Showing papers on "Doxorubicin published in 2007"

HER2 and Response to Paclitaxel in Node-Positive Breast Cancer

Abstract: BACKGROUND The status of human epidermal growth factor receptor type 2 (HER2) in breast-cancer cells predicts clinical outcomes in women who receive adjuvant anthracycline-based chemotherapy. We hypothesized that HER2 positivity predicts a benefit from adjuvant doxorubicin doses above standard levels, from the addition of paclitaxel after adjuvant chemotherapy with doxorubicin plus cyclophosphamide, or from both. METHODS We randomly selected 1500 women from 3121 women with node-positive breast cancer who had been randomly assigned to receive doxorubicin (60, 75, or 90 mg per square meter of body-surface area) plus cyclophosphamide (600 mg per square meter) for four cycles, followed by four cycles of paclitaxel (175 mg per square meter) or observation. Tissue blocks from 1322 of these 1500 women were available. Immunohistochemical analyses of these tissue specimens for HER2 with the CB11 monoclonal antibody against HER2 or with a polyclonal-antibody assay kit and fluorescence in situ hybridization for HER2 amplification were performed. RESULTS No interaction was observed between HER2 positivity and doxorubicin doses above 60 mg per square meter. HER2 positivity was, however, associated with a significant benefit from paclitaxel. The interaction between HER2 positivity and the addition of paclitaxel to the treatment was associated with a hazard ratio for recurrence of 0.59 (P=0.01). Patients with a HER2-positive breast cancer benefited from paclitaxel, regardless of estrogen-receptor status, but paclitaxel did not benefit patients with HER2-negative, estrogen-receptor-positive cancers. CONCLUSIONS The expression or amplification, or both, of HER2 by a breast cancer is associated with a benefit from the addition of paclitaxel after adjuvant treatment with doxorubicin (<60 mg per square meter) plus cyclophosphamide in node-positive breast cancer, regardless of estrogen-receptor status. Patients with HER2-negative, estrogen-receptor-positive, node-positive breast cancer may gain little benefit from the administration of paclitaxel after adjuvant chemotherapy with doxorubicin plus cyclophosphamide.

Topoisomerase IIβ–Mediated DNA Double-Strand Breaks: Implications in Doxorubicin Cardiotoxicity and Prevention by Dexrazoxane

Abstract: Doxorubicin is among the most effective and widely used anticancer drugs in the clinic. However, cardiotoxicity is one of the life-threatening side effects of doxorubicin-based therapy. Dexrazoxane (Zinecard, also known as ICRF-187) has been used in the clinic as a cardioprotectant against doxorubicin cardiotoxicity. The molecular basis for doxorubicin cardiotoxicity and the cardioprotective effect of dexrazoxane, however, is not fully understood. In the present study, we showed that dexrazoxane specifically abolished the DNA damage signal gamma-H2AX induced by doxorubicin, but not camptothecin or hydrogen peroxide, in H9C2 cardiomyocytes. Doxorubicin-induced DNA damage was also specifically abolished by the proteasome inhibitors bortezomib and MG132 and much reduced in top2beta(-/-) mouse embryonic fibroblasts (MEF) compared with TOP2beta(+/+) MEFs, suggesting the involvement of proteasome and DNA topoisomerase IIbeta (Top2beta). Furthermore, in addition to antagonizing Top2 cleavage complex formation, dexrazoxane also induced rapid degradation of Top2beta, which paralleled the reduction of doxorubicin-induced DNA damage. Together, our results suggest that dexrazoxane antagonizes doxorubicin-induced DNA damage through its interference with Top2beta, which could implicate Top2beta in doxorubicin cardiotoxicity. The specific involvement of proteasome and Top2beta in doxorubicin-induced DNA damage is consistent with a model in which proteasomal processing of doxorubicin-induced Top2beta-DNA covalent complexes exposes the Top2beta-concealed DNA double-strand breaks.

Targeted delivery of doxorubicin to the rat brain at therapeutic levels using MRI-guided focused ultrasound.

Abstract: The clinical application of chemotherapy to brain tumors has been severely limited because antitumor agents are typically unable to penetrate an intact blood-brain barrier (BBB). Although doxorubicin (DOX) has been named as a strong candidate for chemotherapy of the central nervous system (CNS), the BBB often prevents cytotoxic levels from being achieved. In this study, we demonstrate a noninvasive method for the targeted delivery of DOX through the BBB, such that drug levels shown to be therapeutic in human tumors are achieved in the normal rat brain. Using MRI-guided focused ultrasound with preformed microbubbles (Optison) to locally disrupt the BBB and systemic administration of DOX, we achieved DOX concentrations of 886 +/- 327 ng/g tissue in the brain with minimal tissue effects. Tissue DOX concentrations of up to 5,366 +/- 659 ng/g tissue were achieved with higher Optison doses, but with more significant tissue damage. In contrast, DOX accumulation in nontargeted contralateral brain tissue remained significantly lower for all paired samples (p < 0.001). These results suggest that targeted delivery by focused ultrasound may render DOX chemotherapy a viable treatment option against CNS tumors, despite previous accessibility limitations. In addition, MRI signal enhancement in the sonicated region correlated strongly with tissue DOX concentration (r = 0.87), suggesting that contrast-enhanced MRI could perhaps indicate drug penetration during image-guided interventions. Our technique using MRI-guided focused ultrasound to achieve therapeutic levels of DOX in the brain offers a large step forward in the use of chemotherapy to treat patients with CNS malignancies.

Pulsed-high intensity focused ultrasound and low temperature-sensitive liposomes for enhanced targeted drug delivery and antitumor effect.

Abstract: Purpose: To determine if pulsed-high intensity focused ultrasound (HIFU) could effectively serve as a source of hyperthermia with thermosensitive liposomes to enhance delivery and efficacy of doxorubicin in tumors. Experimental Design: Comparisons in vitro and in vivo were carried out between non–thermosensitive liposomes (NTSL) and low temperature–sensitive liposomes (LTSL). Liposomes were incubated in vitro over a range of temperatures and durations, and the amount of doxorubicin released was measured. For in vivo experiments, liposomes and free doxorubicin were injected i.v. in mice followed by pulsed-HIFU exposures in s.c. murine adenocarcinoma tumors at 0 and 24 h after administration. Combinations of the exposures and drug formulations were evaluated for doxorubicin concentration and growth inhibition in the tumors. Results: In vitro incubations simulating the pulsed-HIFU thermal dose (42°C for 2 min) triggered release of 50% of doxorubicin from the LTSLs; however, no detectable release from the NTSLs was observed. Similarly, in vivo experiments showed that pulsed-HIFU exposures combined with the LTSLs resulted in more rapid delivery of doxorubicin as well as significantly higher i.t. concentration when compared with LTSLs alone or NTSLs, with or without exposures. Combining the exposures with the LTSLs also significantly reduced tumor growth compared with all other groups. Conclusions: Combining low-temperature heat-sensitive liposomes with noninvasive and nondestructive pulsed-HIFU exposures enhanced the delivery of doxorubicin and, consequently, its antitumor effects. This combination therapy could potentially produce viable clinical strategies for improved targeting and delivery of drugs for treatment of cancer and other diseases.

Collateral damage in cancer chemotherapy: oxidative stress in nontargeted tissues.

Abstract: Injury to nontargeted tissues in chemotherapy often complicates cancer treatment by limiting therapeutic dosages of anticancer drugs and by impairing the quality of life of patients during and after treatment. Oxidative stress, directly or indirectly caused by chemotherapeutics as exemplified by doxorubicin, is one of the underlying mechanisms of the toxicity of anticancer drugs in noncancerous tissues, including the heart and brain. A comprehensive understanding of the mechanisms of oxidative injury to normal tissue will be essential for the improvement of strategies to prevent or attenuate the toxicity of chemotherapeutic agents without compromising their chemotherapeutic value.

Selective induction of chemotherapy resistance of mammary tumors in a conditional mouse model for hereditary breast cancer

Abstract: We have studied in vivo responses of “spontaneous” Brca1- and p53-deficient mammary tumors arising in conditional mouse mutants to treatment with doxorubicin, docetaxel, or cisplatin. Like human tumors, the response of individual mouse tumors varies, but eventually they all become resistant to the maximum tolerable dose of doxorubicin or docetaxel. The tumors also respond well to cisplatin but do not become resistant, even after multiple treatments in which tumors appear to regrow from a small fraction of surviving cells. Classical biochemical resistance mechanisms, such as up-regulated drug transporters, appear to be responsible for doxorubicin resistance, rather than alterations in drug-damage effector pathways. Our results underline the promise of these mouse tumors for the study of tumor-initiating cells and of drug therapy of human cancer.

Anthracycline-induced cardiotoxicity and the cardiac-sparing effect of liposomal formulation.

Abstract: The anthracyclines are a group of antibiotics that are among the most potent chemotherapeutic agents. They are highly effective against a broad spectrum of malignancies, including lymphoma, gastric cancer, small cell lung cancer, sarcoma, and breast cancer. Unfortunately, these agents also exhibit a well-recognized cumulative-dose related cardiotoxic profi le that limits the extent to which they can be used safely. In clinical practice, most clinicians limit the cumulative dose of doxorubicin (the most widely used agent in this group) to 400-450 mg/m 2 , but considerable cardiac damage is now known to occur at cumulative dosages considerably below this level. Regimens using newer combinations of agents, the most widely studied of which is the monoclonal antibody trastuzumab, are known to augment the cardiotoxicity of anthracyclines. The application of nanotechnology to medicine involves the use of devices that will interact with the body at the molecular level. These methods can lead to target and tissue specifi c clinical application, often with minimal or reduced side effects. Liposomal preparations incorporate such technology, thereby altering some important characteristics of the parent compound and facilitating concentration at the tumor site. In the case of liposomal doxorubicin, cardiotoxicity is reduced signifi cantly. This review summarizes the important information on the liposomal preparation of anthracyclines.

Roles of DNA topoisomerase II isozymes in chemotherapy and secondary malignancies

Abstract: Drugs that target DNA topoisomerase II (Top2), including etoposide (VP-16), doxorubicin, and mitoxantrone, are among the most effective anticancer drugs in clinical use. However, Top2-based chemotherapy has been associated with higher incidences of secondary malignancies, notably the development of acute myeloid leukemia in VP-16-treated patients. This association is suggestive of a link between carcinogenesis and Top2-mediated DNA damage. We show here that VP-16-induced carcinogenesis involves mainly the beta rather than the alpha isozyme of Top2. In a mouse skin carcinogenesis model, the incidence of VP-16-induced melanomas in the skin of 7,12-dimethylbenz[a]anthracene-treated mice is found to be significantly higher in TOP2beta(+) than in skin-specific top2beta-knockout mice. Furthermore, VP-16-induced DNA sequence rearrangements and double-strand breaks (DSBs) are found to be Top2beta-dependent and preventable by cotreatment with a proteasome inhibitor, suggesting the importance of proteasomal degradation of the Top2beta-DNA cleavage complexes in VP-16-induced DNA sequence rearrangements. VP-16 cytotoxicity in transformed cells expressing both Top2 isozymes is, however, found to be primarily Top2alpha-dependent. These results point to the importance of developing Top2alpha-specific anticancer drugs for effective chemotherapy without the development of treatment-related secondary malignancies.

Role of anthracyclines in the era of targeted therapy

Abstract: Anthracyclines such as doxorubicin, epirubicin, and daunorubicin are among the most active cytoxic agents for treatment of a wide variety of solid tumors and hematological malignancies. The downside associated with chronic administration of anthracyclines is the induction of cardiomyopathy and congestive heart failure, usually refractory to common treatments. Anthracycline liposomal formulations are currently the best-known alternatives to improve the index and spectrum of anticancer activity of these drugs and decrease their cardiotoxicity. In the current target therapy era in oncology, anthracyclines increase the antitumor effects in more than additive fashion, being excellent partners for other active agents like taxanes and trastuzumab. It is important to note, however, that the enhanced antitumor activity of these combination therapies is often accompanied with increased cardiotoxicity. The issue of anthracycline cardiotoxicity has not been solved so far and it is also important to stress the current lack of proper prevention and treatment strategies.

Improving Penetration in Tumors With Nanoassemblies of Phospholipids and Doxorubicin

Abstract: Background Drug delivery and penetration into neoplastic cells distant from tumor vessels is critical for the effectiveness of solid tumor chemotherapy. We hypothesized that 10- to 20-nm nanoassemblies of phospholipids containing doxorubicin would improve the drug's penetration, accumulation, and antitumor activity. Methods Doxorubicin was incorporated into polyethylene glycol-phosphatidylethanolamine (PEG-PE) block copolymer micelles by a self-assembly procedure to form nanoassemblies of doxorubicin and PEG-PE. In vitro cytotoxicity of micelle-encapsulated doxorubicin (M-Dox) against A549 human non-small-cell lung carcinoma cells was examined using the methylthiazoletetrazolium assay, and confocal microscopy, total internal reflection fluorescence microscopy, and flow cytometry were used to examine intracellular distribution and the cellular uptake mechanism. C57BI/6 mice (n = 10-40 per group) bearing subcutaneous or pulmonary Lewis lung carcinoma (LLC) tumors were treated with M-Dox or free doxorubicin, and tumor growth, doxorubicin pharmacokinetics, and mortality were compared. Toxicity was analyzed in tumor-free mice. All statistical tests were two-sided. Results Encapsulation of doxorubicin in PEG-PE micelles increased its internalization by A549 cells into lysosomes and enhanced cytotoxicity. Drug-encapsulated doxorubicin was more effective in inhibiting tumor growth in the subcutaneous LLC tumor model (mean tumor volumes in mice treated with 5 mg/kg M-Dox = 1126 mm 3 and in control mice = 3693 mm 3 , difference = 2567 mm 3 , 95% confidence interval [Cl] = 2190 to 2943 mm 3 , P<.001) than free doxorubicin (mean tumor volumes in doxorubicin-treated mice = 3021 mm 3 and in control mice = 3693 mm 3 , difference = 672 mm 3 , 95% Cl = 296 to 1049 mm 3 , P=.0332, Wilcoxon signed rank test). M-Dox treatment prolonged survival in both mouse models and reduced metastases in the pulmonary model; it also reduced toxicity. Conclusions We have developed a novel PEG-PE-based nanocarrier of doxorubicin that increased cytotoxicity in vitro and enhanced antitumor activity in vivo with low systemic toxicity. This drug packaging technology may provide a new strategy for design of cancer therapies.

Artesunate Induces ROS-Mediated Apoptosis in Doxorubicin-Resistant T Leukemia Cells

Abstract: Background A major obstacle for successful cancer treatment often is the development of drug resistance in cancer cells during chemotherapy Therefore, there is an urgent need for novel drugs with improved efficacy against tumor cells and with less toxicity on normal cells Artesunate (ART), a powerful anti-malarial herbal compound, has been shown to inhibit growth of various tumor cell lines in vitro and of xenografted Kaposi's sarcoma in mice in vivo However, the molecular mechanisms by which ART exerts its cytotoxicity have not been elucidated The ART-class of anti-malarial compounds is attractive due to their activity against multidrug-resistant Plasmodium falciparum and Plasmodium vivax strains Another salient feature of these compounds is the lack of severe side effects in malaria patients

Phase III trial of two investigational schedules of ifosfamide compared with standard-dose doxorubicin in advanced or metastatic soft tissue sarcoma: a European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group Study

Abstract: Purpose Single-agent doxorubicin remains the standard treatment for advanced soft tissue sarcomas. Combining doxorubicin with standard-dose ifosfamide has not been shown to improve survival and is associated with a significantly increased toxicity; it is not known whether higher dose single-agent ifosfamide is superior to doxorubicin.

CD74: A New Candidate Target for the Immunotherapy of B-Cell Neoplasms

Abstract: CD74 is an integral membrane protein that functions as a MHC class II chaperone. Moreover, it has recently been shown to have a role as an accessory-signaling molecule and has been implicated in malignant B-cell proliferation and survival. These biological functions combined with expression of CD74 on malignant B cells and limited expression on normal tissues implicate CD74 as a potential therapeutic target. The anti-CD74 monoclonal antibody LL1 has been humanized (hLL1 milatuzumab or IMMU-115) and can provide the basis for novel therapeutic approaches to B-cell malignancies, particularly because this antibody shows rapid internalization into CD74+ malignant cells. This article reviews the preclinical evaluations of LL1, its humanized form, and isotope, drug, and toxin conjugates. These studies show that unconjugated hLL1 and conjugates of hLL1 constructs with radioisotopes, doxorubicin, and frog RNase have high antitumor activity in non-Hodgkin's lymphoma and multiple myeloma in vitro and in tumor xenograft models. Single-dose studies of hLL1 in monkeys showed no adverse effects but did decrease circulating B and T lymphocytes and natural killer cells. When evaluated in combination with rituximab, either equivalent or improved efficacy, compared with either antibody alone, was observed. CD74 is a new candidate target for the immunotherapy of neoplasms expressing this antigen, which can be exploited using either a naked antibody or conjugated to isotopes, drugs, or toxins.

Riboregulator H19 induction of MDR1-associated drug resistance in human hepatocellular carcinoma cells

Abstract: Acquisition of drug resistance is one of the main obstacles encountered in cancer chemotherapy. Overexpression of multi-drug resistance 1 (MDR1) gene and its protein product P-glycoprotein, accompanied with a decrease in doxorubicin accumulation level, was observed in doxorubicin-resistant R-HepG2 cells, a subline derived by selection of human hepatocellular carcinoma HepG2 cells with doxorubicin. In addition, Northern-blot analysis revealed an eight fold upregulation of the imprinted H19 mRNA in R-HepG2 cells. H19 knockdown by transfection with antisense H19 oligonucleotides suppressed the MDR1/P-glycoprotein expression, increased the cellular doxorubicin accumulation level and sensitized doxorubicin toxicity in both HepG2 parent cells and R-HepG2 cells. Results from methylation-specific polymerase chain reaction analysis indicated that the MDR1 gene promoter was hypomethylated in R-HepG2 cells. Antisense H19 oligonucleotides transfection induced a marked increase in the percentage of MDR1 promoter methylation and decrease in MDR1 expression in R-HepG2 cells. Thus, the H19 gene is believed to induce P-glycoprotein expression and MDR1-associated drug resistance at least in liver cancer cells through regulation of MDR1 promoter methylation.

Role of human longevity assurance gene 1 and C18-ceramide in chemotherapy-induced cell death in human head and neck squamous cell carcinomas

Abstract: In this study, quantitative isobologram studies showed that treatment with gemcitabine and doxorubicin, known inducers of ceramide generation, in combination, supraadditively inhibited the growth of human UM-SCC-22A cells in situ. Then, possible involvement of the human homologue of yeast longevity assurance gene 1 (LASS1)/ C18-ceramide in chemotherapy-induced cell death in these cells was examined. Gemcitabine/doxorubicin combination treatment resulted in the elevation of mRNA and protein levels of LASS1 and not LASS2-6, which was consistent with a 3.5-fold increase in the endogenous (dihydro)ceramide synthase activity of LASS1 for the generation of C18-ceramide. Importantly, the overexpression of LASS1 (both human and mouse homologues) enhanced the growth-inhibitory effects of gemcitabine/ doxorubicin with a concomitant induction of caspase-3 activation. In reciprocal experiments, partial inhibition of human LASS1 expression using small interfering RNA (siRNA) prevented cell death by about 50% in response to gemcitabine/doxorubicin. In addition, LASS1, and not LASS5, siRNA modulated the activation of caspase-3 and caspase-9, but not caspase-8, in response to this combination. Treatment with gemcitabine/doxorubicin in combination also resulted in a significant suppression of the head and neck squamous cell carcinoma (HNSCC) tumor growth in severe combined immunodeficiency mice bearing the UM-SCC-22A xenografts. More interestingly, analysis of endogenous ceramide levels in these tumors by liquid chromatography/mass spectroscopy showed that only the levels of C18-ceramide, the main product of LASS1, were elevated significantly (about 7-fold) in response to gemcitabine/doxorubicin when compared with controls. In conclusion, these data suggest an important role for LASS1/C18-ceramide in gemcitabine/doxorubicininduced cell death via the activation of caspase-9/3 in HNSCC. [Mol Cancer Ther 2007;6(2):712 – 22]

The rates of chemotherapy-induced amenorrhea in patients treated with adjuvant doxorubicin and cyclophosphamide followed by a taxane

Abstract: Objective:Adjuvant chemotherapy in premenopausal women with breast cancer may induce amenorrhea, which can affect fertility, choice of hormonal therapy, and increase the risk of late toxicity. The incidence of chemotherapy-induced amenorrhea (CIA) resulting from doxorubicin and cyclophosphamide (AC)

Expression of the IAP protein family is dysregulated in pancreatic cancer cells and is important for resistance to chemotherapy.

Abstract: Pancreatic cancer is one of the most aggressive human tumors with a 5-year survival rate of only 3% and a striking resistance to chemotherapy and radiotherapy. The search for new therapeutic approaches includes strategies exploiting the deregulation of apoptotic pathways commonly found in cancer cells. The IAP proteins are inhibitors of apoptosis that have altered activity in numerous cancer types and are implicated in resistance to chemotherapy, and therefore are potentially interesting as therapeutic targets. We investigated alterations in the expression of IAPs and their inhibitors in pancreatic adenocarcinoma by using real-time PCR, in situ hybridization and immunohistochemistry. We found differential expression of various IAPs in this malignancy, and particularly we observed overexpression of cIAP-2, survivin, livin and XIAP. We also looked for correlations between the expression of IAPs and resistance to paclitaxel, doxorubicin, CDDP and 5-fluorouracil, and found that resistance to these drugs correlates most significantly with expression of cIAP-2. Using RNAi to downregulate these proteins we further confirmed that the levels of cIAP-2 and XIAP influence the response to the anti-cancer drugs, although only marginally for 5-FU. We conclude that anti-tumor strategies based on the inhibition of particular IAPs can be useful in targeting pancreatic adenocarcinoma.

DOXO-EMCH (INNO-206): the first albumin-binding prodrug of doxorubicin to enter clinical trials.

Abstract: The (6-maleimidocaproyl)hydrazone derivative of doxorubicin (DOXO-EMCH) is an albumin-binding prodrug of doxorubicin with acid-sensitive properties that demonstrates superior antitumor efficacy in murine tumor models and a favorable toxicity profile in mice, rats and dogs, including significantly reduced cardiotoxicity. After intravenous administration, DOXO-EMCH binds rapidly to the Cys-34 position of circulating albumin and accumulates in solid tumors due to passive targeting. In a clinical Phase I study, the dose of doxorubicin could be increased by a factor of 4.5-340 mg/m(2) when 75 mg/m(2) of free doxorubicin is considered to be the dose that can be administered as a single agent concomitant with the typical spectrum of side effects (i.e., myelotoxicity and mucositis). DOXO-EMCH was able to induce tumor regressions in anthracycline-sensitive tumors (i.e., breast cancer, small cell lung cancer and sarcoma). Phase II studies will be initiated at the beginning of 2007.

Chemosensitization of cancer in vitro and in vivo by nitric oxide signaling.

Abstract: Purpose: Hypoxia contributes to drug resistance in solid cancers, and studies have revealed that low concentrations of nitric oxide (NO) mimetics attenuate hypoxia-induced drug resistance in tumor cells in vitro . Classic NO signaling involves activation of soluble guanylyl cyclase, generation of cyclic GMP (cGMP), and activation of cGMP-dependent protein kinase. Here, we determined whether chemosensitization by NO mimetics requires cGMP-dependent signaling and whether low concentrations of NO mimetics can chemosensitize tumors in vivo . Experimental Design: Survival of human prostate and breast cancer cells was assessed by clonogenic assays following exposure to chemotherapeutic agents. The effect of NO mimetics on tumor chemosensitivity in vivo was determined using a mouse xenograft model of human prostate cancer. Drug efflux in vitro was assessed by measuring intracellular doxorubicin-associated fluorescence. Results: Low concentrations of the NO mimetics glyceryl trinitrate (GTN) and isosorbide dinitrate attenuated hypoxia-induced resistance to doxorubicin and paclitaxel. Similar to hypoxia-induced drug resistance, inhibition of various components of the NO signaling pathway increased resistance to doxorubicin, whereas activation of the pathway with 8-bromo-cGMP attenuated hypoxia-induced resistance. Drug efflux was unaffected by hypoxia and inhibitors of drug efflux did not significantly attenuate hypoxia-induced chemoresistance. Compared with mice treated with doxorubicin alone, tumor growth was decreased in mice treated with doxorubicin and a transdermal GTN patch. The presence of GTN and GTN metabolites in plasma samples was confirmed by gas chromatography. Conclusion: Tumor hypoxia induces resistance to anticancer drugs by interfering with endogenous NO signaling and reactivation of NO signaling represents a novel approach to enhance chemotherapy.

Anthracycline cardiotoxicity in breast cancer patients: synergism with trastuzumab and taxanes.

Abstract: Doxorubicin is known to cause cardiomyopathy and congestive heart failure (CHF) upon chronic administration. A major obstacle to doxorubicin-containing multiagent therapies pertains to the possible development of cardiomyopathy and CHF at lower than expected cumulative doses of doxorubicin. For example, the cardiac toxicity of doxorubicin is aggravated by the anti-HER2 antibody Trastuzumab or by the tubulin-active taxane paclitaxel; however, the mechanisms by which Trastuzumab and paclitaxel aggravate doxorubicin-induced cardiotoxicity are mechanistically distinct: Trastuzumab interferes with cardiac-specific survival factors that help the heart to withstand stressor agents like anthracyclines, while paclitaxel acts by stimulating the formation of anthracycline metabolites that play a key role in the mechanism of cardiac failure. Here, we briefly review the molecular mechanisms of the cardiotoxic synergism of Trastuzumab or paclitaxel with doxorubicin, and we attempt to briefly outline how the mechanistic know-how translates into the clinical strategies for improving the safety of anthracycline-based multiagent therapies.

Functional p53 Signaling in Kaposi's Sarcoma-Associated Herpesvirus Lymphomas: Implications for Therapy

Abstract: The Kaposi's sarcoma-associated herpesvirus (KSHV/HHV8) is associated with Kaposi's sarcoma (KS) as well as primary effusion lymphomas (PEL). The expression of viral proteins capable of inactivating the p53 tumor suppressor protein has been implicated in KSHV oncogenesis. However, DNA-damaging drugs such as doxorubicin are clinically efficacious against PEL and KS, suggesting that p53 signaling remains intact despite the presence of KSHV. To investigate the functionality of p53 in PEL, we examined the response of a large number of PEL cell lines to doxorubicin. Two out of seven (29%) PEL cell lines harbored a mutant p53 allele (BCBL-1 and BCP-1) which led to doxorubicin resistance. In contrast, all other PEL containing wild-type p53 showed DNA damage-induced cell cycle arrest, p53 phosphorylation, and p53 target gene activation. These data imply that p53-mediated DNA damage signaling was intact. Supporting this finding, chemical inhibition of p53 signaling in PEL led to doxorubicin resistance, and chemical activation of p53 by the Hdm2 antagonist Nutlin-3 led to unimpaired induction of p53 target genes as well as growth inhibition and apoptosis.

Convection-enhanced delivery of nanoliposomal CPT-11 (irinotecan) and PEGylated liposomal doxorubicin (Doxil) in rodent intracranial brain tumor xenografts

Abstract: We have previously shown that convection-enhanced delivery (CED) of highly stable nanoparticle/liposome agents encapsulating chemotherapeutic drugs is effective against intracranial rodent brain tumor xenografts In this study, we have evaluated the combination of a newly developed nanoparticle/liposome containing the topoisomerase I inhibitor CPT-11 (nanoliposomal CPT-11 [nLs-CPT-11]), and PEGylated liposomal doxorubicin (Doxil) containing the topoisomerase II inhibitor doxorubicin Both drugs were detectable in the CNS for more than 36 days after a single CED application Tissue half-life was 167 days for nLs-CPT-11 and 109 days for Doxil The combination of the two agents produced synergistic cytotoxicity in vitro In vivo in U251MG and U87MG intracranial rodent xenograft models, CED of the combination was also more efficacious than either agent used singly Analysis of the parameters involved in this approach indicated that tissue pharmacokinetics, tumor microanatomy, and biochemical interactions of the drugs all contributed to the therapeutic efficacy observed These findings have implications for further clinical applications of CED-based treatment of brain tumors

Dexrazoxane prevents doxorubicin‐induced long‐term cardiotoxicity and protects myocardial mitochondria from genetic and functional lesions in rats

Abstract: Background and purpose: Doxorubicin causes a chronic cardiomyopathy in which reactive oxygen species (ROS) accumulate over time and are associated with genetic and functional lesions of mitochondria. Dexrazoxane is a cardioprotective iron chelator that interferes with ROS production. We aim to analyze the effects of dexrazoxane on mitochondria in the prevention of doxorubicin-induced chronic myocardial lesions. Experimental approach: Wistar rats (11 weeks of age) were injected with intravenous doxorubicin (0.8 mg kg -1 weekly for 7 weeks) with or without simultaneous dexrazoxane (8 mg kg -1 ). Animals were killed at 48 weeks. Cardiomyopathy was scored clinically and histologically and cardiac mitochondria were analyzed. Key results: Compared to control rats receiving saline, rats treated with doxorubicin alone developed a clinical, macroscopic, histological and ultrastructural cardiomyopathy with low cytochrome c-oxidase (COX) activity (26% of controls). The expression of the mtDNA-encoded COX II subunit was reduced (64% of controls). Myocardia exhibited a high production of ROS (malondialdehyde 338% and superoxide 787% of controls). Mitochondria were depleted of mitochondrial DNA (mtDNA copy number 46% of controls) and contained elevated levels of mtDNA deletions. Dexrazoxane co-administration prevented all these effects of doxorubicin on mitochondria, except that hearts co-exposed to doxorubicin and dexrazoxane had a slightly lower mtDNA content (81% of controls) and mtDNA deletions at low frequency. Conclusions and Implications: Dexrazoxane prevented doxorubicin induced late-onset cardiomyopathy and also protected the cardiac mitochondria from acquired ultrastructural, genetic and functional damage. British Journal of Pharmacology (2007) 151, 771–778; doi:10.1038/sj.bjp.0707294; published online 21 May 2007