Doxorubicin Monotherapy Research Articles

Olaratumab: A New Strategy in the Treatment of Advanced Soft-Tissue Sarcoma

Olaratumab is a monoclonal antibody that recently received accelerated approval for the treatment of advanced soft-tissue sarcomas in combination with doxorubicin for a histologic subtype in which anthracycline-containing regimens is appropriate and disease is not amenable to curative surgery or radiotherapy. It inhibits platelet-derived growth factor receptor alpha, leading to the inhibition of tumor cell proliferation, angiogenesis, and metastasis. In a phase II clinical trial, olaratumab in combination with doxorubicin met its predefined primary endpoint of improving progression-free survival and secondary endpoint of overall survival compared to doxorubicin monotherapy in patients with advanced soft-tissue sarcoma. Common adverse events associated with the combination of olaratumab and doxorubicin include nausea, mucositis, neutropenia, and infusion-related reactions.

Developments in the management of advanced soft-tissue sarcoma - olaratumab in context.

Lartruvo® (olaratumab) is a fully human immunoglobulin G subclass 1 (IgG1) monoclonal antibody that inhibits platelet-derived growth factor receptor alpha (PDGFRα). The antitumor activity of olaratumab has been tested in vitro and in vivo, and inhibition of tumor growth has been observed in cancer cell lines, including glioblastoma and leiomyosarcoma cells. It represents the first-in-class antibody to be approved by regulatory authorities for the treatment of advanced soft-tissue sarcomas (STSs) in combination with doxorubicin, based on the results of the Phase Ib/II trial by Tap et al. The median progression-free survival (PFS), which was the primary end point of the study, was improved for patients treated with olaratumab plus doxorubicin compared to those treated with doxorubicin monotherapy (6.6 vs 4.1 months, respectively; HR 0.672, 95% CI 0.442–1.021, p=0.0615). Moreover, final analysis of overall survival (OS) showed a median OS of 26.5 months with olaratumab plus doxorubicin vs 14.7 months with doxorubicin, with a gain of 11.8 months (HR 0.46, 95% CI 0.30–0.71, p=0.0003). In October 2016, olaratumab was admitted in the Accelerated Approval Program by the US Food and Drug Administration (FDA) for use in combination with doxorubicin for the treatment of adult patients with STSs. In November 2016, the European Medicines Agency (EMA) granted conditional approval for olaratumab in the same indication under its Accelerated Assessment Program. A double-blind, placebo-controlled, randomized Phase III study (ANNOUNCE trial, NCT02451943) is being performed in order to confirm the survival advantage of olaratumab and to provide definitive drug confirmation by regulators. The study is ongoing, but enrollment is closed. The purpose of this review was to evaluate the rationale of olaratumab in the treatment of advanced STSs and its emerging role in clinical practice.

Outcome for Advanced or Metastatic Soft Tissue Sarcoma of Nonextremities Treated with Doxorubicin-Based Chemotherapy: A Retrospective Study from a Single Cancer Institution.

Background Doxorubicin is the key drug for treatment of advanced soft tissue sarcoma (STS). The appropriate dosage of doxorubicin, regarding monotherapy or the role of combination therapy, is unclear. Methods We retrospectively reviewed patients with advanced or metastatic STS of nonextremities who were treated with doxorubicin-based chemotherapies in our institution. Time to treatment failure (TTF), overall survival (OS), overall response, and prognostic factors for OS were evaluated. Results Seventy-five patients were enrolled. The median TTF was 4.7 months, and the median OS was 20.1 months. The overall response rate was 20%. Doses of doxorubicin monotherapy did not show significant difference either in TTF or in OS. There were no significant differences in OS between combination therapy and monotherapy, but the TTF with combination therapy was better than monotherapy. The overall response for combination therapy indicated a better response rate. Less number of involved organs, no bulky mass, and a normal CRP level were independent favorable prognostic factors for OS. Conclusions Combination therapy showed better response and TTF than monotherapy but did not show better OS. Possible prognostic factors for OS were indicated. This retrospective study was approved by the institutional review board. This trial is registered with UMIN000028787.

Suppression of p53R2 gene expression with specific siRNA sensitizes HepG2 cells to doxorubicin

Introductionp53R2 is a p53-inducible protein that contributes to DNA repair by providing dNTPs in response to DNA damage. The roles of p53R2 in cancer cells and malignancies still remain controversial. Herein, we examined the effects of p53R2 silencing on HepG2 human hepatocellular carcinoma (HHC) cell line (wild-type p53) viability, apoptosis and cell cycle arrest in the presence and absence of doxorubicin. MethodsCell transfection was performed using a liposomal approach. Gene silencing was determined by quantitative real-time PCR and western blot analysis. To evaluate the cell growth rate after transfection, trypan blue dye exclusion assay was employed. The cytotoxicity of the doxorubicin and p53R2 siRNA as single agents or in combination against HepG2 cell was analyzed by MTT assay and the drug combination effects was evaluated by calculating the combination index. The effects of treatments on different stages of cell cycle were analyzed by flow cytometry using propidium iodide (PI) and induction of apoptosis was assessed using DNA-histone ELISA. ResultsWe found that silencing of p53R2 alone had a strong effect on growth inhibition and spontaneous apoptosis in HepG2 cells. p53R2 siRNA synergistically enhanced the cytotoxic effect of doxorubicin. Furthermore, when used in combination with doxorubicin (0.4μM), a significant increase in the rate of apoptosis was observed (P<0.05). Moreover, cell cycle at S and G2/M phases progressed at a lower rate after p53R2 combination treatment compared with doxorubicin mono-therapy. ConclusionThese findings suggest that siRNA-mediated silencing of p53R2 has great potential as a therapeutic tool and adjuvant in chemotherapy.

SY9-2 - Treatment strategy for advanced soft tissue sarcoma

Soft tissue sarcoma (STS) is a rare tumor with more than 50 histologic subtypes. Many types of STS are not sensitive to chemotherapy, so patients with advanced diseases have poor prognosis. Development of novel anticancer therapy is in urgent need. Doxorubicin monotherapy is currently the standard first line treatment of advanced STS, but there is no standard for second line therapy. Recently, three new drugs: pazopanib, trabectedin, and eribulin have been approved for the second line treatment of patients with advanced STS, but the best treatment sequence of those drugs are not known. Sensitivity of STS to each drug seems to vary by histologic subtypes. For instance, liposarcoma seems be more sensitive to eribulin and less sensitive to pazopanib. Translocation related sarcoma (TRS) such as myxoid liposarcoma seems to be sensitive to trabectedin. Furthermore, these drugs have different safety profiles, so subtypes and patient characteristics must be considered for treatment selection. Development of specific molecular target therapy for each type of STS is necessary. There are specific chromosome translocations in 20-30% of STS, but their products are mostly transcriptional factors, and target therapy for those factors are difficult to develop. Trabectedin inhibits function of transcriptional factors, and shows higher efficacy for TRS. As molecular target therapies for gene mutations, success in molecular target therapy for c-kit and PDGFR mutation in gastrointestinal stromal tumor was followed by efficacy for rare sarcomas such as inflammatory myofibroblastic tumor or dermatofibrosarcoma protuberans, but there are few developments in other sarcomas. STS are associated with angiogenesis to a greater or lesser extent, so angiogenesis inhibitors such as pazopanib show good efficacy in some subtypes. Immune checkpoint inhibitors also have been developed for STS and show some efficacy in subtypes such as undifferentiated pleomorphic sarcoma.

A retrospective cohort study to assess adjuvant concurrent chemoradiation (CCRT) compared to adjuvant radiation therapy (RT) in the treatment of grade 2 and 3 extremity soft tissue sarcomas

PurposeTo evaluate the efficacy and tolerance of adjuvant concurrent chemoradiation (CCRT) as treatment of grade 2 and 3 (G2-3) localized extremity soft tissue sarcomas (STS) by comparing CCRT with standard adjuvant radiation therapy (RT). Patients and methodsThis monocentric retrospective study included non-pediatric patients (>16years) treated by adjuvant RT with or without chemotherapy (CT) after conservative resection of non-recurrent G2-3 extremity STS. ResultsA total of 80 patients were treated between 1990 and 2012: 51 by RT and 29 by CCRT. Of the 29 CCRT patients, 25 received doxorubicin monotherapy (75mg/m2/3weeks). The CCRT group contained a greater proportion of grade 3 extremity STS (p<0.001). Median follow up was 68months (9–284). Multivariate analysis revealed greater local control in the CCRT group (1 local recurrence vs 8 in the RT group; HR=0.082, 95% CI 0.011–0.321) and incomplete resection as the major risk factor of local recurrence (HR=25.2, 95% CI 4.767–133.226). The two groups exhibited no differences in distant failure-free survival (HR=1.469, 95% CI 0.668–3.228), disease-free survival (HR=1.096, 95% CI 0.519–2.315) or overall survival (HR=1.378, 95% CI 0.498–3.814). Grade 3 was an adverse prognostic factor for overall survival (HR=3.11, 95% CI 1.04–9.32). Our analyses also revealed that CCRT tended to increase the risk of both grade ≥3 acute dermatitis (14 events vs 6 in the RT group; OR=6.99, 95% CI 2.28–21.47) and grade ≥2 late toxicity (6 events vs 3 in the RT group; p=0.0572). ConclusionCCRT could improve local control as part of a limb-preservation strategy. However, with a limited number of patients, CCRT showed no improvement in either distant control or survival and increased toxicity.

Olaratumab: A Novel Platelet-Derived Growth Factor Receptor α-Inhibitor for Advanced Soft Tissue Sarcoma.

To review and summarize data on olaratumab, which was approved by the US Food and Drug Administration (FDA) in October 2016, in combination with doxorubicin, for the treatment of advanced soft tissue sarcoma. A literature search using PubMed was conducted using the search terms olaratumab, IMC-3G3, and advanced soft tissue sarcoma from January 2005 to June 2017. The literature search was confined to human studies published in English. Trials of olaratumab for advanced soft tissue sarcomas were prioritized. Olaratumab is a human antiplatelet-derived growth factor receptor α monoclonal antibody. Its accelerated FDA approval was based on a phase II randomized trial of olaratumab plus doxorubicin (n = 66) versus doxorubicin monotherapy (n = 67) in patients with advanced soft tissue sarcoma. Olaratumab 15 mg/kg was administered intravenously (IV) on days 1 and 8 in combination with doxorubicin 75 mg/m2 IV on day 1 every 21 days for a total of 8 cycles compared to doxorubicin 75 mg/m2 IV monotherapy. The response rate was 18.2% with combination therapy versus 11.9% with monotherapy and median progression-free survival of 6.6 and 4.1 months, respectively. Additionally, overall survival was increased by 11.8 months in the olaratumab arm (26.5 months vs 14.7 months). Clinically relevant adverse effects in the olaratumab + doxorubicin arm included neutropenia (58%), mucositis (53%), nausea (73%), vomiting (45%), and diarrhea (34%). Olaratumab, in combination with doxorubicin, represents a novel treatment strategy for advanced soft tissue sarcoma and provides a significant survival advantage for this rare disease state with limited treatment options.

Systemic Therapy for Soft Tissue Sarcoma: Proposals for the Optimal Use of Pazopanib, Trabectedin, and Eribulin

Soft tissue sarcoma (STS) is a rare tumor with more than 50 histologic subtypes. Although treatment outcomes for patients with STS have improved greatly over the past few decades owing to the adoption of a multidisciplinary approach, patients with advanced disease have a poor prognosis. The development of anticancer drugs has been directed toward improving overall survival (OS). Doxorubicin monotherapy is currently the only standard option for the first-line treatment of STS. However, there is no standard therapy for second-line and later treatment at present. Since 2012, three anticancer drugs—pazopanib, trabectedin, and eribulin—have been approved in Japan for the second-line or later treatment of patients with advanced STS of any histologic subtype. However, the chemosensitivity of STS to each of these drugs varies by histologic subtype and their safety profiles differ; thus, histologic subtype and patient characteristics must be considered when determining optimal treatment. In this article, we review data from clinical studies related to the efficacy of all three drugs, including their effect on OS, and propose optimal treatment strategies for advanced STS by histologic subtype. In addition, with regard to the safety profiles, we highlight the key issues to be considered when selecting patients for treatment with pazopanib, trabectedin, or eribulin and ensuring their appropriate use, based on our combined clinical experience as specialists in the treatment of patients with STS. The proposed treatment strategies as well as treatment precautions based on clinical experience would benefit patients by maximizing the therapeutic effects and enhancing the proper use of these drugs. Funding: Eisai Co., Ltd.

The most prevalent side effects of pegylated liposomal doxorubicin monotherapy in women with metastatic breast cancer: a systematic review of clinical trials.

Despite benefits of systemic chemotherapy in breast cancer treatment, several patients with early-stage breast cancer will develop metastatic breast cancer (MBC). Doxorubicin is among the most active agents against MBC. However, the use of doxorubicin is related to some life-threatening side effects including cardiotoxicity. Many efforts were made to lessen the side effects of doxorubicin and improve its efficacy. Pegylated liposomal doxorubicin (PLD) is a product claimed to achieve these two objectives because of its different pharmacokinetic profile. The aim of this study was to determine the side-effect profile of PLD in MBC through a systematic review of phase II clinical trials. A literature search in PubMed-MEDLINE was performed using terms covering nano-based pharmaceutical systems, 'breast cancer' and 'doxorubicin'. Articles were evaluated according to the inclusion criteria. Reported hematological and non-hematological side effects were categorized. Out of 718 articles that were initially identified, 8 were in accordance with the inclusion criteria. We found that the most important side effects of PLD were skin toxicity and mucositis, but the proportion of patients who showed grade III and IV of these side effects was relatively low. On the other hand, the occurrence of cardiotoxicity, the most important problem with doxorubicin, was considerably reduced in patients treated with PLD. Although PLD has demonstrated a lower toxicity profile than conventional anthracyclines, it has also new side effects. However, it seems that the reduced cardiotoxicity of PLD has made it a more appropriate option in patients with MBC, especially in those with risk factors for cardiac diseases.

The efficacy and safety of pegylated liposomal doxorubicin monotherapy and combination therapy with carboplatin in Korean patients with recurrent ovarian, fallopian tube, or primary peritoneal cancer: a single-institution experience

ObjectiveThis study aimed to evaluate the efficacy and safety of pegylated liposomal doxorubicin (PLD) with or without carboplatin in Korean patients with recurrent ovarian cancer (ROC), fallopian tube, or primary peritoneal cancer.MethodsThis retrospective study included 52 patients with ROC, fallopian tube, or primary peritoneal cancer who received PLD (50 mg/m2) between 1st December 2014 and 31th July 2016.ResultsThe mean number of chemotherapy cycles was 3.8 (range, 2 to 9) in the PLD monotherapy group and 7 (range, 2 to 13) in the PLD combined with carboplatin (PLD-C) group. In overall response rates and clinical beneficial rates, PLD monotherapy group shows 5.0% and 17.5%, and PLD-C group shows 33.3% and 75.0%. The mean progression-free survival (PFS) was 5 and 13 months in the PLD monotherapy and PLD-C groups, respectively. At 6 months after treatment initiation, absence of disease progression was confirmed in 6 (15%) and 10 (83.3%) patients in the PLD monotherapy and PLD-C groups. Hematological adverse events (e.g., neutropenia and thrombocytopenia) were more common in the PLD-C group (P<0.001, P=0.004). The incidence of anemia and non-hematological adverse events, including mucositis, hand-foot syndrome, and allergic reactions, was similar in both groups.ConclusionThis study demonstrated the efficacy and safety of PLD monotherapy and PLD-C combination in Korean patients with ROC. This study would be helpful to consider the degree of worry about side effects and treatment expectations after treatment. Further retrospective studies with larger samples are required to confirm the efficacy of PLD monotherapy in Asian patients with platinum-resistant ROC.

Mono- and Combined Therapy of Metastasizing Breast Carcinoma 4T1 with Zoledronic Acid and Doxorubicin.

The efficiency of monotherapy with zoledronic acid (Resorba), doxorubicin, and their combination was studied on the model of metastasizing breast carcinoma in BALB/c mice. Doxorubicin monotherapy was accompanied by a significant increase in median survival up to 57 days (vs. 34 and 35 days in control groups); 27% animals survived for 90 days (duration of the study). Bioluminescence area of the primary tumor significantly decreased on days 21 and 28; the total number of visceral metastases also decreased according to magnetic-resonance imaging data. Resorba monotherapy produced no general toxic effect, the median survival increased to 64 days, and 90-day survival was 33%. Imaging techniques (magnetic-resonance imaging, microtomography, bioluminescent analysis) showed that Resorba delayed the development of the primary tumor (regression of luminescence area on days 21 and 28, regression of standardized bioluminescence intensity on day 28) and significantly reduced the number of visceral metastases in comparison with the control. Combination therapy was less effective than monotherapy with the same medications. Median survival was 55 days, 90-day survival was 13%, but magnetic-resonance imaging and bioluminescence analysis after combination therapy also showed delayed growth of the primary tumor and reduced number of visceral metastases. Microtomography revealed bone metastases in ~30% animals of the control group; in experimental groups, no bone metastases were found. The experiment with periosteal (distal epiphysis of the femur) injection of 4T1-Luc2 tumor cells demonstrated pronounced selective effectiveness of Resorba in relation to bone metastases. Monotherapy with Resorba can prevent the development of not only bone, but also visceral metastases of breast cancer.

Abstract 4037: Enhancement of efferocytosis by rhoA kinase inhibitor following doxorubicin treatment synergistically reduces tumor growth

Abstract Massive dying of tumor cells after chemotherapy may promote chronic inflammation which favors tumor growth by uncleared secondary necrotic cells. Given that defects in apoptotic cell clearance have been linked with various inflammatory diseases and autoimmunity, the prompt removal of apoptotic cells by phagocytes is important for anti-tumor immunity. To improve the anti-tumor effect of doxorubicin, we investigated the role of RhoA-kinase (ROCK) inhibitors on efferocytosis by macrophages, which is important for anti-tumor immunity and tissue regeneration. Treatment of bone marrow-derived macrophages (BMDMs) with ROCK inhibitor increased efferocytosis of dying tumor cells by doxorubicin in vitro. ROCK-blockade after doxorubicin treatment group showed effective inhibition of tumor growth and also T cell-mediated elimination of immunogenic tumors more than the doxorubicin monotherapy group in established tumor models. Furthermore, we also confirmed that macrophage depletion abrogated the therapeutic effect of ROCK inhibitor after doxorubicin treatment on tumor growth. Taken together, our findings indicate that ROCK inhibitor following doxorubicin treatment reduced tumor growth via efferocytosis enhancement. Citation Format: Gihoon Nam, In-San Kim. Enhancement of efferocytosis by rhoA kinase inhibitor following doxorubicin treatment synergistically reduces tumor growth. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4037.

EL2 - Standards of care for Soft Tissue Sarcoma

The mainstay of care for unresectable, metastatic, and relapsed sarcoma is chemotherapy, and the principle treatment aims are disease palliation and control. Historically, all soft tissue sarcoma (STS) subtypes have been treated similarly, because of the lack of information about the outcome differences for conventional chemotherapy. The treatment strategies for sarcomas need to be adapted considering the histological subtype and tumor characteristics. However the rarity of STS makes it difficult to develop personalized treatment for advanced STS based on the phenotype or genotype.Doxorubicin is the most frequently used agent in first-line treatment of metastatic STS, and results in response rates of 10–20%. Multiple phase III clinical trials of doxorubicin-containing chemotherapy have been conducted in study groups in the US and Europe, but no treatment has shown superior activity considering the survival benefit compared to doxorubicin monotherapy. The combination of doxorubicin and ifosfamide is used as one of the options for situations in which tumor shrinkage is required, such as symptom palliation or when a critical structure is threatened.Currently, the clinical development of targeted therapy for STS has been initiated. For STSs, the multi-targeted TKI pazopanib, which has activity against VEGFR 1–3, PDGFRA and PDGFRB, and KIT, was approved in Japan 3 years ago. Potential drug targets in STS have been reported, such as the ALK fusion gene in inflammatory myofibroblastic tumors, activation of PDGFRB in dermatofibrosarcoma protuberans, and amplification of MDM2 and CDK4 in well-differentiated and de-differentiated liposarcoma. Other targets have also been reported, and the clinical utility of targeted therapy for specific histological subtypes harboring such target genes has been indicated in some cases. Thus, histology- or target-based therapies for advanced STS are expected to be introduced in clinical practice in the future. The mainstay of care for unresectable, metastatic, and relapsed sarcoma is chemotherapy, and the principle treatment aims are disease palliation and control. Historically, all soft tissue sarcoma (STS) subtypes have been treated similarly, because of the lack of information about the outcome differences for conventional chemotherapy. The treatment strategies for sarcomas need to be adapted considering the histological subtype and tumor characteristics. However the rarity of STS makes it difficult to develop personalized treatment for advanced STS based on the phenotype or genotype. Doxorubicin is the most frequently used agent in first-line treatment of metastatic STS, and results in response rates of 10–20%. Multiple phase III clinical trials of doxorubicin-containing chemotherapy have been conducted in study groups in the US and Europe, but no treatment has shown superior activity considering the survival benefit compared to doxorubicin monotherapy. The combination of doxorubicin and ifosfamide is used as one of the options for situations in which tumor shrinkage is required, such as symptom palliation or when a critical structure is threatened. Currently, the clinical development of targeted therapy for STS has been initiated. For STSs, the multi-targeted TKI pazopanib, which has activity against VEGFR 1–3, PDGFRA and PDGFRB, and KIT, was approved in Japan 3 years ago. Potential drug targets in STS have been reported, such as the ALK fusion gene in inflammatory myofibroblastic tumors, activation of PDGFRB in dermatofibrosarcoma protuberans, and amplification of MDM2 and CDK4 in well-differentiated and de-differentiated liposarcoma. Other targets have also been reported, and the clinical utility of targeted therapy for specific histological subtypes harboring such target genes has been indicated in some cases. Thus, histology- or target-based therapies for advanced STS are expected to be introduced in clinical practice in the future.

Concomitant inactivation of the p53- and pRB- functional pathways predicts resistance to DNA damaging drugs in breast cancer in vivo

Chemoresistance is the main obstacle to cancer cure. Contrasting studies focusing on single gene mutations, we hypothesize chemoresistance to be due to inactivation of key pathways affecting cellular mechanisms such as apoptosis, senescence, or DNA repair. In support of this hypothesis, we have previously shown inactivation of either TP53 or its key activators CHK2 and ATM to predict resistance to DNA damaging drugs in breast cancer better than TP53 mutations alone. Further, we hypothesized that redundant pathway(s) may compensate for loss of p53-pathway signaling and that these are inactivated as well in resistant tumour cells. Here, we assessed genetic alterations of the retinoblastoma gene (RB1) and its key regulators: Cyclin D and E as well as their inhibitors p16 and p27. In an exploratory cohort of 69 patients selected from two prospective studies treated with either doxorubicin monotherapy or 5-FU and mitomycin for locally advanced breast cancers, we found defects in the pRB-pathway to be associated with therapy resistance (p-values ranging from 0.001 to 0.094, depending on the cut-off value applied to p27 expression levels). Although statistically weaker, we observed confirmatory associations in a validation cohort from another prospective study (n = 107 patients treated with neoadjuvant epirubicin monotherapy; p-values ranging from 7.0 × 10−4 to 0.001 in the combined data sets). Importantly, inactivation of the p53-and the pRB-pathways in concert predicted resistance to therapy more strongly than each of the two pathways assessed individually (exploratory cohort: p-values ranging from 3.9 × 10−6 to 7.5 × 10−3 depending on cut-off values applied to ATM and p27 mRNA expression levels). Again, similar findings were confirmed in the validation cohort, with p-values ranging from 6.0 × 10−7 to 6.5 × 10−5 in the combined data sets. Our findings strongly indicate that concomitant inactivation of the p53- and pRB- pathways predict resistance towards anthracyclines and mitomycin in breast cancer in vivo.

Quercetin, Menadione, Doxorubicin combination as a potential alternative to Doxorubicin monotherapy of acute lymphoblastic leukemia

Abstract Doxorubicin is a widely used chemotherapeutic drug, effective on patients with acute lymphoblastic leukemia but associated with significant long term cardio-toxicity. Menadione (vitamine K3) and the flavonoid quercetin are known as strong apoptogens in human leukemia Jurkat T cells. We explored the potential synergic cytotoxic effects of doxorubicin in association with quercetin and Menadione in this cellular model for acute lymphoblastic leukemia. Cellular viability, apoptosis, necrosis oxidative stress and cellular cycle were determined by flow cytometry utilizing Jurkat lymphoblasts labeled with Annexin V-FITC/7-AAD, CM-H2DCFDA/7-AAD and propidium iodide respectively. Results indicate a dose-dependent oxidative-stress generation, cell cycle arrest and apoptosis induction by doxorubicin alone, correlated with a decrease of the required doses when the anticancer drug was associated with quercetin and menadione, hence supporting the theory of an additive cytotoxic effect on leukemia cells. Introducing QC-MD combinations in leukemia doxorubicin-based treatment could significantly increase the treatment’s efficacy. The main mechanism responsible for this effect appears to be the increase in DOX affinity for DNA, which enables lowering of the therapeutic dose.

Prise en charge des sarcomes des tissus mous avancés : quelle chimiothérapie après échappement aux anthracyclines ?

Doxorubicin monotherapy is the standard first-line treatment in patients with advanced soft-tissue sarcomas. Ifosfamide still remains the standard 2nd line treatment after doxorubicin-failure. However, recent data have demonstrated that histological subtypes differ in their sensitivity to cytotoxic drugs. Therefore, gemcitabine should be considered as the best option after doxorubicin failure in leiomyosarcoma patients. Trabectedine should be used preferentially in myxoid liposarcomas and leiomyosarcomas patients whereas paclitaxel should be considered as a first or second-line treatment of choice in angiosarcoma patients. Further studies are needed in order to identify predictive factors of clinical benefit in advanced soft-tissue sarcoma patients treated with cytotoxic agents in combination or not with targeted therapies.

Salinomycin decreases doxorubicin resistance in hepatocellular carcinoma cells by inhibiting the β-catenin/TCF complex association via FOXO3a activation

Doxorubicin is a conventional and effective chemotherapy drug against hepatocellular carcinoma (HCC). However, during long-term doxorubicin monotherapy, HCC cells may eventually develop acquired-resistance to doxorubicin which results in recurrence and a poor prognosis. Salinomycin, an ionophore antibiotic, was recently reported to selectively kill human cancer stem cells (CSCs) which were response for chemoresistance. In this study, salinomycin was found to exert synergistic cytotoxicity with doxorubicin in HCC cells and be capable of inhibiting doxorubicin-induced epithelial-mesenchymal transition (EMT), an important cellular process involved in the acquired chemoresistance of tumors. Further experiments revealed that FOXO3a, a multifunctional transcription factor that can be activated by salinomycin, was vital in mediating doxorubicin-induced EMT. In addition, activated FOXO3a disturbed the interaction between β-catenin and TCF and inhibited the expression of β-catenin/TCF target genes (ZEB1, c-Myc and CyclinD1), which played important roles in doxorubicin-induced EMT in HCC cells. Finally, the enhanced curative efficacy of combination treatment of doxorubicin and salinomycin for HCC was confirmed in established xenograft models. In summary, the present study identifies a new doxorubicin-based chemotherapy for advanced HCC and provides a potential anti-cancer strategy targeting FOXO3a and related cell pathway molecules.

Efficiency of Combining Free and Polymer-Immobilized Prospidin with Doxorubicin for Treatment of Zajdel Ascites Hepatoma in Rats

The antitumor activity and side effects of the drug combinations prospidin + doxorubicin and prospidin hydrogel + doxorubicin were studied in rats with transplanted Zajdel ascites hepatoma. Test animals were divided into one control group and five test groups depending on the therapy protocol. Control animals were not treated. Test groups received (i) an aqueous solution of prospidin; (ii) prospidin hydrogel; (iii) doxorubicin; (iv) prospidin + doxorubicin; and (v) prospidin hydrogel + doxorubicin. The maximum tolerated doses (MTDs) of the drugs were used in monotherapy; half the MTD, in combination chemotherapy. The antitumor activity was evaluated in terms of lethality, lethality from tumor progression, total cure rate, average life expectancy, and prolonged life expectancy. Side and toxic effects were evaluated using data on the blood cell composition and biochemical parameters. It was established that the antitumor activity of combined aqueous prospidin and doxorubicin did not exceed the activity of doxorubicin monotherapy. Side effects of this combination had the same character as those of doxorubicin and were represented by leuko- and thrombocytopenia and nephropathy. The antitumor effect of combined prospidin hydrogel + doxorubicin with respect to lethality was significantly more pronounced than the effect of each individual component. This combination had a statistically significantly lower toxicity than that of the most toxic component.

Silencing NOB1 enhances doxorubicin antitumor activity of the papillary thyroid carcinoma in vitro and in vivo

Doxorubicin (DOX), a broad‑spectrum anthra-cyclin, is in wide clinical use for the treatment and prevention of thyroid cancer. However, the effectiveness of the treatment remains limited due to inherent tumor resistance to DOX. Results of a previous study demonstrated that downregulation of NIN1/RPN12 binding protein 1 homolog (NOB1) expression via adenovirus expression vector carrying NOB1 siRNA (Ad/sh-NOB1) induced cancer apoptosis and increased the radiosensitivity of papillary thyroid carcinoma (PTC) cells. However, whether knockout NOB1 can decrease DOX resistance remains unclear. Therefore, in the present study, the effect of Ad/sh-NOB1 infection, independently or in combination with DOX, was determined in a PTC cell line to identify more effective therapeutics against PTC cancer. Furthermore, tumor growth ability in nude mice was determined to identify the combination treatment effect in tumorigenesis in vivo. The results showed that Ad/sh-NOB1 combined with DOX treatment in PTC cells significantly suppressed proliferation, colony formation, migration and invasion, and induced cell apoptosis and arrest in the G0/G1 stage as compared to Ad/sh-NOB1 or DOX monotherapy. We also found that this combination suppressed the tumor growth of a nude mouse model as compared to Ad/sh-NOB1 or DOX monotherapy. In addition, Ad/sh-NOB1 combined with DOX treatment significantly increased activation of the p38 MAPK pathway, which may contribute to inhibition of PTC cell growth and decreased DOX resistance. Taken together, the experimental results indicate that Ad/sh-NOB1 combined with DOX treatment is a potential drug candidate for the treatment of papillary thyroid carcinoma.

Эффективность комбинации свободной и полимер-связанной форм проспидина с доксорубицином у крыс с асцитной гепатомой Зайдела

Исследована противоопухолевая активность и побочные и токсические эффекты комбинаций проспидин + доксорубицин и проспидин — гидрогель + доксорубицин у крыс с трансплантированной асцитной гепатомой Зайдела. В зависимости от характера терапии животные были разделены на 6 групп (1 контрольную и 5 опытных). В контрольной группе животные лечения не получали, в опытных проводилась химиотерапия по следующим схемам: 1-я — проспидин, водный раствор, 2-я — проспидин-гидрогель; 3-я — доксорубицин; 4-я — проспидин + доксорубицин; 5-я — проспидин-гидрогель + доксорубицин при монохимиотерапии использовали максимально переносимые дозы, при комбинированной химитерапии — половинные от максимально переносимых. Для оценки противоопухолевой активности исследовали летальность, летальность от прогрессирования опухоли, частоту полного излечения; среднюю продолжительность жизни и увеличение продолжительности жизни. Для оценки побочных и токсических эффектов проводили исследование клеточного состава и биохимических показателей крови. Установлено, что при асцитной гепатоме Зайдела комбинация водного раствора проспидина с доксорубицином по противоопухолевой активности не превосходит монотерапию доксорубицином. Побочные эффекты данной комбинации соответствуют таковым у доксорубицина и представлены лейко- и тромбоцитопенией и нефропатией. Противоопухолевый эффект комбинации проспидин-гидрогеля с доксорубицином по влиянию на летальность достоверно более выражен, чем у каждого из ее компонентов. Комбинация отличается достоверно меньшей гематотоксичностью по сравнению с наиболее токсичным из ее составляющих.