations, Speakers Bureau;AbbVie:Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees;BMS:Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Amgen:Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.
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Paulenka, Yuliya, Maritza Cotto, Christine Rickette, and Krystal Hunter. "Latent atherosclerosis as a risk factor in chemotherapy-induced cardiomyopathy." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): e12525-e12525. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.e12525.
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e12525 Background: Anthracyclines and monoclonal antibodies targeting HER2/neu receptors are widely used antineoplastic agents in breast cancer treatment. Both therapies have been known to cause cardiovascular adverse effects, notably chemotherapy-induced congestive heart failure, especially if used in combination. Multiple factors have been postulated to increase the risk of doxorubicin and trastuzumab-associated cardiotoxicity, including a pre-existing coronary artery disease, but the role of latent atherosclerosis has not been widely studied. Methods: We retrospectively reviewed health records of female breast cancer patients at our institution treated with doxorubicin or trastuzumab between 2012 and 2017. Using echocardiography, we identified patients with underlying atherosclerotic lesions at the start of the treatment and those who subsequently developed cardiotoxicity. Chemotherapy-induced cardiomyopathy was defined as a drop in the ejection fraction (EF) to < 50% from the normal EF of > 53% pre-therapy. We used a χ2 test to search for the relationship between atherosclerosis and subsequent cardiotoxicity. Results: A total of 518 patient records were reviewed. Of 518 patients with breast cancer, 93 (18%) received doxorubicin or trastuzumab-based chemotherapy. The median age for breast cancer diagnosis was 58. Sixty-one patients (66%) were identified to have atherosclerosis on echocardiography at the time of the first chemotherapy cycle. The most common location for atherosclerotic lesions was in the aortic arch and proximal upper abdominal aorta. Of 61 patients with atherosclerosis, ten (16.4%) subsequently developed chemotherapy-induced cardiomyopathy (p = 0.77). A post hoc analysis was performed to compare the two cohorts aged 40 to 50 (p = 0.49) and 51 to 75 (p = 1.00) as they represented the majority of breast cancer cases. Conclusions: The role of atherosclerosis in doxorubicin and trastuzumab-induced toxicity remains unclear. We did not observe any statistical correlation between atherosclerosis at the start of chemotherapy and increased rates of cardiac injury. A younger population may be more susceptible to cardiotoxicity, but further research is needed as the study has limitations. Although we identified patients with latent atherosclerosis, additional evaluation via carotid artery intima-media thickness measurements would yield more precision. Other methods such as the use of computed tomography and coronary artery calcium scores would also allow for assessing atherosclerotic plaque burden. Still, not all patients were subjected to these techniques. Furthermore, the study was challenged by the small sample size and its retrospective nature. Larger prospective studies are essential to explore this area further. Identifying the means of reducing cardiovascular complications remains a priority as heart disease is currently the leading cause of death among breast cancer survivors.
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Creutzig, Ursula, Martin Zimmermann, Gertjan Kaspers, and Dirk Reinhardt. "Liposomal Daunorubicin Causes Only Low Cardiotoxicity in Pediatric AML Patients." Blood 112, no. 11 (November 16, 2008): 1940. http://dx.doi.org/10.1182/blood.v112.11.1940.1940.
Full textAbstract:
Abstract Anthracyclines are effective and important antineoplastic drugs in the treatment of acute myelogenous leukemia (AML). However, their use is limited by their cardiomyopathic effect, which occurs in children already at cumulative doses of 300 mg/m2 (given as daunorubicin [DNR] dosages). A clear correlation between acute cardiotoxicity and late cardiomyopathy has been shown. Liposomal daunorubicin (DaunoXome™, L-DNR) is a modified formulation of DNR with a unilamellar liposomal transport system. Several preclinical data show that L-DNR has less cardiotoxic effects than free DNR (Forssen, 1994) Therapy: L-DNR was used during induction in the relapse study AML-BFM 97 (3x60mg/m2, 1-hour infusion, combined with cytarabine), in the ongoing international study Relapsed AML 2001/01 (3x60mg/m2, 1-hour infusion, combined with fludarabine, cytarabine, G-CSF) and in the ongoing study AML-BFM 2004 (3x80mg/m2, 2-hour infusion, combined with cytarabine, etoposide). All included patients were <18 years. Method: To evaluate anthracycline-associated cardiomyopathy, the incidence of early and late (</>1 year after intensive AML chemotherapy) subclinical (NCI criteria grade I–II) and clinical (grade III–V) cardiotoxicity was analyzed (late cardiotoxicity only in study relapse AML-BFM 97). Cumulative anthracycline doses were in the range of 600mg/m2 for relapse patients [calculated as equivalence dose to DNR using a dose ratio of 1:5 for idarubicin and mitoxantrone; this ratio was the preferred dosage of the AML Collaborative Group (AML Collaborative Group, BJH 1998) and represents proven equivalent doses concerning toxicity (Creutzig, 2001)]. Results: Early cardiotoxicity: Relapse study AML-BFM 97 (n = 69): No subclinical or clinical cardiotoxicity was reported after induction. International study Relapsed AML 2001/01 (AML-BFM patients only): 85 patients were treated with L-DNR; early subclinical cardiotoxicity was reported in 6 patients, clinical cardiotoxicity with reduced cardiac function and/or arrhythmia (grade III) occurred in 3 patients (3.5%) after induction. AML-BFM 2004: Early subclinical cardiotoxicity of grade 1 was seen in 8 L-DNR and in 6 idarubicin patients and reduced cardiac function or arrhythmia (grade III/IV) in 2 out of 124 L-DNR patients (1.6%) compared to 5 of 135 (3.7%) patients treated with idarubicin after induction (pFisher 0.44). All patients with early clinical cardiotoxicity suffered concurrently from grade II–IV infections. Late cardiotoxicity: Study relapse AML-BFM 97: One of 13 longterm survivors (median 9 years) presented with clinical cardiomyopathy after relapse (persistent decreased shortening fraction [SF] of <28% after a cumulative anthracycline dose of 490mg/m2, but SF normalized within 14 months. When comparing early clinical cardiotoxicity after induction with L-DNR (3x80mg/m2) to that seen after DNR (3x60mg/m2) or idarubicin in the AML BFM93/98 studies (n=885 patients), the incidence rate was low (both 1.6%). Furthermore, early clinical cardiotoxicity seen after relapse treatment was low despite high cumulative anthracycline doses. Conclusion: Preliminary data on L-DNR during induction in de novo and relapsed AML patients do not show significant early clinical cardiotoxicity. As early cardiotoxicity is a risk factor for the occurrence of late cardiotoxicity, our results may indicate also a lower risk for late cardiomyopathy after administration of L-DNR.