The pivotal role of microRNA-21 in osteoclastogenesis inhibition by anthracycline glycoside aloin.

Osteopenic disorders such as osteoporosis and rheumatoid arthritis are characterized by excessive bone resorption by osteoclasts relative to bone formation by osteoblasts. MicroRNAs are emerging as key players in bone remodeling, modulating the functions of both osteoblasts and osteoclasts. Among them, miR-21 is highly expressed in osteoclast precursors and is known to regulate genesis, differentiation, and apoptosis of osteoclasts. The pro-osteoclastogenic nature of miR-21 makes it a potential candidate as a therapeutic target to treat bone disorders. We had previously demonstrated that anthroglycoside aloin derived from Aloe vera was effective in promoting osteoblastogenesis and inhibiting osteoclastogenesis. The present study investigated the role of miR-21 in aloin's inhibitory effect on osteoclast differentiation. Aloin effectively suppressed receptor activator of nuclear factor kappa-B (NFĸB) ligand (RankL)-induced miR-21 expression via repression of NFĸB activation. MiR-21 suppression resulted in upregulation of osteoclast suppressor programmed cell death protein 4 (PDCD4), and downregulation of osteoclast marker cathepsin K. Knockdown or gain-of-function studies revealed that miR-21 was pivotal to aloin's inhibitory effect on osteoclastogenesis. This study also highlights the dynamic potential of aloin as a therapeutic agent to treat osteopenic disorders.

Antimycobacterial activity of an anthracycline produced by an endophyte isolated from Amphipterygium adstringens.

The search for new compounds effective against Mycobacterium tuberculosis is still a priority in medicine. The evaluation of microorganisms isolated from non-conventional locations offers an alternative to look for new compounds with antimicrobial activity. Endophytes have been successfully explored as source of bioactive compounds. In the present work we studied the nature and antimycobacterial activity of a compound produced by Streptomyces scabrisporus, an endophyte isolated from the medicinal plant Amphipterygium adstringens. The active compound was detected as the main secondary metabolite present in organic extracts of the streptomycete and identified by NMR spectroscopic data as steffimycin B (StefB). This anthracycline displayed a good activity against M. tuberculosis H37Rv ATCC 27294 strain, with MIC100 and SI values of 7.8 µg/mL and 6.42, respectively. When tested against the rifampin mono resistant M. tuberculosis Mtb-209 pathogen strain, a better activity was observed (MIC100 of 3.9 µg/mL), suggesting a different action mechanism of StefB from that of rifampin. Our results supported the endophyte Streptomyces scabrisporus as a good source of StefB for tuberculosis treatment, as this anthracycline displayed a strong bactericidal effect against M. tuberculosis, one of the oldest and more dangerous human pathogens causing human mortality.

RESILIENCE: Phase III Randomized, Double-Blind Trial Comparing Sorafenib With Capecitabine Versus Placebo With Capecitabine in Locally Advanced or Metastatic HER2-Negative Breast Cancer.

INTRODUCTION: Sorafenib is a multikinase inhibitor with antiangiogenic/antiproliferative activity. In this randomized, double-blind, placebo-controlled phase III trial, we assessed first- or second-line capecitabine with sorafenib or placebo in patients with locally advanced/metastatic HER2-negative breast cancer resistant to a taxane and anthracycline and with known estrogen/progesterone receptor status. PATIENTS AND METHODS: A total of 537 patients were randomized to capecitabine 1000 mg/m2 orally twice per day for days 1 to 14 every 21 days with oral sorafenib 600 mg/d or placebo. The primary end point was progression-free survival (PFS). Patients were stratified according to hormone receptor status, previous chemotherapies for metastatic breast cancer, and geographic region. RESULTS: Treatment with sorafenib with capecitabine, compared with capecitabine with placebo, did not prolong median PFS (5.5 vs. 5.4 months; hazard ratio [HR], 0.973; 95% confidence interval [CI], 0.779-1.217; P = .811) or overall survival (OS; 18.9 vs. 20.3 months; HR, 1.195; 95% CI, 0.943-1.513; P = .140); or enhance overall response rate (ORR; 13.5% vs. 15.5%; P = .515). Any grade toxicities (sorafenib vs. placebo) included palmar-plantar erythrodysesthesia syndrome (PPES; 79.2% vs. 59.6%), diarrhea (47.3% vs. 37.8%), mucosal inflammation (15.4% vs. 6.7%), and hypertension (26.2% vs. 5.6%). Grade 3/4 toxicities included PPES (15.4% vs. 7.1%), diarrhea (4.2% vs. 6.4%), and vomiting (3.5% vs. 0.7%). CONCLUSION: The combination of sorafenib with capecitabine did not improve PFS, OS, or ORR in patients with HER2-negative advanced breast cancer. Rates of Grade 3 toxicities were higher in the sorafenib arm.

PARP inhibitors in acute myeloid leukaemia therapy: How a synthetic lethality approach can be a valid therapeutic alternative.

Acute myeloid leukaemia (AML) is a malignancy in need of new therapeutic options. The current standard of care chemotherapy, leads to complete remission (CR) in the vast majority of adult patients under the age of 60. In contrast, CR rates in patients over the age of 60 reaches only 40-60%. While achievement of a CR is an important stepping stone in the treatment of AML, the majority of these patients experience relapse and die of their disease without adequate consolidation chemotherapy. Blood and marrow transplantation (BMT) can improve outcome in a select patient with AML but unfortunately, it is not a valid treatment option for the majority of older patients. Thus, the development of novel chemotherapy regimens that capitalizes on AML biology to eliminate the malignant clone with little to no side effects on the normal haematopoiesis is paramount in the treatment of elderly patients. In the current paper, we propose to take advantage of the dysfunctional DNA repair mechanisms present in AML cells and induce synthetic lethality using a combination of PARP inhibitors with low dose anthracycline and DNMT inhibitors. Such a combination, while effectively eliminating leukaemia should be well tolerated and thus, suitable for the treatment of frail patients.

Have all-trans retinoic acid and arsenic trioxide replaced all-trans retinoic acid and anthracyclines in APL as standard of care.

Until recently, the standard of care in the treatment of APL has involved the combination of all-trans retinoic acid with anthracycline-based chemotherapy during both induction and consolidation. Additionally, the intensity of consolidation chemotherapy has evolved according to a universally accepted relapse-risk stratification algorithm based on the white cell and platelet counts at presentation. That standard of care is being challenged by the increasing incorporation of arsenic trioxide into front-line treatment protocols, based on two complementary observations. The first is the undoubted anti-leukaemic activity of arsenic trioxide as shown in the relapsed and refractory setting, and in the initial management of low- and intermediate-risk patients. The second is an improved understanding of the action of both all-trans retinoic acid and arsenic trioxide in mediating APL cell eradication, with increasing recognition that PML-RARA fusion protein degradation rather than direct induction of terminal differentiation is the primary mechanism for their ability to eliminate leukaemia initiating cells. As a result, we believe the standard of care for initial therapy in APL is shifting towards an all-trans retinoic acid plus arsenic trioxide-based approach, with additional chemotherapy reserved for patients with high-risk disease.

Oxidative stress, redox signaling, and metal chelation in anthracycline cardiotoxicity and pharmacological cardioprotection.

SIGNIFICANCE: Anthracyclines (doxorubicin, daunorubicin, or epirubicin) rank among the most effective anticancer drugs, but their clinical usefulness is hampered by the risk of cardiotoxicity. The most feared are the chronic forms of cardiotoxicity, characterized by irreversible cardiac damage and congestive heart failure. Although the pathogenesis of anthracycline cardiotoxicity seems to be complex, the pivotal role has been traditionally attributed to the iron-mediated formation of reactive oxygen species (ROS). In clinics, the bisdioxopiperazine agent dexrazoxane (ICRF-187) reduces the risk of anthracycline cardiotoxicity without a significant effect on response to chemotherapy. The prevailing concept describes dexrazoxane as a prodrug undergoing bioactivation to an iron-chelating agent ADR-925, which may inhibit anthracycline-induced ROS formation and oxidative damage to cardiomyocytes. RECENT ADVANCES: A considerable body of evidence points to mitochondria as the key targets for anthracycline cardiotoxicity, and therefore it could be also crucial for effective cardioprotection. Numerous antioxidants and several iron chelators have been tested in vitro and in vivo with variable outcomes. None of these compounds have matched or even surpassed the effectiveness of dexrazoxane in chronic anthracycline cardiotoxicity settings, despite being stronger chelators and/or antioxidants. CRITICAL ISSUES: The interpretation of many findings is complicated by the heterogeneity of experimental models and frequent employment of acute high-dose treatments with limited translatability to clinical practice. FUTURE DIRECTIONS: Dexrazoxane may be the key to the enigma of anthracycline cardiotoxicity, and therefore it warrants further investigation, including the search for alternative/complementary modes of cardioprotective action beyond simple iron chelation.

A phase I study of vinflunine in combination with capecitabine in patients with metastatic breast cancer previously treated with anthracyclines and taxanes.

PURPOSE: A phase I study was performed to determine the maximal tolerated dose (MTD), recommended dose (RD), safety and efficacy of vinflunine when combined with capecitabine in patients with metastatic breast cancer (MBC) previously treated with anthracyclines and taxanes, with pharmacokinetic blood sampling to test potential drug-drug interactions. PATIENTS AND METHODS: Sixteen patients with MBC who had received anthracyclines and taxanes in the neo/adjuvant setting, if progression occurred during or within 12 months of chemotherapy completion, and/or as first-line chemotherapy of MBC were enrolled. Vinflunine (VFL) was given on day 1 with capecitabine (CAPE) twice daily from days 1 to 14, every 3 weeks. Three dose levels (DL) were investigated (DL1: VFL 280 mg/m² and CAPE 1,650 mg/m²/day, DL2: VFL 320 mg/m² and CAPE 1,650 mg/m²/day and DL3: VFL 280 mg/m² and CAPE 2,000 mg/m²/day). RESULTS: The RD was established as vinflunine 280 mg/m² on day 1 plus capecitabine 1,650 mg/m²/day on days 1 to 14 given every 3 weeks. Dose-limiting toxicities were grade 4 neutropenia lasting at least 7 days for 2 patients, anorexia with fatigue for 1 patient and diarrhoea with fatigue, anorexia and febrile neutropenia for 1 patient. Neutropenia was the main toxicity of the combination, it was reported in 15 patients (93.8%) with grade 3 in 7 patients (43.8%) and 22.6% of cycles and grade 4 in 7 patients (43.8%) and 19.8% of cycles. Complications were rare with only one patient experiencing febrile neutropenia at DL exceeding the RD. The most frequent non-haematological toxicities were fatigue and gastrointestinal disorders; however, no grade 3 or 4 episode was observed at the RD. Hand-foot syndrome was reported in 5 patients (31.3%) and 22.6% of cycles, no episode of grade 3 was seen. Concerning pharmacokinetics, no modifications were detected for VFL, while slight accumulation between days 1 and 14 was observed for 5-FU formed from CAPE. The risk of clinical significant drug-drug interaction was considered weak. Objective partial responses were reported in 7 patients, yielding a response rate of 43.8% in the all-treated population according to the investigator assessment. CONCLUSIONS: The combination of vinflunine and capecitabine is safe and showed promising antitumour activity in MBC patients who have failed prior anthracyclines and taxanes. Further clinical development of this combination is warranted.

Pharmacological foundations of cardio-oncology.

Anthracyclines and many other antitumor drugs induce cardiotoxicity that occurs "on treatment" or long after completing chemotherapy. Dose reductions limit the incidence of early cardiac events but not that of delayed sequelae, possibly indicating that any dose level of antitumor drugs would prime the heart to damage from sequential stressors. Drugs targeted at tumor-specific moieties raised hope for improving the cardiovascular safety of antitumor therapies; unfortunately, however, many such drugs proved unable to spare the heart, aggravated cardiotoxicity induced by anthracyclines, or were safe in selected patients of clinical trials but not in the general population. Cardio-oncology is the discipline aimed at monitoring the cardiovascular safety of antitumor therapies. Although popularly perceived as a clinical discipline that brings oncologists and cardiologists working together, cardio-oncology is in fact a pharmacology-oriented translational discipline. The cardiovascular performance of survivors of cancer will only improve if clinicians joined pharmacologists in the search for new predictive models of cardiotoxicity or mechanistic approaches to explain how a given drug might switch from causing systolic failure to inducing ischemia. The lifetime risk of cardiotoxicity from antitumor drugs needs to be reconciled with the identification of long-lasting pharmacological signatures that overlap with comorbidities. Research on targeted drugs should be reshaped to appreciate that the terminal ballistics of new "magic bullets" might involve cardiomyocytes as innocent bystanders. Finally, the concepts of prevention and treatment need to be tailored to the notion that late-onset cardiotoxicity builds on early asymptomatic cardiotoxicity. The heart of cardio-oncology rests with such pharmacological foundations.

Cyclophosphamide dose intensification may circumvent anthracycline resistance of p53 mutant breast cancers.

The predictive value of p53 for the efficacy of front-line anthracycline-based chemotherapy regimens has been a matter of significant controversy. Anthracyclines are usually combined with widely different doses of alkylating agents, which may significantly modulate tumor response to these combinations. We analyzed three series of de novo stage II-III breast cancer patients treated front line with anthracycline-based regimens of various cyclophosphamide dose intensities: 65 patients with estrogen receptor (ER)(-) tumors treated with anthracyclines alone (Institut Jules Bordet, Brussels), 51 unselected breast cancer patients treated with intermediate doses of cyclophosphamide (MD Anderson Cancer Center, Houston, TX), and 128 others treated with a dose-dense anthracycline-cyclophosphamide combination (St. Louis, Paris). After chemotherapy and surgery, pathologic complete response (pCR) was evaluated. p53 status was determined by a yeast functional assay on the pretreatment tumor sample. In a multivariate analysis of the pooled results, a lack of ER expression and high-dose cyclophosphamide administration were associated with a higher likelihood of pCR. A sharp statistical interaction was detected between p53 status and cyclophosphamide dose intensity. Indeed, when restricting our analysis to patients with ER(-) tumors, we confirmed that a mutant p53 status was associated with anthracycline resistance, but found that p53 inactivation was required for response to the dose-intense alkylating regimen. The latter allowed very high levels of pCR in triple-negative tumors. Thus, our data strongly suggest that cyclophosphamide dose intensification in ER(-) p53-mutated breast cancer patients could significantly improve their response.

Practical strategies for suppressing hypoxia-inducible factor activity in cancer therapy.

The utility of anti-angiogenic strategies for cancer control is strongly compromised by hypoxia-driven phenotypic changes in cancer cells, which make cancer cells more invasive and more prone to give rise to metastases. A key mediator of this phenotypic shift is the transcription factor hypoxia-inducible factor-1 (HIF-1), which acts directly and indirectly to promote the epidermal-mesenchymal transition, boost cancer invasiveness, increase production of angiogenic factors, and induce chemoresistance. In some cancers, HIF-1 activity is constitutively elevated even in aerobic environments, making the cancer harder to treat and control. Practical strategies for suppressing HIF-1 activation may include the following: inhibiting NF-kappaB activation with salicylic acid and/or silibinin, which should decrease transcription of the HIF-1alpha gene; suppressing translation of HIF-1alpha mRNA with drugs that inhibit mTOR or topoisomerase I; supporting the effective activity of prolyl hydroxylases - which promote proteasomal degradation of HIF-1alpha under aerobic conditions - with antioxidant measures, alpha-ketoglutarate, and possibly dichloroacetate; promoting the O(2)-independent proteasomal degradation of HIF-1alpha with agents that inhibit the chaperone protein Hsp90; and blocking HIF-1 binding to its DNA response elements with anthracyclines. The utility of various combinations of these strategies should be tested in cancer cell cultures and rodent xenograft models; initial efforts in this regard have yielded encouraging results. Comprehensive strategies for suppressing HIF-1 activity can be expected to complement the efficacy of cancer chemotherapy and of effective anti-angiogenic regimens.

Anticancer drugs and cardiotoxicity: Insights and perspectives in the era of targeted therapy.

Drug-induced cardiotoxicity is emerging as an important issue among cancer survivors. For several decades, this topic was almost exclusively associated with anthracyclines, for which cumulative dose-related cardiac damage was the limiting step in their use. Although a number of efforts have been directed towards prediction of risk, so far no consensus exists on the strategies to prevent and monitor chemotherapy-related cardiotoxicity. Recently, a new dimension of the problem has emerged when drugs targeting the activity of certain tyrosine kinases or tumor receptors were recognized to carry an unwanted effect on the cardiovascular system. Moreover, the higher than expected incidence of cardiac dysfunction occurring in patients treated with a combination of old and new chemotherapeutics (e.g. anthracyclines and trastuzumab) prompted clinicians and researchers to find an effective approach to the problem. From the pharmacological standpoint, putative molecular mechanisms involved in chemotherapy-induced cardiotoxicity will be reviewed. From the clinical standpoint, current strategies to reduce cardiotoxicity will be critically addressed. In this perspective, the precise identification of the antitarget (i.e. the unwanted target causing heart damage) and the development of guidelines to monitor patients undergoing treatment with cardiotoxic agents appear to constitute the basis for the management of drug-induced cardiotoxicity.

Amrubicin for the treatment of advanced lung cancer.

Although the advancement of the chemotherapy of non-small cell lung cancer and small cell lung cancer is remarkable in recent years, it is still unsatisfactory. Therefore, some new agents or a new treatment strategy for lung cancer is required. Amrubicin is a totally synthetic anthracycline anticancer drug that acts as a potent topoisomerase II inhibitor. Recently, amrubicin has been approved in Japan for the treatment of small- and non-small cell lung cancers and some clinical trials about amrubicin were conducted in Japan, and promising results have been reported for the treatment of small cell lung cancer in particular. The preclinical, pharmacology and clinical data of amrubicin for the treatment of advanced lung cancer are reviewed.

Simian immunodeficiency virus is susceptible to inhibition by carbohydrate-binding agents in a manner similar to that of HIV: implications for further preclinical drug development.

Carbohydrate-binding agents (CBAs), such as the plant lectins Hippeastrum hybrid agglutinin (HHA) and Urtica dioica agglutinin (UDA), but also the nonpeptidic antibiotic pradimicin A (PRM-A), inhibit entry of HIV into its target cells by binding to the glycans of gp120. Given the high sequence identity and similarity between the envelope gp120 glycoproteins of HIV and simian immunodeficiency virus (SIV), the inhibitory activity of a variety of CBAs were evaluated against HIV-1, HIV-2, and SIV. There seemed to be a close correlation for the inhibitory potential of CBAs against HIV-1, HIV-2, and SIV replication in cell culture and syncytia formation in cocultures of persistently SIV-infected HUT-78 cell cultures and uninfected CEM cells. CBAs also inhibit transmission of the SIV to T lymphocytes after capture of the virus by dendritic cell-specific ICAM3-grabbing nonintegrin (DC-SIGN)-expressing cells. A total of 8 different SIV strains were isolated after prolonged HHA, UDA, and PRM-A exposure in virus-infected cell cultures. Each virus isolate consistently contained at least 2 or 3 glycan deletions in its gp120 envelope and showed decreased sensitivity to the CBAs and cross-resistance toward all CBAs. Our data revealed that CBAs afford SIV and HIV-1 inhibition in a similar manner regarding prevention of virus infection, DC-SIGN-directed virus capture-related transmission, and selection of drug-resistant mutant virus strains. Therefore, SIV(mac251)-infected monkeys might represent a relevant animal model to study the efficacy of CBAs in vivo.

Antiviral activity of carbohydrate-binding agents against Nidovirales in cell culture.

Coronaviruses are important human and animal pathogens, the relevance of which increased due to the emergence of new human coronaviruses like SARS-CoV, HKU1 and NL63. Together with toroviruses, arteriviruses, and roniviruses the coronaviruses belong to the order Nidovirales. So far antivirals are hardly available to combat infections with viruses of this order. Therefore, various antiviral strategies to counter nidoviral infections are under evaluation. Lectins, which bind to N-linked oligosaccharide elements of enveloped viruses, can be considered as a conceptionally new class of virus inhibitors. These agents were recently evaluated for their antiviral activity towards a variety of enveloped viruses and were shown in most cases to inhibit virus infection at low concentrations. However, limited knowledge is available for their efficacy towards nidoviruses. In this article the application of the plant lectins Hippeastrum hybrid agglutinin (HHA), Galanthus nivalis agglutinin (GNA), Cymbidium sp. agglutinin (CA) and Urtica dioica agglutinin (UDA) as well as non-plant derived pradimicin-A (PRM-A) and cyanovirin-N (CV-N) as potential antiviral agents was evaluated. Three antiviral tests were compared based on different evaluation principles: cell viability (MTT-based colorimetric assay), number of infected cells (immunoperoxidase assay) and amount of viral protein expression (luciferase-based assay). The presence of carbohydrate-binding agents strongly inhibited coronaviruses (transmissible gastroenteritis virus, infectious bronchitis virus, feline coronaviruses serotypes I and II, mouse hepatitis virus), arteriviruses (equine arteritis virus and porcine respiratory and reproductive syndrome virus) and torovirus (equine Berne virus). Remarkably, serotype II feline coronaviruses and arteriviruses were not inhibited by PRM-A, in contrast to the other viruses tested.

WP760, a melanoma selective drug.

PURPOSE: Our goal was to perform studies on the specificity and antimelanoma mechanism of a novel bis-anthracycline, WP760. WP760 initially identified in the NCI 160 screen as anti-melanoma. METHODS: The methyl thiazolyl tetrazolium reduction (MTT) assay was used to test tumor cell growth inhibition; confocal microscopy to view WP760 intracellular distribution; flow cytometry for cell-cycle arrest and apoptosis; and Western blotting was employed to identify and compare quantities and kinetics of cell growth related molecule levels. RESULTS: WP760 induced G(2)/M-phase cell-cycle arrest and apoptosis in melanoma cell lines and short-term melanoma explants established from clinical specimens in a time and concentration dependent manner at nM concentrations. In contrast, effects on fibroblasts and A549 lung cancer cells required higher concentrations, suggesting that WP760 possesses selectivity for melanoma. Molecular studies indicated that WP760 induced p53 stabilization, checkpoint kinase 2 and p27(Kip1) protein upregulation, and activation of caspase-3. Endogenous nitric oxide (NO) production has been implicated in the chemoresistance of melanoma; WP760 caused inhibition of the inducible nitric oxide synthase (iNOS) protein as well as inhibition of phosphorylation of ERK, known to drive the iNOS pathway. Based on WP760 localization into mitochondria, and caspase-3 inhibitor block the killing of WP760, the intrinsic pathway of apoptosis appears to have been activated. CONCLUSIONS: Our results indicate that WP760 affects a critical and unique set of growth regulatory effects in melanoma, and is a promising candidate for further preclinical studies.

[A case of recurrent breast cancer with life-threatening multiple lung metastasis markedly responding to CMF as third-line chemotherapy].

A 35-year-old woman with taxane and anthracycline-resistant recurrent breast cancer with multiple lung metastasis and carcinomatous lymphangitis was treated with CMF as third-line chemotherapy. A complete response was achieved,and the toxicities were tolerable. We thought that CMF could be a useful regimen as third-line chemotherapy for metastatic breast cancer.

The design, synthesis, and evaluation of two universal doxorubicin-linkers: preparation of conjugates that retain topoisomerase II activity.

The design, synthesis, and evaluation of two N-alkylmaleimide aldehydes have been achieved, which upon reductive alkylation with the C3'-amino group of doxorubicin (DOX) permits the preparation of DOX conjugates via Michael addition of thiol-containing vectors. This method enables the mild, facile, and high-throughput preparation of DOX conjugates that retain the basic C3'-nitrogen, a pre-requisite for topoisomerase II inhibition. Seven DOX-amino acid conjugates were prepared, each displaying similar inhibitory activity as the parent drug.

Gemcitabine/capecitabine in patients with metastatic breast cancer pretreated with anthracyclines and taxanes.

PURPOSE: Gemcitabine and capecitabine are 2 anticancer drugs with a mechanism of action involving metabolism of pyrimidine nucleotides. Both are among the few agents active in patients with metastatic breast cancer (MBC) progressing after therapy with anthracyclines and taxanes. We have conducted a phase II trial of gemcitabine/capecitabine in patients with disease progression after treatment with anthracyclines and taxanes. PATIENTS AND METHODS: Treatment included gemcitabine 2000 mg/m2 on day 1 every 3 weeks and capecitabine 2500 mg/m2 daily (divided into 2 doses) on days 1-14 every 3 weeks; treatment was administered until disease progression or unacceptable toxicity was documented. All patients received concomitant oral pyridoxine 300 mg twice daily to prevent hand-foot syndrome (HFS). Of 39 patients treated, 33 had received previous treatment with anthracyclines, 6 had medical contraindication to anthracyclines, 35 had previously received taxanes, and 23 had received vinorelbine. Fourteen patients had previous high-dose chemotherapy with stem cell rescue and 5 had previously received trastuzumab. Patients were 31-79 years of age (median, 55 years) and, altogether, were given 386 courses of therapy (range, 1-36 courses per patient; median, 6 courses). RESULTS: Grade 3/4 toxicities included HFS (11 courses, 6 patients), stomatitis (6 courses, 2 patients), diarrhea (5 courses, 4 patients), anemia (5 courses, 2 patients), thrombocytopenia (5 courses, 2 patients), and neutropenia (1 course, 1 patient). Response rate (all 39 patients were evaluable) was 48.7% (partial response, n = 19; stable disease, n = 7; progressive disease, n = 13). Thirty-six patients died because of disease progression, and 3 are alive with progressive disease. Median follow-up was 26 months or until death. Median duration of response was 15 months (range, 3-26 months). Median time to disease progression was 5 months (range, 1-26 months). Median overall survival duration was 10 months (range, 1-37 months). CONCLUSION: In this cohort of patients heavily pretreated with anthracyclines and taxanes, the response rate to gemcitabine/capecitabine is encouraging, although response duration is limited.

Coenzyme q10 for prevention of anthracycline-induced cardiotoxicity.

Preclinical and clinical studies suggest that anthracycline-induced cardiotoxicity can be prevented by administering coenzyme Q10 during cancer chemotherapy that includes drugs such as doxorubicin and daunorubicin. Studies further suggest that coenzyme Q10 does not interfere with the antineoplastic action of anthracyclines and might even enhance their anticancer effects. Preventing cardiotoxicity might allow for escalation of the anthracycline dose, which would further enhance the anticancer effects. Based on clinical investigation, although limited, a cumulative dose of doxorubicin of up to 900 mg/m2, and possibly higher, can be administered safely during chemotherapy as long as coenzyme Q10 is administered concurrently. The etiology of the dose-limiting cardiomyopathy that is induced by anthracyclines can be explained by irreversible damage to heart cell mitochondria, which differ from mitochondria of other cells in that they possess a unique enzyme on the inner mitochondrial membrane. This enzyme reduces anthracyclines to their semiquinones, resulting in severe oxidative stress, disruption of mitochondrial energetics, and irreversible damage to mitochondrial DNA. Damage to mitochondrial DNA blocks the regenerative capability of the organelle and ultimately leads to apoptosis or necrosis of myocytes. Coenzyme Q10, an essential component of the electron transport system and a potent intracellular antioxidant, appears to prevent damage to the mitochondria of the heart, thus preventing the development of anthracycline-induced cardiomyopathy.