Doxorubicin Therapy Research Articles

Bone Marrow Molecular Markers Associated with Relapsed/Refractory Activated B-Cell-Like Diffuse Large B-Cell Lymphoma.

Activated B-cell-like diffuse large B-cell lymphoma (ABC-DLBCL) is a common subtype of non-Hodgkin's lymphoma and is very likely to infiltrate the bone marrow. Over 30% of patients are converted to relapsed/refractory DLBCL after first-line rituximab combined with cyclophosphamide, doxorubicin, vincristine, and prednisone therapy, with a poor prognosis. Our aim was to identify molecular markers that might be utilized to predict relapsed/refractory ABC-DLBCL patients. Hence, we collected bone marrow aspirate smears from 202 patients with ABC-DLBCL and detected expression of bone marrow molecular marker proteins by immunocytochemistry. Signal transducer and activator of transcription (Stat)3, nuclear factor (NF)-κB p65, Syk, Bruton's tyrosine kinase (BTK), and Bcl2 proteins were strongly expressed in bone marrow aspirate smears of ABC-DLBCL patients. The same smear could present positive expression of multiple proteins simultaneously. Positive combinations of protein expression were associated with resistance. The most significant finding was that the Stat3+NF-κB+ group developed resistance, which was significantly higher than that of the Stat3−NF-κB−group (80 vs. 14%). There was a significant difference in two-year relapse-free survival between protein-positive and protein-negative combinations of Stat3-NF-κB (P = 0.005), Bcl2-Stat3 (P = 0.009), Bcl2-Pax5 (P = 0.003), and BTK-Syk (P < 0.001). Thus, we detected key molecules in multiple signaling pathways in bone marrow aspirate smears. At the same time, the results provide further clinical evidence of ABC-DLBCL drug-resistant molecules and provide a theoretical basis for rational second-line treatment after drug resistance.

Operative R0 resection of diffuse large B-cell lymphoma of the pelvis: a case report

BackgroundDiffuse large B-cell lymphoma is the most common subtype of non-Hodgkin lymphoma with or without involvement of extranodal sites. Rituximab in combination with cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP) therapy represents the current standard therapy, achieving a rather dissatisfying outcome in approximately 30–40% of all cases.Case presentationWe present the case of a 43-year-old Austrian woman with an incidentally detected large pelvic mass which was diagnosed as diffuse large B-cell lymphoma. Initially, the lymphoma intraoperatively appeared to be an inoperable conglomerate tumor. Soon, intestinal perforation induced by tumor infiltration occurred, which initiated a closure of the small intestine and application of a jejunal probe and a percutaneous endoscopic gastrotomy tube. Treatment utilizing the gold standard rituximab in combination with cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP) was performed, partly resulting in remission according to radiological follow-up. In view of diagnosis and primary treatment development, the predictive outcome appeared unsound. However, within the procedure of the latest surgical intervention, which was intended to at least reconstruct the intestinal passage in order to improve quality of life, a surgical R0 resection of the residual tumor mass was achieved.ConclusionsThe case presented here reports an unanticipated process of diffuse large B-cell lymphoma, underlining the importance of interdisciplinary cooperation and surgical intervention within the realms of state-of-the-art treatment.

Treatment of malignant primary cardiac lymphoma with tumor resection using minimally invasive cardiac surgery

BackgroundPrimary cardiac lymphoma (PCL) is extremely rare and progresses rapidly. The treatment of PCL has not yet been established. Unlike lymphoma that arises from other organs, PCL causes cardiovascular events. We report the complete remission (CR) of PCL after tumor resection using minimally invasive cardiac surgery (MICS) and chemotherapy.Case presentationThe patient was a 79-year-old man who visited our hospital with chief complaints of weight loss and leg edema. A 40 × 30 mm mobile pedunculated tumor continuous with the right ventricular heart muscle was present in the right atrium upon echocardiography and extended cardiac surgery was difficult to perform. Tumor embolism-induced sudden death was prevented and a pathological diagnosis was obtained by making a 4-cm skin incision, and tumor resection with MICS was performed through a right fourth intercostal thoracotomy with a cardiopulmonary system. The histopathological diagnosis was diffuse large B cell malignant lymphoma. Eight cycles of postoperative rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) therapy were performed. Three years after surgery, the tumor was not visible on imaging and CR was maintained.ConclusionsThis case highlights that tumor resection using MICS is effective for avoiding the risk of sudden death. This technique was useful for the diagnosis and treatment of a malignant cardiac tumor in an elderly patient that required a difficult extended cardiac surgery.

Predictive value of soluble ST-2 for changes of cardiac function and structure in breast cancer patients receiving chemotherapy

The current study was to evaluate soluble ST-2 level and left ventricular ejection fraction (LVEF) in patients with breast cancer receiving doxorubicin or trastuzumab treatment for 6 months and determine whether soluble ST-2 level can be used to predictive left ventricular function impairment.Patients who were diagnosed as having breast cancer receiving doxorubicin or trastuzumab or combined therapy were enrolled. Demographic data, prior medical history and related medical therapy, and site and stage of breast cancer information were collected from electronic health record. Fasting blood was used to detect soluble ST-2 and brain natriuretic peptide (BNP) levels before and after 6 months doxorubicin or trastuzumab therapy. Echocardiography was performed before and after 6 months of doxorubicin or trastuzumab therapy.Participants were divided into 3 groups based on tertiary soluble ST-2 level. Compared with 1st tertiary group, patients in the 3rd tertiary group had higher proportion receiving combined therapy (14.3% vs 4.7%, P < .05). Baseline soluble ST-2 level was similar across groups. After 6 months’ therapy, soluble ST-2 level was significantly higher in the 3rd tertiary group. Pearson correlation analysis showed that soluble ST-2 level was positively correlated with left ventricular volume and E/e’ ratio while negatively correlated with LVEF. Doxorubicin, trastuzumab, combined therapy, soluble ST-2 level, and angiotensin-converting enzyme inhibitor/angiotensin receptor blocker treatment were all independently associated with LVEF change.In breast cancer patients receiving doxorubicin or trastuzumab therapy, soluble ST-2 level can be used to predict cardiac function and structure changes.

Efficacy and tolerability of rituximab and reduced-dose cyclophosphamide, doxorubicin, vincristine, and prednisolone therapy for elderly patient with diffuse large B-cell lymphoma

ABSTRACTObjectives: Chemoimmunotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisolone combined with rituximab (R-CHOP) is currently the first-line therapy for diffuse large B-cell lymphoma (DLBCL). However, management of elderly patients is challenging and often requires dose reductions or prolonged treatment intervals. We investigated the proper dose of R-CHOP for them.Methods: At our institute, for DLBCL patients aged 65–79 and ≥80 years, we had reduced CHOP dose to 5/6 and 7/12, respectively, and retrospectively evaluated the reduced-dose R-CHOP.Results: Although the median age in the standard, 5/6, and 7/12-dose groups was 57, 73, and 84 years, respectively (p < 0.001), the 3-year event-free survival (EFS) rate did not differ between the standard and 5/6-dose groups (60.2 and 56.7%); however, 7/12-dose group had significantly inferior survival (25.9%). When patients aged 60–80 were evaluated, no difference in EFS was observed between the standard and 5/6-dose groups using the same international prognostic index. The neutrophil nadir and the frequency of infection were comparable among the three dose groups.Discussion and Conclusions: Reduced-dose R-CHOP chemotherapy is a promising treatment for elderly patients with DLBCL in terms of efficacy and toxicity.

Metronomic oral doxorubicin in combination of Chk1 inhibitor MK-8776 for p53-deficient breast cancer treatment

Metronomic chemotherapy, which is defined as a low-dose and frequent administration of cytotoxic drugs without drug-free breaks, has been recently emerged as an alternative to traditional MTD therapy and has shown therapeutic benefit in breast cancer patients in numbers of clinical studies. Unlike MTD, metronomic chemotherapy acts by multiple mechanisms including antiangiogenic effect and immunomodulation, but the direct cytotoxic effect only playing a minor role due to the lowered dose. In this light, within the limits of p53-deficient breast cancer, we demonstrate the enhanced anticancer effect of metronomic chemotherapy using doxorubicin when combined with Chk1 inhibitor MK-8776 by specifically augmenting the direct cytotoxic effect on cancer cells. Since the oral drug is greatly favored in metronomic chemotherapy due to the frequent and potential long-term administration, we prepared an oral doxorubicin by producing an ionic complex with deoxycholic acid, which showed sufficient bioavailability and anticancer effect when administered orally. MK-8776 selectively enhanced the cytotoxic effect of low-concentration doxorubicin in p53-deficient breast cancer cells by abrogating the Chk1-dependent cell cycle arrest in vitro. Consistently, combining MK-8776 significantly improved the anticancer effect of the daily administered oral doxorubicin in p53-deficient breast cancer xenografts especially in a lower dose of doxorubicin without evident systemic toxicities. Combination therapy of MK-8776 and metronomic oral doxorubicin would be thus promising in the treatment of p53-deficient breast cancer benefited from the augmented direct cytotoxic effect and low risk of toxicities.

Protective Role of Silymarin in Early Doxorubicin-induced Cardiac Dysfunction in Children with Acute Lymphoblastic Leukemia.

Doxorubicin is a well-established chemotherapeutic agent for the treatment of childhood acute lymphoblastic leukemia (ALL), but its efficacy is often limited by its related cardiotoxicity. Protection against doxorubicin-induced cardiotoxicity can be of great value, especially for children. Silymarin has a potent antioxidant property that can be helpful in preventing cardio-toxicity. 'To assess the possible protective role of silymarin against early doxorubicin-induced cardiotoxicity in children with ALL'. This study was conducted on 80 children with ALL, including 40 patients under doxorubicin therapy and silymarin 420 mg/day for one week after each doxorubicin dose starting from the day of doxorubicin infusion (Group I) and 40 patients under doxorubicin therapy and placebo (Group II). 'Conventional echo-Doppler measures of left ventricular systolic and diastolic functions and pulsed wave tissue Doppler of lateral mitral annulus were done for all patients'. After doxorubicin therapy, there was a significant higher reduction of systolic function [ejection fraction (EF), fraction shortening (FS) and s wave] in Group II compared with Group I and non-significant reduction of diastolic function [E/A ratio or e/a ratio] in both Groups. Although serum troponin increases in both groups after doxorubicin therapy, the increase of troponin is significantly lower in group I compared with group II. Silymarin decreased early Doxorubicin-induced left ventricular systolic function disturbances and can be recommended as an adjuvant drug in patients with ALL under doxorubicin therapy. 'Multicenter studies on a large number of patients with longer follow up' periods to prove the protective role of silymarin in early and late Doxorubicin-induced cardiotoxicity.

TP53-dependence on the effect of doxorubicin and Src inhibitor combination therapy.

The anticancer effects of Src kinase inhibitors are controversial. This study found an association between alterations in the TP53 gene and the synergy score for combination treatment with doxorubicin and an Src kinase inhibitor using human osteosarcoma cell lines (MG63 and U2OS) and human colon cancer cell line. Doxorubicin was found to activate signal transducer and activator of transcription 3 via Src kinase in cancer cells harboring alterations in TP53. A drug combination study using patient-derived cells confirmed that an Src kinase inhibitor synergizes with doxorubicin in cancer cells harboring alterations in TP53, while antagonizing its effect in cancer cells expressing wild-type TP53. Our findings suggest that genetic alterations in TP53 are a critical factor in determining the use of a combination treatment of doxorubicin and Src inhibitors.

Nebivolol effect on doxorubicin-induced cardiotoxicity in breast cancer.

PurposeThe aim of this study was to assess whether nebivolol treatment could have beneficial effects in the prevention of anthracyclines-induced cardiotoxicity.Patients and methodsOur prospective study included 60 women, mean age 52.6±13 years, with HER2 negative breast cancer, scheduled to undergo treatment with doxorubicin. The patients were randomly divided into two groups: the treatment group (n=30) which received nebivolol 5 mg once daily for the duration of chemotherapy and the control group (n=30) without treatment with nebivolol. Cytostatic treatment was performed with doxorubicin 70 mg/m2 administered intravenously every 21 days for six cycles. The average cumulative dose of doxorubicin was 520±8 mg/m2. Echocardiography was performed immediately before and after six cycles of doxorubicin therapy.ResultsWe found no significant differences between the two groups regarding baseline clinical and echocardiographic parameters. The two groups reached a similar cumulative dose of doxorubicin. No patient died during the study. None of the patients withdrew from chemotherapy. After six cycles of doxorubicin therapy, the left ventricular (LV) ejection fraction, shortening fraction, and LV diameters changed, but not significantly. Tissue Doppler imaging (TDI) detected in the control group a significant decrease of myocardial velocities, indicating a LV diastolic dysfunction. In the same group, speckle tracking imaging (STI) revealed a statistically significant alteration of the ventricular deformation, which means a decrease in LV systolic function. In the nebivolol treatment group, no significant alterations in the LV systolic and diastolic function were observed.ConclusionThe results of this study show the benefit of new echocardiographic imaging methods such as TDI and STI in the screening of early cardiac dysfunction induced by cytostatic treatment. Nebivolol treatment prevented the occurrence of anthracyclines-induced cardiomyopathy in the short term. In order to confirm these preliminary results, larger studies with a longer follow-up period are required.

Curcumin loaded selenium nanoparticles synergize the anticancer potential of doxorubicin contained in self-assembled, cell receptor targeted nanoparticles

Doxorubicin (DOX) has been extensively used to treat a wide range of cancers in free and nanotized form. Nanotization of DOX has alleviated its toxicity and efflux-mediated resistance. However, frequent upregulation of anti-apoptotic pathways, chemotherapy-enhanced inflammation, and epithelial-mesenchymal transition (EMT), present additional aspects of cellular DOX résistance. Nanoparticle-mediated combination therapy of DOX with additional anticancer agents is expected to offer greater therapeutic benefit by alleviating the overall drug résistance. We synthesized CD44-targeted DOX loaded nanoparticles (PSHA-DOXNPs) and evaluated their anticancer efficacy in combination with curcumin loaded selenium nanoparticles (Se-Cur NPs), previously developed by our group (Kumari et al., 2017). Combination of these nanoparticles (NPs) increased ROS level, decreased mitochondrial membrane potential, induced cell cycle arrest and apoptosis in HCT116 cells. This combination decreased the expressions of NFκB, Phospho-NFκB, EMT-metastasis-associated proteins (Snail, Vimentin, N-cadherin, CD44, MMP-2 and MMP-9), autophagy-associated proteins (Beclin-1 and LC-3BII), as well as anti-apoptotic protein Bcl-2, increased the expression of pro-apoptotic protein Bax, and increased cyt c release, which indicated decrease in inflammation, metastasis, and autophagy with increase in apoptosis. Moreover, the combination of NPs decreased tumor burden and increased survival of Ehrlich’s ascites carcinoma (EAC)-bearing mice.

Doxorubicin combined with Notch1-targeting siRNA for the treatment of gastric cancer.

Notch1, a transmembrane receptor that has a notable role in gastric cancer (GC) as an oncogene, has been reported to be involved in doxorubicin resistance. Thus, Notch1 is a potential therapeutic target for GC. In the present study, the protein levels of Notch1 intracellular domain (NICD; a marker of Notch1 activation) in human GC cell lines and tumor tissues was measured by western blotting. Next, the effects of Notch1 depletion in SGC7901 cells were evaluated. Finally, the efficacy of Notch1 small interfering RNA (siRNA) combined with doxorubicin therapy for GC was examined in vitro and in vivo. The results revealed that NICD levels were high in GC cells, and that the inhibition of NICD by transfection with Notch1 siRNA induced apoptosis and inhibited proliferation. Ectopic downregulation of Notch1 expression enhanced the sensitivity of GC tumors to doxorubicin, which suppressed the development of GC. These data demonstrated that Notch1 was a significant regulator of cell proliferation and apoptosis in GC. Thus, the combination of doxorubicin with Notch1 siRNA is a potential strategy for the treatment of GC.

Case of immune‐mediated necrotizing myopathy associated with anti‐signal recognition particle antibodies: Dramatic improvement after rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone therapy for intravascular large B‐cell lymphoma

AbstractImmune‐mediated necrotizing myopathy associated with anti‐signal recognition particle antibodies (anti‐SRP myopathy) is representative of several subtypes of necrotizing immune‐mediated myopathy, and is characterized by rapidly progressive proximal muscle weakness, dysphagia and poor responsiveness to conventional immunosuppressive therapies. We report a 71‐year‐old man who developed anti‐SRP myopathy followed by malignant lymphoma, and whose condition dramatically improved with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone therapy. He showed progressive proximal muscle weakness with severe dysphagia, and was diagnosed with anti‐SRP myopathy by antibody tests and pathological examination. He was treated with conventional immunosuppressive therapies, specifically corticosteroids, intravenous immunoglobulin and tacrolimus; however, none of these therapies were effective. Two months after starting tacrolimus, the patient developed intravascular large B‐cell lymphoma, which was suspected to be an iatrogenic immunodeficiency‐associated lymphoproliferative disorder. Rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone therapy resulted in not only complete remission of lymphoma, but also dramatic improvement of anti‐SRP myopathy. The present case suggests that rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone therapy is a potential treatment for anti‐SRP myopathy.

Pharmacogenetics of Chemotherapy-Induced Cardiotoxicity.

The goal of this review is to summarize current understanding of pharmacogenetics and pharmacogenomics in chemotherapy-induced cardiotoxicity. Most of the studies rely on in vitro cytotoxic assays. There have been several smaller scale candidate gene approaches and a handful of genome-wide studies linking genetic variation to susceptibility to chemotherapy-induced cardiotoxicity. Currently, pharmacogenomic testing of all childhood cancer patients with an indication for doxorubicin or daunorubicin therapy for RARG rs2229774, SLC28A3 rs7853758, and UGT1A6*4 rs17863783 variants is recommended. There is no recommendation regarding testing in adults. There is clear evidence pointing to the role of pharmacogenetics and pharmacogenomics in cardiotoxicity susceptibility to chemotherapeutic agents. Larger scale studies are needed to further identify susceptibility markers and to develop pharmacogenomics-based risk profiling to improve quality of life and life expectancy in cancer survivors.

Effect of Simultaneous Treatment with Royal Jelly and Doxorubicin on the Survival of the Prostate Cancer Cell Line (PC3): An In Vitro Study

Background: Doxorubicin (DOX) therapy is the first step in the treatment of several malignancies such as prostate cancer. Drug resistance is the main drawback of this agent. Royal jelly (RJ), used to prevent or cure many diseases, is a substance produced by honey bee. Objectives: The aim of this study was to determine the cytotoxic effect of DOX and RJ on prostate cancer cells, PC3. Methods: Cell viability of the three experimental groups (RJ-treated cells, DOX-treated cells and RJ followed by DOX-treated cells) was assessed by 3-(4,5-dimethylthiazoyl-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Results: RJ-treatment increased the cytotoxic effect of DOX on PC3 cells. Namely, the effect of low dose of DOX in combination with RJ was approximately similar to that of high dose of DOX without RJ combination. Conclusions: Any natural substances that amplify the cytotoxic effect of DOX and have the potential to save normal cells can be potentially used as a therapeutic agent which can decrease the side effects of DOX-treatment. RJ has shown to play this role in the present study.

Anemia associated with worse outcome in diffuse large B-cell lymphoma patients: a single-center retrospective study

ObjectiveUseful prognostic biomarkers for diffuse large B-cell lymphoma (DLBCL) patients have been reported. To determine the prognostic value of hemoglobin (Hb) level in DLBCL patients, we performed a retrospective study.Materials and MethodsWe evaluated disease outcome, progression-free survival (PFS), overall survival as the endpoint, and clinical and laboratory factors affecting the outcome of 185 DLBCL patients who had received rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone therapy during 2004-2014.ResultsThe study group included 121 men and 64 women with a median age of 66 years minimum-maximum: 21-83 years. In univariate analysis, factors independently associated with worse PFS were Eastern Cooperative Oncology Group performance status ≥2, Ann Arbor stage III or IV, anemia with Hb levels of <10 g/dL, and serum albumin of <3.5 g/dL. In multivariate analysis, anemia with Hb levels of <10 g/dL and Ann Arbor stage III or IV were found to be international index-independent prognostic factors (hazard ratio: 2.4; p=0.04).ConclusionAnemia is an independent prognostic marker of poor outcome in DLBCL patients. Hb can be an easily available prognostic marker for risk stratification in these patients.

Magnetic Graphene Oxide for Dual Targeted Delivery of Doxorubicin and Photothermal Therapy.

To develop a pH-sensitive dual targeting magnetic nanocarrier for chemo-phototherapy in cancer treatment, we prepared magnetic graphene oxide (MGO) by depositing Fe3O4 magnetic nanoparticles on graphene oxide (GO) through chemical co-precipitation. MGO was modified with polyethylene glycol (PEG) and cetuximab (CET, an epidermal growth factor receptor (EGFR) monoclonal antibody) to obtain MGO-PEG-CET. Since EGFR was highly expressed on the tumor cell surface, MGO-PEG-CET was used for dual targeted delivery an anticancer drug doxorubicin (DOX). The physico-chemical properties of MGO-PEG-CET were fully characterized by dynamic light scattering, transmission electron microscopy, X-ray diffraction, Fourier transform Infrared spectroscopy, thermogravimetric analysis, and superconducting quantum interference device. Drug loading experiments revealed that DOX adsorption followed the Langmuir isotherm with a maximal drug loading capacity of 6.35 mg/mg, while DOX release was pH-dependent with more DOX released at pH 5.5 than pH 7.4. Using quantum-dots labeled nanocarriers and confocal microscopy, intracellular uptakes of MGO-PEG-CET by high EGFR-expressing CT-26 murine colorectal cells was confirmed to be more efficient than MGO. This cellular uptake could be inhibited by pre-incubation with CET, which confirmed the receptor-mediated endocytosis of MGO-PEG-CET. Magnetic targeted killing of CT-26 was demonstrated in vitro through magnetic guidance of MGO-PEG-CET/DOX, while the photothermal effect could be confirmed in vivo and in vitro after exposure of MGO-PEG-CET to near-infrared (NIR) laser light. In addition, the biocompatibility tests indicated MGO-PEG-CET showed no cytotoxicity toward fibroblasts and elicited minimum hemolysis. In vitro cytotoxicity tests showed the half maximal inhibitory concentration (IC50) value of MGO-PEG-CET/DOX toward CT-26 cells was 1.48 µg/mL, which was lower than that of MGO-PEG/DOX (2.64 µg/mL). The IC50 value could be further reduced to 1.17 µg/mL after combining with photothermal therapy by NIR laser light exposure. Using subcutaneously implanted CT-26 cells in BALB/c mice, in vivo anti-tumor studies indicated the relative tumor volumes at day 14 were 12.1 for control (normal saline), 10.1 for DOX, 9.5 for MGO-PEG-CET/DOX, 5.8 for MGO-PEG-CET/DOX + magnet, and 0.42 for MGO-PEG-CET/DOX + magnet + laser. Therefore, the dual targeting MGO-PEG-CET/DOX could be suggested as an effective drug delivery system for anticancer therapy, which showed a 29-fold increase in therapeutic efficacy compared with control by combining chemotherapy with photothermal therapy.

A Phase Ib/II Study of Ganetespib With Doxorubicin in Advanced Solid Tumors Including Relapsed-Refractory Small Cell Lung Cancer.

Small cell lung cancer (SCLC) accounts for 15% of all lung cancers and is characterized by high response rates to cytotoxic chemotherapy and equally high rates of relapse. Many resistance mechanisms have been proposed including resistance to doxorubicin via induction of a heat shock response. Ganetespib is a novel and potent non-geldanamycin heat shock protein 90 (Hsp90) inhibitor. In preclinical studies, synergy between ganetespib and doxorubicin was shown. We conducted a phase Ib/II study of the safety, tolerability, and preliminary efficacy of the combination of ganetespib and doxorubicin. Patients eligible for the phase Ib portion had advanced tumors that would be appropriate for doxorubicin therapy and those in the phase II portion had relapsed or refractory SCLC. All patients had an ECOG performance status, 0-1 and adequate organ function, including a cardiac ejection fraction ≥50%. Patients who received a lifetime cumulative doxorubicin dose of >150 mg/m2 or who had symptomatic brain metastases were excluded. Patients received ganetespib on Days 1 and 8 and doxorubicin 50 mg/m2 on day 1 in 21-day cycles. Eleven patients were enrolled including nine in the phase Ib dose escalation and two in the phase II expansion. The study was terminated by the sponsor. The dose recommended for future study is ganetespib 150 mg/m2 in combination with doxorubicin at a dose of 50 mg/m2. The most common adverse events of the combination were grade 1/2 diarrhea, nausea, fatigue, and transaminitis. No dose limiting toxicities were observed. Response rate was 25% and median duration of response was 137 days. Ganetespib plus doxorubicin was a well-tolerated combination and there remains potential for the clinical development of Hsp90 inhibitors in SCLC. https://ClinicalTrials.gov/ct2/show/NCT02261805, identifier NCT02261805.

Effective phthalocyanines mediated photodynamic therapy with doxorubicin or methotrexate combination therapy at sub-micromolar concentrations in vitro.

To improve a cancer patient's quality of life, short treatment duration resulting in rapid tumour removal while sparing normal tissue are highly desirable. Photodynamic therapy (PDT) commonly applied in a single treatment, while often effective can be limited at low photosensitizer or light doses. Combination therapies can overcome the efficacy limitations while not increasing treatment-associated morbidity. Here the efficacy of combination therapy comprised of doxorubicin (DOX) or methotrexate (MTX) with Photosens mediated PDT was investigated in three cell lines in vitro, employing multiple incubation sequences. Photosense is a mixture of aluminium phthalocyanines with different sulfonation. The results demonstrated higher synergistic effects when DOX or MTX-mediated chemotherapy preceded PDT light activation by 24 h. MTX is marginally more cytotoxic than DOX, when combined with Photosens (AlPcS2-4) mediated PDT. While MTX and DOX exposure prior to AlPcS2-4 incubation may enhance mitochondrial localisation photosensitizer, the simultaneous targeting of DNA, proteins, and lipids of the combination therapies leads to the observed high cytotoxicity at sub μM drug doses.

Programmed drug delivery system based on optimized “size decrease and hydrophilicity/hydrophobicity transformation” for enhanced hepatocellular carcinoma therapy of doxorubicin

Requirements on drug delivery systems to surmount a complex series of pathophysiological barriers bear “cascading contradictions”, especially size and hydrophilicity/hydrophobicity contradiction. Herein, a programmed drug delivery system (GNPs-Dox-Lac) based on optimized “size decrease and hydrophilicity/hydrophobicity transformation” was developed by combination the gelatin nanoparticle (GNPs) and prodrug Doxorubicin-Lactose (Dox-Lac). The results showed that GNPs-Dox-Lac (133.3 nm) were kinetically stable in blood circulation and inclined to accumulate at the tumor site. Then the degradation of the GNPs triggered by tumor extracellular matrix metalloproteinase-2 (MMP2) led to the release of prodrug Dox-Lac (Mw 898 Da) to facilitate the tumor tissue penetration and cellular uptake. Last, pH-responsive disassociation of Dox-Lac in tumor cells resulted in the free Dox (Mw 543 Da) release to induce toxicity. As expected, GNPs-Dox-Lac achieved superior tumor inhibition rate of 90.8% with low toxicity in vivo, suggesting its potential for enhanced hepatocellular carcinoma (HCC) therapy of doxorubicin in future.

An inflammation-based cumulative prognostic score system in patients with diffuse large B cell lymphoma in rituximab era

BackgroundSystemic inflammatory parameters are associated with poor outcomes in malignant patients. Several inflammation-based cumulative prognostic score systems were established for various solid tumors. However, there is few inflammation based cumulative prognostic score system for patients with diffuse large B cell lymphoma (DLBCL).MethodsWe retrospectively reviewed 564 adult DLBCL patients who had received rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP) therapy between Nov 1 2006 and Dec 30 2013 and assessed the prognostic significance of six systemic inflammatory parameters evaluated in previous studies by univariate and multivariate analysis:C-reactive protein(CRP), albumin levels, the lymphocyte-monocyte ratio (LMR), the neutrophil-lymphocyte ratio(NLR), the platelet-lymphocyte ratio(PLR)and fibrinogen levels.ResultsMultivariate analysis identified CRP, albumin levels and the LMR are three independent prognostic parameters for overall survival (OS). Based on these three factors, we constructed a novel inflammation-based cumulative prognostic score (ICPS) system. Four risk groups were formed: group ICPS = 0, ICPS = 1, ICPS = 2 and ICPS = 3. Advanced multivariate analysis indicated that the ICPS model is a prognostic score system independent of International Prognostic Index (IPI) for both progression-free survival (PFS) (p < 0.001) and OS (p < 0.001). The 3-year OS for patients with ICPS =0, ICPS =1, ICPS =2 and ICPS =3 were 95.6, 88.2, 76.0 and 62.2%, respectively (p < 0.001). The 3-year PFS for patients with ICPS = 0–1, ICPS = 2 and ICPS = 3 were 84.8, 71.6 and 54.5%, respectively (p < 0.001).ConclusionsThe prognostic value of the ICPS model indicated that the degree of systemic inflammatory status was associated with clinical outcomes of patients with DLBCL in rituximab era. The ICPS model was shown to classify risk groups more accurately than any single inflammatory prognostic parameters. These findings may be useful for identifying candidates for further inflammation-related mechanism research or novel anti-inflammation target therapies.