Potential applicability of clinical hyperthermia using a Thermotron-RF8 as assessed from thermal distribution in an agar phantom containing hydroxyapatite

We have already reported the antitumour effect of hydroxyapatite (HAP) containing anticancer drugs. In this study, we found an increased temperature effect around HAP particle(s) in an agar phantom in comparison with other areas when a Thermotron-RF8 (RF generator) was used for heating. Furthermore, it was revealed that the quantity of doxorubicin hydrochloride (DOX) released from HAP containing the drug (DOX-HAP complex) was increased by raising the temperature. These results indicated that the antitumor effect of the DOX-HAP complex + hyperthermia system was greater than that of either the DOX-HAP complex or hyperthermia system alone.     

Enhancement by hyperthermia of the in vivo antitumour effect of doxorubicin hydrochloride (DOX) and buthionine sulfoximine (BSO)-hydroxyapatite (HAP) complex

We have developed a new type of drug delivery system (DDS) comprising a complex of porous hydroxyapatite (HAP) with the anticancer drug doxorubicin hydrochloride (DOX) and the glutathione inhibitor buthionine sulfoximine (BSO) (DOX and BSO-HAP complex). We then studied the antitumour effect of DOX and BSO-HAP combined with 44 degrees C hyperthermia for 40 min. It was found that in mice this combined treatment suppressed the growth of sarcoma 180 in terms of tumour volume to 36% in comparison viith mice given plain HAP, and was more effective than HAP + hyperthermia or DOX- and BSO-HAP. These results were also confirmed by histological observation.     

Antitumor effects of Doxorubicin hydrochloride (dox) and buthionine sulfoximine (bso)-hydroxyapatite (hap) complex on transplanted tumors in-vivo

We prepared hydroxyapatite (HAP) beads containing doxorubicin hydrochloride (DOX) and buthionine sulfoximine (BSO), as a DOX and BSO-HAP complex. When the complex was implanted into mice bearing sarcoma 180 tumor, the antitumor effect of the complex was intensified 1.5-fold, as assessed using tumor volume, on day 27 as compared with that of a complex of DOX-HAP only. Therefore, we concluded that the antitumor effect of the DOX and BSO-HAP complex was increased through depletion of the intracellular radical scavenger glutathione (GSH) by released BSO and subsequently free radicals produced by released DOX.     

Development of a slow release system of anti-cancer drugs retained in calcium-hydroxyapatite ceramic

A new type of anticancer material with sustained release by enclosure of cisplatin (CDDP) into porous calcium hydroxyapatite ceramic (CDDP-CHA) was developed. A slow release of anticancer drug from CDDP-CHA was confirmed in in vitro experiments. When this material was implanted into normal thigh muscle of mouse, a sustained release of CDDP was observed during over 8 weeks after implantation. The diffusion of drug into blood and other organs from the implanted site was very small. CDDP-CHA placed into the implanted tumor of mouse allowed a slow release and high drug level from the material in the tumor. The concentration of the drug in other organs such as liver and kidney was very low compared with that of the tumor. These results suggest that this material has an important role for cancer chemotherapy, particularly in bone tumors for the reasons of calcium hydroxyapatite ceramic carrier having a mechanical strength.     

Hydroxyapatite beads containing Doxorubicin hydrochloride (dox) and buthionine sulfoximine (bso) - a new anticancer drug design for local treatment with multiple-drugs

Doxorubicin hydrochloride (DOX) and buthionine sulfoximine (BSO) were adsorbed on to a drug-carrier, hydroxyapatite (HAP), to form a DOX and BSO-HAP complex. The time-course of the release of these drugs from the complex into phosphate-buffered saline (PBS) was measured photometrically at 37-degrees-C in vitro. After 3 h of incubation, almost all the BSO in the DOX and BSO-HAP complex was released into the PBS, whereas 48.7% of the DOX was released during this period. DOX was released continuously over 10 h of incubation, the rate of release being 7.3%h of the total amount released. Both DOX and BSO were eluted from the DOX and BSO-HAP complex over the first 3 h of incubation. From the 4 h of incubation, only DOX was released, indicating a slow-release property of the complex. The DOX and BSO-HAP complex developed in this study may in future have an in vivo application. It is possible that intracellular glutathione could be depleted first by the rapidly released BSO and that DNA strand breaks could then be intensified by the slowly released DOX. Therefore, this complex has potential as a new drug delivery system (DDS) in cancer chemotherapy.     

Folate-mediated mitochondrial targeting with doxorubicin-polyrotaxane nanoparticles overcomes multidrug resistance

Resistance to treatment with anticancer drugs is a significant obstacle and a fundamental cause of therapeutic failure in cancer therapy. Functional doxorubicin (DOX) nanoparticles for targeted delivery of the classical cytotoxic anticancer drug DOX to tumor cells, using folate-terminated polyrotaxanes along with dequalinium, have been developed and proven to overcome this resistance due to specific molecular features, including a size of approximately 101 nm, a zeta potential of 3.25 mV and drug-loading content of 18%. Compared with free DOX, DOX hydrochloride, DOX nanoparticles, and targeted DOX nanoparticles, the functional DOX nanoparticles exhibited the strongest anticancer efficacy in vitro and in the drug-resistant MCF-7/ Adr (DOX) xenograft tumor model. More specifically, the nanoparticles significantly increased the intracellular uptake of DOX, selectively accumulating in mitochondria and the endoplasmic reticulum after treatment, with release of cytochrome C as a result. Furthermore, the caspase-9 and caspase-3 cascade was activated by the functional DOX nanoparticles through upregulation of the pro-apoptotic proteins Bax and Bid and suppression of the antiapoptotic protein Bcl-2, thereby enhancing apoptosis by acting on the mitochondrial signaling pathways. In conclusion, functional DOX nanoparticles may provide a strategy for increasing the solubility of DOX and overcoming multidrug-resistant cancers.     

Antimetastatic Effect by Anti-adhesion Therapy with Cell-adhesive Peptide of Fibronectin in Combination with Anticancer Drugs

We have investigated the therapeutic effect of CH-271 fusion polypeptide containing both cell-binding domain (C-274) and heparin-binding domain (H-271) of fibronectin in combination with anticancer drugs such as doxorubicin (DOX) or mitomycin C (MMC) on tumor metastasis of different types of tumors. CH-271 fusion polypeptide alone significantly inhibited both liver and lung metastasis when it was co-injected with L5178Y-ML25 T-lymphoma, RAW117-H10 B-lymphoma or B16-BL6 melanoma cells, and spontaneous lung metastasis of B16-BL6 melanoma cells when administered i.v. seven times before or after surgical excision of the primary tumors. Combined treatments with CH-271 and either DOX or MMC significantly inhibited liver and lung metastasis of lymphoma or melanoma cells respectively, as compared with either treatment alone or the untreated control. Administrations of CH-271 and DOX in combination substantially prolonged the survival time of mice injected i.v. with L5178Y-ML25 cells. CH-271 or DOX was effective for inhibiting the invasion of LS178Y-ML25 cells into Matrigel in a concentration-dependent manner. Our previous study has shown that CH-271-mediated inhibition of tumor invasion may be due in part to the anti-cell adhesive property without affecting the cell growth, whereas the anti-invasive effect of DOX was established to have resulted from the growth inhibition of tumor cells. Moreover, the combination of CH-271 with DOX provided a more effective inhibition of tumor invasion into Matrigel than did either alone. Thus, we have demonstrated that the combination of anti-cell adhesive CH-271 and anticancer drugs such as DOX or MMC, i.e. anti-adhesion therapy and chemotherapy, is a new approach that offers enhanced (additive) inhibitory effects on tumor metastasis and invasion.     

透明质酸修饰的pH响应型阿霉素纳米递送系统靶向多发性骨髓瘤的体外研究

目的:构建一种特异性靶向多发性骨髓瘤的pH响应型纳米递送系统,实现对多发性骨髓瘤细胞靶向释放化疗药物阿霉素。方法:采用酸敏感的DSPE-PEOz和阳离子类脂DOTAP包封模型药物阿霉素（doxorubicin,DOX）,得到阿霉素纳米递送系统（DOX-NDS）,并经HA-PEG2000-DSPE（HA）靶向长循环修饰,最终制得阿霉素靶向纳米递送系统（DOX-HA-NDS）;纳米粒度电位仪分析DOX-HA-NDS的粒径和Zeta电位;多功能酶标仪检测DOX-HA-NDS的包封率（encapsulation efficiency,EE）和载药量（drug loading,DL）;透析法研究DOX-HA-NDS在pH 5.0和pH 7.4条件下的体外释药行为;流式细胞仪检测其细胞摄入;CCK-8法评价空白靶向纳米递送系统（Blank-HA-NDS）的毒性和DOX-HA-NDS的细胞增殖抑制作用。结果:构建的DOX-HA-NDS粒径为（193.1±5.0）nm,Zeta电位为（-41.1±2.0）mV,离心法和透析法测得包封率分别高达93%和90%,载药量为32.76%和32%,4 ℃存储能稳定6个月以上。在pH 7.4条件下,DOX-HA-NDS的释药缓慢,且6 h累积释放率仅为30%,而在pH 5.0条件下,DOX-HA-NDS的释药明显加快,6 h累积释放率高达97%,表明构建的阿霉素靶向纳米递送系统具有pH响应控释性能。细胞摄入实验结果表明,经HA修饰后的阿霉素纳米递送系统可以更有效靶向肿瘤细胞;体外抗肿瘤活性结果表明,Blank-HA-NDS基本无细胞毒性,DOX-HA-NDS对人多发性骨髓瘤细胞（ARH-77）的增殖抑制作用最强。结论:构建的阿霉素靶向纳米递送系统不仅包封率高,而且兼具主动靶向和pH响应控释性能,提高对DOX的输送效率,从而增强了其对ARH-77的细胞增殖抑制作用。     

Three percent dietary fish oil concentrate increased efficacy of doxorubicin against MDA-MB 231 breast cancer xenografts.

Omega 3 polyunsaturated fatty acids (the type of fat found in fish oil) have been used to kill or slow the growth of cancer cells in culture and in animal models and to increase the effectiveness of cancer chemotherapeutic drugs. An AIN-76 diet containing 5% corn oil (CO) was modified to contain 3% w/w fish oil concentrate (FOC) and 2% CO to test whether a clinically applicable amount of FOC is beneficial during doxorubicin (DOX) treatment of cancer xenografts in mice. Compared with the diet containing 5% CO, consumption of FOC increased omega 3 polyunsaturated fatty acids and lipid peroxidation in tumor and liver, significantly decreased the ratio of glutathione peroxidase activity to superoxide dismutase activity (a putative indicator of increased oxidative stress) in tumor but not in the liver, and significantly decreased the tumor-growth rate. The decreased glutathione peroxidase:superoxide dismutase ratio, indicating an altered redox state, in the tumor of FOC-fed mice was significantly correlated with decreased tumor-growth rate. Assay of the body weight change, blood cell counts, and number of micronuclei in peripheral erythrocytes indicated that the toxicity of DOX to the host mouse was not increased in mice fed FOC. Thus, a small amount of FOC increased the effectiveness of DOX but did not increase the toxicity of DOX to the host mouse. These positive results justify clinical testing of FOC in conjunction with cancer chemotherapy.     

Doxorubicin encapsulated in sterically stabilized liposomes exhibits renal and biliary clearance properties that are independent of valspodar (PSC 833) under conditions that significantly inhibit nonencapsulated drug excretion.

Coadministration of anticancer drugs and multidrug resistance modulators directed against P-glycoprotein over-expressed in tumors also results in nonspecific blockade of this drug efflux pump in excretory tissues such as the liver and kidneys. These interactions often result in impaired renal and biliary clearance for anticancer agents such as doxorubicin (DOX). In the present investigation, we characterized the excretory processes associated with liposomal DOX administration to elucidate how liposome encapsulation may bypass adverse pharmacokinetic interactions between DOX and (3'-keto-Bmt1)-(Val2)-cyclosporin (Valspodar). Renal and biliary clearance properties of liposome-encapsulated DOX were compared with those for nonencapsulated DOX in the presence and absence of Valspodar using an instrumented rat model with implanted jugular vein and bile duct catheters for continuous sampling. Two types of liposomal DOX formulations were used, a drug-permeable egg phosphatidyl choline/cholesterol system and a sterically stabilized polyethylene glycol/1,2 distearoyl-sn-glycero-3-phosphocholine/cholesterol system to establish the relative roles of liposome-encapsulated and released drug on the pharmacokinetic and excretion alterations induced by Valspodar. DOX and its primary metabolites were quantitated using high-performance liquid chromatography. When Valspodar was coadministered with nonencapsulated DOX, 3.5- and 37.5-fold reductions in renal clearance (CLr) and biliary clearance (CLb), respectively, were observed, which resulted in increased plasma DOX concentrations and total exposure. However, Valspodar-induced alterations in CLr and CLb were less profound with egg phosphatidyl choline/cholesterol DOX (1.7- and 2.0-fold reductions, respectively) and negligible with the long-circulating polyethylene glycol-containing liposomal formulation. These results indicate that liposomes may circumvent Valspodar-induced DOX pharmacokinetic changes by reducing the rate of drug excretion in liver and kidney tissue to a level that is within the renal and biliary excretion capacity in the presence of P-glycoprotein blockade.     

N-(2-hydroxypropyl)methacrylamide copolymers targeted to the hepatocyte galactose-receptor: pharmacokinetics in DBA2 mice.

N-(2-Hydroxypropyl)methacrylamide (HPMA) copolymers containing doxorubicin (DOX) and galactosamine can be targeted to the hepatocyte galactose receptor for organ-specific chemotherapy of primary and metastatic liver cancer. Here we report the dose-dependent pharmacokinetics of this macromolecular conjugate. Following intravenous administration to mice most efficient liver targeting was seen at low dose (0.05 mg DOX kg-1), with receptor saturation observed using higher bolus doses. Repeated low dose bolus injections did not cause down-regulation of the galactose receptor and targeted drug delivery rates of greater than or equal to 2 micrograms DOX g-1 liver h-1 were achieved. DOX is released from such conjugates intracellularly via action of lysosomal proteinases. It was shown that isolated rat liver lysosomal enzymes (Tritosomes) can release unmodified DOX from the peptidyl side chain Gly-Phe-Leu-Gly at a rate greater than or equal to 3 micrograms DOX g-1 liver h-1 i.e. the hydrolytic capacity is greater than the observed rate of drug delivery to the liver lysosomes in vivo. Although most conjugate would be captured by normal hepatocytes following intravenous administration, it was shown that the human hepatoma cell line HepG2 retains the galactose receptor, accumulating and processing the conjugate efficiently. Potential dose limiting toxicities of such drug conjugates could include cardio- or hepatotoxicity. Administration of conjugate reduced the 15 min heart level of DOX approximately 100-fold compared with that observed for an equivalent dose of free drug. Preliminary experiments showed that plasma levels of alkaline phosphatase, alanine transaminase and asparate transaminase did not change following administration of HPMA copolymer-daunorubicin (DNR) (10 mg DNR kg-1) indicating no significant heptatoxicity.     

Experimental studies on subrenal capsule assay using cyclosporin A treated mice--the optimal treatment schedules of CsA and anticancer agents (mitomycin C and 5-fluorouracil)

We studied fundamentally subrenal capsule assay, using human tumor specimens (breast, gastric and colon cancers) serially transplanted in nude mice. When cancer anticancer agents such as mitomycin C (MMC) and 5-fluorouracil (5-FU) were injected into immunocompetent mice treated with various dosages of cyclosporin A (CsA) after tumor implantation, optimal schedule of each drug was examined on the points of effects and toxicity against host mice. The following results were obtained. Control groups were set up as immunocompetent mice which treated daily with 60 mg/kg CsA from day 1 after tumor implantation. Optimal treatment schedule was judged as MMC 3 mg/kg i.v. injection on day 1 following by daily 60 mg/kg CsA treatment, and 5-FU was injected 25 mg/kg subcutaneous injection every day from day 1 without CsA treatment, each schedule showed an appropriate anti-tumor activity profiles against implanted tumor xenografts, and had less toxicity to the hosts.     

Regional treatment of esophageal liver metastasis by intra-arterial low-dose 5-FU therapy

The prognosis of esophageal liver metastasis remains poor because of the high incidence of synchronous metastasis in other area and insufficient response to systemic chemotherapy. We assessed loco-regional anticancer potential of intra-arterial 5-FU chemotherapy for esophageal liver metastasis aimed at combination with systemic chemotherapy, radiotherapy and ablation therapy as a multidisciplinary treatment. Six patients of esophageal cancer with liver metastasis and without extra-hepatic metastasis were enrolled. Intra-aortic chemotherapy consisted of 5-FU (250 mg/body) in a one-shot infusion or a continuous infusion for 7 days with 2-week intervals until failure. The responses of liver metastasis were 2 cases of CR, 3 of PR and 1 of SD. The response rate and the local control rate were 83% and 100%, respectively. The maximum time to progression was 53 months. Grade 3/4 toxicity was not observed. Two cases had catheter failure and the treatment was interrupted. Liver metastases were controlled well until death in all cases except one. Low-dose intra-aortic 5-FU chemotherapy provided a good regional response and a combination with systemic chemotherapy may prolong survival for the patients of liver metastasis of esophageal cancer.     

Dosage regimen optimization in cancer chemotherapy using a mathematical model

In cancer chemotherapy, it is important to design treatment strategies that ensure a desired rate of tumor cell kill without unacceptable toxicity. To optimize treatment, we used a mathematical model describing the pharmacokinetics of anticancer drugs, antitumor efficacy, and drug toxicity. This model was associated with constraints on the allowed plasma concentrations, drug exposure, and leukopenia. Given a schedule of drug administrations, the mathematical model optimized the drug doses that could minimize the tumor burden while limiting toxicity on the white blood cells. Simulation suggests that the optimal drug administration is an initial high dose chemotherapy up to saturation of constraints associated with normal cell toxicity followed by a maintenance continuous infusion at a moderate rate. Data related to etoposide investigations were next used in a feasibility study. Simulations made with the usual clinical protocols and optimized protocols revealed that model-based optimal drug doses lead to greater cytoreduction. Also, examples showed how to use this new approach for the dose ranging problem and they evaluated the sensitivity of the optimized protocols with respect to the clinical constraints.     

HPMA-hydrogels result in prolonged delivery of anticancer drugs and are a promising tool for the treatment of sensitive and multidrug resistant leukaemia

Treatment of an established BCL1 leukaemia in mice showed that the use of hydrogels is advantageous in comparison with free doxorubicin (DOX), partially due to the different pharmacokinetic profile of the drug release. Pharmacologically active concentrations ranging from 100 to 800 ng/ml were detectable in the bloodstream for more than 4 days when DOX-loaded hydrogels were implanted into mice. Animals treated with free DOX survived for 35 days, survival of hydrogel-DOX treated animals increased up to 60 days and long-term survivors were achieved, when the second hydrogel was implanted 2 weeks after the first one. Hydrogels containing vinblastine (VLB) were ineffective. N-(2-hydroxypropyl)methacrylamide (HPMA) hydrogels were also used in combined therapy against multidrug resistant leukaemia P388-MDR to achieve a synergistic effect of both the cytostatic drug and chemosensitising agent. It was shown that when 4 times the maximal tolerated dose (MTD) of free DOX was incorporated into HPMA-hydrogels, tumour volume was reduced by approximately 50% after implantation of the hydrogel containing DOX and cyclosporine A (CsA) and survival was slightly prolonged.     

Efficacy and safety of tigecycline monotherapy versus combination therapy for the treatment of hospital-acquired pneumonia (HAP): a meta-analysis of cohort studies

The broad spectrum antibiotic tigecycline shows promising efficacy against many multiple drug resistant (MDR) pathogens. However, its clinical efficacy in the treatment of hospital-acquired pneumonia (HAP) is unclear. Several studies have reported on the treatment failures of tigecycline monotherapy, suggesting that it may not be sufficient to control severe infections. Combination therapy has become an option to treat MDR bacterial infections. We conducted a literature search using PubMed, Cochrane Library, Embase, Elsevier and the Web of Knowledge databases up to 29 February 2017 to identify relevant published studies. Studies were considered eligible if they were a cohort study that assessed mortality and the safety of tigecycline monotherapy versus combination therapy with other antimicrobial agents for HAP. The primary outcome was treatment mortality rate, while the secondary outcomes were adverse events. Meta-analysis was done using fixed-effects models. Five trials were included. The monotherapy tigecycline had a higher mortality compared to the combination therapy group. There was a significant difference for the treatment of HAP. However, two prospective cohort studies showed that there was no significant difference in mortality rate between the tigecycline monotherapy and the tigecycline combination therapy. Three retrospective cohort studies showed that tigecycline monotherapy had a high mortality rate. Tigecycline combination therapy efficiently treats HAP. There is a great need for well-designed studies to evaluate the effectiveness and safety of combination therapies as they compare to tigecycline monotherapy.     

Enhancing the efficacy of chemotherapeutic drugs by the suppression of antiapoptotic cellular defense

The study was aimed at evaluating the combination of a traditional anticancer drug doxorubicin (DOX) with a suppressor of antiapoptotic cellular defense--synthetic peptide corresponding to the minimal sequence of BCL-2 homology 3 (BH3) domain. BH3 peptide was delivered into cells by fusion with a peptide corresponding to the Antennapedia (Ant) internalization sequence. The cytotoxicity of DOX, Ant-BH3 and Ant-BH3 mixed in with DOX, mitochondrial transmembrane potential, expression of genes encoding pro- and antiapoptotic members of BCL-2 protein family and caspases, caspases activity, apoptosis induction were assessed in human ovarian carcinoma cells. It was found that the combination in one drug formulation of DOX and Ant-BH3 produced two main effects: (1) enhancing the apoptosis induction by an anticancer drug, and (2) preventing the development of antiapoptotic cellular drug resistance. The results confirmed that anticancer drug-BH3 combination might form the basis for a new advanced anticancer proapoptotic drug delivery systems.     

The distribution and retention of paclitaxel and doxorubicin in multicellular layer cultures

Limited distribution of anticancer drugs has been recognized as a significant hurdle to efficacy. We investigated a detailed penetration/distribution profile of paclitaxel-rhodamine (PTX-rd) and doxorubicin (DOX) in multicellular layer (MCL) cultures of human cancer cells as an in vitro model for avascular regions of solid tumors. MCLs were exposed to drugs and fluorescent images of frozen sections were acquired for determination of drug penetration into MCL under various exposure conditions. PTX-rd and DOX showed drastically different profiles of penetration. DOX showed full penetration after 1 h and accumulation over 3 h, whereas PTX-rd showed slow and limited penetration, with accumulation only within the top 20% of layers by 2 h and insignificant penetration even at 72 h. Drug retention in MCL was more dependent on drug concentration, rather than exposure time, i.e., drug distribution increased by 6.3- and 2.5-fold for PTX-rd and DOX, respectively, when exposed to higher concentrations under comparable AUC exposure (1 μM x 24 h vs. 50 μM x 0.5 h). Anti-proliferative activity of PTX and DOX in MCL, as determined by cell cycle analysis, was minimal and may be attributed, at least in part, to their limited distribution in multicellular cultures. Overall, we demonstrated that penetration and retention of PTX and DOX in MCL was not only concentration- and time-dependent, but also schedule-dependent. It is suggested that slow releasing formulations or a slow infusion regimen may not necessarily be desirable, especially for PTX, due to insufficient penetration and accumulation which may result from a low local concentration at the target site.     

A composite polymer nanoparticle overcomes multidrug resistance and ameliorates doxorubicin-associated cardiomyopathy

Acquired chemotherapy resistance is a major contributor to treatment failure in oncology. For example, the efficacy of the common anticancer agent doxorubicin (DOX) is limited by the emergence of multidrug resistance (MDR) phenotype in cancer cells. While dose escalation of DOX can circumvent such resistance to a degree, this is precluded by the appearance of cardiotoxicity, a particularly debilitating condition in children. In vitro studies have established the ability of the natural phytochemical curcumin to overcome MDR; however, its widespread clinical application is restricted by poor solubility and low bioavailability. Building upon our recently developed polymer nanoparticle of curcumin (NanoCurc or NC) that significantly enhances the systemic bioavailability of curcumin, we synthesized a doxorubicin-curcumin composite nanoparticle formulation called NanoDoxCurc (NDC) for overcoming DOX resistance. Compared to DOX alone, NDC inhibited the MDR phenotype and caused striking growth inhibition both in vitro and in vivo in several models of DOX-resistant cancers (multiple myeloma, acute leukemia, prostate and ovarian cancers, respectively). Notably, NDC-treated mice also demonstrated complete absence of cardiac toxicity, as assessed by echocardiography, or any bone marrow suppression, even at cumulative dosages where free DOX and pegylated liposomal DOX (Doxil®) resulted in demonstrable attenuation of cardiac function and hematological toxicities. This improvement in safety profile was achieved through a reduction of DOX-induced intracellular oxidative stress, as indicated by total glutathione levels and glutathione peroxidase activity in cardiac tissue. A composite DOX-curcumin nanoparticle that overcomes both MDR-based DOX chemoresistance and DOX-induced cardiotoxicity holds promise for providing lasting and safe anticancer therapy.     

Doxorubicin versus doxorubicin and cisplatin in endometrial carcinoma: definitive results of a randomised study (55872) by the EORTC Gynaecological Cancer Group.

BACKGROUND: Combination chemotherapy yields better response rates which do not always lead to a survival advantage. The aim of this study was to investigate whether the reported differences in the efficacy and toxicity of monotherapy with doxorubicin (DOX) versus combination therapy with cisplatin (CDDP) in endometrial adenocarcinoma lead to significant advantage in favour of the combination. PATIENTS AND METHODS: Eligible patients had histologically-proven advanced and/or recurrent endometrial adenocarcinoma and were chemo-na?ve. Treatment consisted of either DOX 60 mg/m(2) alone or CDDP 50 mg/m2 added to DOX 60 mg/m2, every 4 weeks. RESULTS: A total of 177 patients were entered and median follow-up is 7.1 years. The combination DOX-CDDP was more toxic than DOX alone. Haematological toxicity consisted mainly of white blood cell toxicity grade 3 and 4 (55% versus 30%). Non-haematological toxicity consisted mainly of grade 3 and 4 alopecia (72% versus 65%) and nausea/vomiting (36 % versus 12%). The combination DOX-CDDP provided a significantly higher response rate than single agent DOX (P <0.001). Thirty-nine patients (43%) responded on DOX-CDDP [13 complete responses (CRs) and 26 partial responses (PRs)], versus 15 patients (17%) on DOX alone (8 CR and 7 PR). The median overall survival (OS) was 9 months in the DOX-CDDP arm versus 7 months in the DOX alone arm (Wilcoxon P = 0.0654). Regression analysis showed that WHO performance status was statistically significant as a prognostic factor for survival, and stratifying for this factor, treatment effect reaches significance (hazard ratio = 1.46, 95% confidence interval 1.05-2.03, P = 0.024). CONCLUSIONS: In comparison to single agent DOX, the combination of DOX-CDDP results in higher but acceptable toxicity. The response rate produced is significantly higher, and a modest survival benefit is achieved with this combination regimen, especially in patients with a good performance status.