Role Of Doxorubicin Research Articles

Nanoceria ameliorates doxorubicin induced cardiotoxicity: Possible mitigation via reduction of oxidative stress and inflammation

Doxorubicin (DOX) is one of the most commonly used anticancer drugs but its use has been limited due to constraints of cardiotoxic side effects. The precise mechanism underlying cardiotoxicity is not yet fully understood but oxidative stress has been found to be a primary mechanism behind this. In addition, DOX induced cardiotoxicity also shows involvement of proinflammatory cytokines such as IL-6 and TNF-α. Since oxidative stress plays major role in DOX induced cardiotoxicity, different antioxidants have been tried to prevent cardiotoxicity of DOX. Nanoparticles have risen up as a promising material with a wide variety of actions, and cerium oxide nanoparticles or nanoceria (NC) is one of such kind with great antioxidant potential. NC has emerged as a promising antioxidant in different pathological conditions. The present study was aimed to investigate possible protective effects of NC in DOX induced cardiotoxicity. Cardiotoxicity was induced in Swiss mice by DOX administration through i.p. route at a dose level of 15 mg/kg in two divided doses on alternate days. In our study, NC was found to mitigate cardiotoxic potential of DOX and prevented weight loss. NC restored the levels of cardiac injury markers lactate dehydrogenase (LDH) and creatinine kinase MB (CK-MB). Moreover, NC reduced malondialdehyde (MDA) levels and increased endogenous antioxidants such as reduced glutathione (GSH) and catalase levels. In addition, NC decreased proinflammatory cytokine levels and also prevented the alteration in normal structure of heart samples. Our study showed protective effects of NC in DOX induced cardiotoxicity which can become a potential therapeutic intervention against DOX induced cardiotoxicity.

MicroRNA-29b Regulates the Mitochondria-Dependent Apoptotic Pathway by Targeting Bax in Doxorubicin Cardiotoxicity

Background/Aims: Myocardial apoptosis plays an important role in doxorubicin (Dox) cardiotoxicity. MicroRNA-29 (miR-29) is suggested to function as an anti-fibrotic factor with potential therapeutic effects on cardiac fibrosis. However, it has not been shown whether there is an association between miR-29b and myocardial apoptosis. Methods: Male Wistar rats were transfected with miR-29b agomir by local delivery to the myocardium prior to Dox treatment. Rat cardiomyocytes were pretreated with miR-29b mimics or inhibitor followed by Dox incubation in vitro. Cardiac function and underlying mechanisms were evaluated by echocardiography, immunofluorescence, flow cytometry, real-time PCR, and western blotting. Results: Our results revealed that miR-29b is the only member of the miR-29 family that was significantly downregulated in myocardium from Dox-treated rats. Delivery of miR-29b agomir to myocardium resulted in a marked improvement of cardiac function. Terminal deoxynucleotidyl transferase dUTP nick end labeling staining showed that rescue of miR-29b expression inhibited Dox-induced myocardial apoptosis, concomitantly with increased Bcl-2 expression and decreased Bax expression and caspase-3 activity. In vitro, miR-29b overexpression mitigated, whereas inhibition of miR-29b promoted, Dox-induced cardiomyocyte apoptosis. Mechanistically, miR-29b negatively regulated Bax expression by directly targeting the 3′ untranslated region of Bax. In Dox-treated cardiomyocytes, upregulation of miR-29b resulted in a significant decrease in Bax expression, with an increase in Bcl-2 expression, accompanied by inhibition of mitochondrial membrane depolarization, cytochrome c release, and caspase activation. However, inhibition of miR-29b produced the opposite effects by further augmenting the effects of Dox. Conclusions: These data demonstrate that miR-29b prevents Dox-induced myocardial apoptosis through inhibition of the mitochondria-dependent pathway by directly targeting Bax, suggesting that miR-29b is a potential novel therapeutic target for the treatment of Dox cardiotoxicity.

A High Throughput Screening Campaign for Inhibitors of RGS6 and RGS17

G Protein Coupled Receptors (GPCRs) are highly targeted proteins for drug discovery, with over 50% of all drugs on the market targeting these receptors. Regulator of G Protein Signaling (RGS) Proteins regulate the signaling cascade of GPCRs by accelerating the intrinsic GTPase activity of G protein alpha subunits and returning the heterotrimeric G protein to its inactive state. Recently RGS proteins have been implicated as being important in a variety of disease states. RGS17 has been identified as being inappropriately upregulated in both lung and prostate cancer. Knockdown of RGS17 resulted in decreased cell proliferation in vitro, and reduced tumor mass and volume when compared to control when cell lines were injected subcutaneously in nude mice. RGS6 has been shown to play an essential role in doxorubicin mediated cardio toxicity, has been shown to have an important role in anxiolytic and depression phenotypes in mice, and has been implicated as a critical mediator of behavioral and pathological responses to alcohol. Here we present the screening of two RGS proteins (RGS6 and RGS17) using Alpha Screen technology against the NCI Next Diversity Library. Assay robustness was determined for both proteins, with RGS6 Z‐factors above 0.7 and RGS17 Z‐factors above 0.6. Approximately 20,000 compounds were screened against RGS6 resulting in identification of 20 hit compounds, and roughly 60,000 compounds (including the 20K also screened against RGS6) were screened against RGS17 resulting in the identification of 131 hit compounds. Tanimoto similarity analysis was performed on all hits to allow for small scale SAR analysis of confirmed lead compounds. Follow up experiments are under way including dose response analysis and structure based analysis utilizing NMR and molecular modeling.Support or Funding InformationSupported in part by RO1CA160470, in part by OVPRED internal funding initiative RAF‐DLR and in part by a Pre‐Doctoral Fellowship from the American Foundation of Pharmaceutical Education (AFPE)

Bisphenol A at the reference level counteracts doxorubicin transcriptional effects on cancer related genes in HT29 cells

Human exposure to Bisphenol A (BPA) results mainly from ingestion of food and beverages. Information regarding BPA effects on colon cancer, one of the major causes of death in developed countries, is still scarce. Likewise, little is known about BPA drug interactions although its potential role in doxorubicin (DOX) chemoresistance has been suggested. This study aims to assess potential interactions between BPA and DOX on HT29 colon cancer cells. HT29 cell response was evaluated after exposure to BPA, DOX, or co-exposure to both chemicals. Transcriptional analysis of several cancer-associated genes (c-fos, AURKA, p21, bcl-xl and CLU) shows that BPA exposure induces slight up-regulation exclusively of bcl-xl without affecting cell viability. On the other hand, a sub-therapeutic DOX concentration (40nM) results in highly altered c-fos, bcl-xl, and CLU transcript levels, and this is not affected by co-exposure with BPA. Conversely, DOX at a therapeutic concentration (4μM) results in distinct and very severe transcriptional alterations of c-fos, AURKA, p21 and CLU that are counteracted by co-exposure with BPA resulting in transcript levels similar to those of control. Co-exposure with BPA slightly decreases apoptosis in relation to DOX 4μM alone without affecting DOX-induced loss of cell viability. These results suggest that BPA exposure can influence chemotherapy outcomes and therefore emphasize the necessity of a better understanding of BPA interactions with chemotherapeutic agents in the context of risk assessment.

Beneficial effects of carnosine and carnosine plus vitamin E treatments on doxorubicin-induced oxidative stress and cardiac, hepatic, and renal toxicity in rats.

Oxidative stress plays an important role in doxorubicin (DOX)-induced toxicity. Carnosine (CAR) is a dipeptide with antioxidant properties. The aim of this study was to evaluate the decreasing or preventive effect of CAR alone or combination with vitamin E (CAR + Vit E) on DOX-induced toxicity in heart, liver, and brain of rats. Rats were treated with CAR (250 mg kg(-1) day(-1); intraperitoneally (i.p.)) or CAR + Vit E (equals 200 mg kg(-1) α-tocopherol; once every 3 days; intramuscularly) for 12 consecutive days. On the 8th day of treatment, rats were injected with a single dose of DOX (30 mg kg(-1), i.p.). Serum cardiac troponin I (cTnI), urea, and creatinine levels; alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities; and oxidative stress parameters in tissues were measured. We also determined thiobarbituric acid reactive substances, diene conjugate, protein carbonyl (PC), and glutathione levels and antioxidant enzyme activities. DOX resulted in increased serum cTnI, ALT, AST, urea, and creatinine levels and increased lipid peroxide and PC levels in tissues. CAR or CAR + Vit E treatments led to decreases in serum cTnI levels and ALT and AST activities. These treatments reduced prooxidant status and ameloriated histopathologic findings in the examined tissues. Our results may indicate that CAR alone, especially in combination with Vit E, protect against DOX-induced toxicity in heart, liver, and kidney tissues of rats. This was evidenced by improved cardiac, hepatic, and renal markers and restoration of the prooxidant state and amelioration of histopathologic changes.

Activation of the p38 MAPK/NF-κB pathway contributes to doxorubicin-induced inflammation and cytotoxicity in H9c2 cardiac cells

A number of studies have demonstrated that inflammation plays a role in doxorubicin (DOX)-induced cardiotoxicity. However, the molecular mechanism by which DOX induces cardiac inflammation has yet to be fully elucidated. The present study aimed to investigate the role of the p38 mitogen-activated protein kinase (MAPK)/nuclear factor-κB (NF-κB) pathway in DOX-induced inflammation and cytotoxicity. The results of our study demonstrated that the exposure of H9c2 cardiac cells to DOX reduced cell viability and stimulated an inflammatory response, as demonstrated by an increase in the levels of interleukin-1β (IL-1β) and IL-6, as well as tumor necrosis factor-α (TNF-α) production. Notably, DOX exposure induced the overexpression of phosphorylated p38 MAPK and phosphorylation of the NF-κB p65 subunit, which was markedly inhibited by SB203580, a specific inhibitor of p38 MAPK. The inhibition of NF-κB by pyrrolidine dithiocarbamate (PDTC), a selective inhibitor of NF-κB, significantly ameliorated DOX-induced inflammation, leading to a decrease in the levels of IL-1β and IL-6, as well as TNF-α production in H9c2 cells. The pretreatment of H9c2 cells with either SB203580 or PDTC before exposure to DOX significantly attenuated DOX-induced cytotoxicity. In conclusion, our study provides novel data demonstrating that the p38 MAPK/NF-κB pathway is important in the induction of DOX-induced inflammation and cytotoxicity in H9c2 cardiac myocytes.

Effects of acute doxorubicin exposure on caspase-mediated apoptosis in cardiomyocytes.

e12036 Background: Doxorubicin binds to DNA-associated enzymes, intercalates the base pairs of the DNA and induces apoptosis in cancerous and healthy tissues especially in cardiomyocytes. Caspase mediated apoptosis in cardiomyocytes remains largely unknown. We investigated the role of doxorubicin via caspase system on apoptosis of cardiomyocytes. Methods: H9C2ratcardiomyocytes were incubated with doxorubicin a concentration of 10-6 Mfor 4 or 24 hours to perform gene expression and activity of caspases, respectively. Total RNA isolated and expression analysis were performed by real time PCR assay. Caspase activity was determined by colorimetric caspase assay kit. At least two fold increases in gene expression were accepted statistically significant. Results: In comparison to controls, bothof caspase expression and activity increased in doxorubicin-treated samples. Increase in expression of Caspase 9 and 2 as initiator caspases and caspases 7 and 3 as effector caspases were detected statistically higher than control values. In contrast, expression of caspase 1, 4, 6, 8 and 12 were detected lower than controls. Activity of both caspase 3 and 9 increased significantly. Conclusions: Acute doxorubicin administration caused a significant caspase activation on apoptosis of cardiomyocytes.

A randomized single blind controlled trial of beads versus doxorubicin-eluting beads for arterial embolization of hepatocellular carcinoma (HCC).

143 Background: HAE using particles is a method of treatment for HCC. The added role of doxorubicin has never been fully understood biologically. To date, no study has demonstrated any difference in outcome using HAE versus trans-arterial chemoembolization (TACE). Methods: Patients (pts) with unresectable Okuda stage I or II HCC with adequate liver function were randomized to BB or LC loaded with 150 mg of doxorubicin. Pts were evaluated by multiphasic CT 2-3 weeks post-treatment. Progression by RECIST and/or evidence of ≤5% necrosis was considered treatment failure. Otherwise pts were followed with CT every 3 months until progression or death. Pts with either recurrent tumor or new tumor outside the treated area could be re-treated. The primary objective was response rate (RR) by RECIST. With 50 pts in each arm response rates can be estimated to within +/- 14%. Secondary objectives included assessing safety and tolerability, time to progression (TTP), progression free survival (PFS), and overall survival (OS). Quantification of tumor necrosis (TN) using CT volumetric data was correlated with outcome. Analyses were intention-to-treat. Results: Between December of 2007 and March of 2012, 101 pts were randomized, 51 to BB and 50 to LC. Demographics in the two groups were comparable: median age was 67, 77% were male and 81% were Okuda I. Median number of embolizations was 2 in both arms. There was no difference in adverse events, the most common being post-embolization syndrome of pain, fever, nausea, or vomiting (84% in both groups). There was no difference in RR: BB 11% vs LC 9% (p=0.58). Median TTP was not reached. 12 month TTP was 49 versus 56% (p=0.84), median PFS was 7 versus 9 (p=0.6), and OS 14 versus 16 months (p=0.7) for BB and LC respectively. Change in TN/tumor volume post treatment did not predict OS in either group (p=0.28). Conclusions: No difference in response was noted between pts treated with BB versus LC. Given the comparable safety profile, TTP, PFS and OS, HAE should be considered a reasonable and cost-effective therapeutic option and may be preferable to LC. Clinical trial information: NCT00539643.

Doxorubicin-induced ovarian toxicity.

BackgroundYoung cancer patients may occasionally face infertility and premature gonadal failure. Apart from its direct effect on follicles and oocytes, chemotherapy may induce ovarian toxicity via an impact on the entire ovary. The role of doxorubicin in potential ovarian failure remains obscure. Our intention was to elucidate doxorubicin-related toxicity within ovaries.MethodsFemale mice were injected intraperitoneally with 7.5 or 10 mg/kg doxorubicin and their ovaries were visualized in vivo by high resolution MRI, one day and one month following treatment. Ovaries of other treated mice were excised and weighed at the same post-treatment intervals. Ovarian histological sections were stained for TUNEL or active caspase-3 and follicles were counted and categorized. Ovulation rates were evaluated in superovulated female mice treated with doxorubicin.ResultsA single injection of doxorubicin resulted in a major reduction in both ovarian size and weight that lasted even one month post treatment. A dramatic reduction in ovulation rate was observed one week after treatment, followed by a partial recovery at one month. Histological examination revealed positive staining of TUNEL and active caspase-3. We observed a significant reduction in the population of secondary and primordial follicles one month following treatment.ConclusionsOur results may imply a mechanism of chemotherapy-induced ovarian toxicity, manifested by reduced ovulation and accompanied by a reduction in ovarian size, caused probably by an acute insult to the ovary.

The role of doxorubicin in non-viral gene transfer in the lung

Proteasome inhibitors have been shown to increase adeno-associated virus (AAV)-mediated transduction in vitro and in vivo. To assess if proteasome inhibitors also increase lipid-mediated gene transfer with relevance to cystic fibrosis (CF), we first assessed the effects of doxorubicin and N-acetyl- l-leucinyl- l-leucinal- l-norleucinal in non-CF (A549) and CF (CFTE29o-) airway epithelial cell lines. CFTE29o- cells did not show a response to Dox or LLnL; however, gene transfer in A549 cells increased in a dose-related fashion ( p < 0.05), up to approximately 20-fold respectively at the optimal dose (no treatment: 9.3 × 10 4 ± 1.5 × 10 3, Dox: 1.6 × 10 6 ± 2.6 × 10 5, LLnL: 1.9 × 10 6 ± 3.2 × 10 5 RLU/mg protein). As Dox is used clinically in cancer chemotherapy we next assessed the effect of this drug on non-viral lung gene transfer in vivo. CF knockout mice were injected intraperitoneally (IP) with Dox (25–100 mg/kg) immediately before nebulisation with plasmid DNA carrying a luciferase reporter gene under the control of a CMV promoter/enhancer (pCIKLux) complexed to the cationic lipid GL67A. Dox also significantly ( p < 0.05) increased expression of a plasmid regulated by an elongation factor 1α promoter (hCEFI) approximately 8-fold. Although administration of Dox before lung gene transfer may not be a clinically viable option, understanding how Dox increases lung gene expression may help to shed light on intracellular bottle-necks to gene transfer, and may help to identify other adjuncts that may be more appropriate for use in man.

Reversible posterior leukoencephalopathy syndrome associated with bevacizumab/doxorubicin regimen

Bevacizumab, a recombinant humanized monoclonal IgG1 antibody binding to vascular endothelial growth factor (VEGF), was the first angiogenesis inhibitor to be approved in combination with chemotherapy, as an anticancer treatment option in daily practice. Its anti-angiogenic activity leads to decreased tumour perfusion, vascular volume and the number of viable and progenitor cells [1]. Arterial hypertension (manageable with conventional antihypertensive drugs) can occur in up to 30% of cases (grade 3 hypertension up to 16%) [2]. A few cases of bevazicumab-induced reversible posterior leukoencephalopathy syndrome (RPLS) have been reported with various clinical symptoms such as lethargy, confusion or loss of vision [3–5]. We report another suspected case of RPLS associated with bevacizumab. A 33-year-old Asiatic woman with a past medical history of breast cancer in 2003 received a three-cycle course of bevacizumab (15 mg kg−1, since May 2007) and also liposomal doxorubicin (30 mg m−2) over 9 weeks (last infusion in 22 June 2007). She had no prior arterial hypertension. During chemotherapy, her blood pressure remained within the usual range (100/70 mmHg). On day 18 after the last infusion, she presented to the emergency department with serious headache (since 10 days) associated suddenly with gastralgia, nausea and vomiting. The first diagnoses were gastro-oesophageal reflux and then carcinomatous meningitis. Clinical examination and laboratory assessments were normal. Cerebrospinal fluid was clear and acellular with an increase of protein concentration to 133 mg dl−1, ruling out a diagnosis of meningitis. Blood pressure was 150/100 mm Hg. Symptomatic treatment including metoclopramide, tramadol, omeprazole orally and NaCl perfusion was administered. However, her condition worsened and blood pressure increased to 170/80 mm Hg the day after. Two days later (13 July 2007), she fell into a reactive coma. Magnetic resonance imaging (MRI) of the brain showed extensive leukoencephalopathy in the subcortical region without effect on the lateral ventricle (Figure 1). Treatment including prednisone (60 mg, i.v. three times daily), infusion of furosemide (40 mg), nicardipine and mannitol (1 g kg−1) as a 20% solution for cerebral oedema was started for 3 days. The following day, the patient's neurological deficits and high blood pressure had completely resolved. An electroencephalogram ruled out encephalopathy or epilepsy. A new MRI performed 4 days later showed a marked improvement in fluid-attenuated inversion recovery high-intensity lesions and resolution of the leukoencephalopathy. Figure 1 MRI scan of the brain with leucoencephalopathy. An axial T2 sequence image shows a subcortical high intensity lesion Considering the physiological role of VEGF in regulating vasomotor tone, arterial hypertension remains the most prominent and ‘expected’ adverse effect of almost all angiogenesis inhibitors (monoclonal antibodies or VEGF tyrosine kinase inhibitors) [2]. Rixe et al. suggested that arterial hypertension should be a predictive factor of sunitinib activity in metastatic renal cell carcinoma [6]. RPLS has been also reported for sunitinib [7]. Nevertheless, the role of doxorubicin should be taken into account in our case since this drug has often been associated with RPLS and the association with bevacizumab could increase the risk of occurrence of this complication [8, 9]. RPLS remains a rare but serious adverse reaction of VEGF inhibitors. The warning symptoms could differ according to the patients and the prompt recognition of this syndrome will allow initiation of immediate treatment. Further studies are needed to investigate the opportunity of rechallenge of bevacizumab in patients showing an improvement of tumoral diseases with appropriate pressure monitoring.

Radiogenomic Analysis to Identify Imaging Phenotypes Associated with Drug Response Gene Expression Programs in Hepatocellular Carcinoma

To determine whether conventional contrast-enhanced computed tomography (CT) could be used to identify imaging phenotypes associated with a doxorubicin drug response gene expression program in hepatocellular carcinoma (HCC) by using an integrated imaging-genomic approach. Thirty HCCs were analyzed and scored individually across six predefined imaging phenotypes. Unsupervised and supervised bioinformatics analyses were performed to correlate the imaging scores with the corresponding tumor microarray data (each microarray contained gene expression measurements across approximately 18,000 genes) to identify relationships between the imaging traits and underlying tumor gene expression. Enrichment for a predefined doxorubicin-response gene expression program was then performed against the imaging phenotype-associated genes and enrichment determined. An imaging phenotype related to tumor margins on arterial phase images demonstrated significant correlation with the doxorubicin-response transcriptional program (P < .05, q < 0.1). It was also significantly associated with HCC venous invasion and tumor stage (P < .05, q < 0.1). Tumors with higher tumor margin scores were more strongly associated with the doxorubicin resistance transcriptional program and had a greater prevalence of venous invasion and worse stage. Tumors with lower tumor margin scores, however, demonstrated a converse relationship. It is possible to identify HCC imaging phenotypes at CT that correlate with a doxorubicin drug response gene expression program. Given the role of doxorubicin in regional therapies for HCC management, it is possible that such an approach could be used to guide HCC therapy on a tumor-by-tumor basis on the basis of underlying tumor gene expression patterns.

The IVADo regimen—A pilot study with ifosfamide, vincristine, actinomycin D, and doxorubicin in children with metastatic soft tissue sarcoma

The role of doxorubicin (Doxo) as part of multidrug regimens used to treat children with soft tissue sarcoma (STS) is controversial. To evaluate the feasibility of combining Doxo with the well established ifosfamide, vincristine, and actinomycin D (IVA) regimen, the Italian STS Committee performed a pilot study on a series of children with metastatic STS. Between July 2002 and February 2004, 29 evaluable patients were enrolled in this study; 19 patients had rhabdomyosarcoma, 5 patients had peripheral neuroectodermal tumor, and 5 patients had other types of STS. The IVA-Doxo (IVADo) regimen included ifosfamide 3 g/m(2) on Days 1 and 2, vincristine 1.5 mg/m(2) on Day 1, actinomycin D 1.5 mg/m(2) on Day 1, and Doxo 30 mg/m(2) on Days 1 and 2. Three courses of IVADo were to be administered in the initial part of treatment and analyzed for toxicity and tumor response. Overall, 92 cycles were delivered. Major regimen-related toxicity was myelosuppression, with Grade 4 neutropenia in 67% of cycles and fever and neutropenia in 37% of cycles. Nonhematologic toxicity included Grade 3-4 mucositis (6.5% of cycles), constipation (9.7%), and peripheral neuropathy (6.5%). Other manifestations of major toxicity were venoocclusive disease and seizures, which occurred in one patient each. All but 1 patient with a malignant schwannoma showed some degree of tumor volume reduction; however, considering only complete and partial remissions, the response rate was 76% (+/- 7.9%). The intensive IVADo regimen was effective against pediatric STS with acceptable toxicity. This combination will be investigated in high-risk patients with rhabdomyosarcoma in a randomized trial launched by the European pediatric Soft tissue sarcoma Study Group.

Treatment of intermediate risk rhabdomyosarcoma and undifferentiated sarcoma with alternating cycles of vincristine/doxorubicin/cyclophosphamide and etoposide/ifosfamide

Over 50% of patients with newly diagnosed rhabdomyosarcoma (RMS) are in the ‘intermediate risk’ group with a 3-year progression-free survival of approximately 65%. This group consists of stage 1, group III, non-orbit tumours; stage 2, group II and III; and all stage 3 patients utilising the Intergroup Rhabdomyosarcoma Study (IRS) staging system. The role of doxorubicin in the treatment of RMS has been controversial. Ifosfamide, both alone and in combination with etoposide, has significant activity in patients with RMS. The aim of this pilot study was to examine the efficacy and toxicity of a chemotherapy regimen of alternating cycles of vincristine/doxorubicin/cyclophosphamide and etoposide/ifosfamide for intermediate risk RMS. 30 patients with intermediate risk RMS or undifferentiated sarcoma (US) were treated with alternating cycles of vincristine/doxorubicin/cyclophosphamide (VDC) and etoposide/ifosfamide (EI) at planned intervals of 3 weeks. Local treatment of the tumour in most cases was performed after four cycles of chemotherapy, followed by an additional 10 cycles of chemotherapy. At a median follow-up of 37.5 months, the Kaplan–Meier estimate of 3-year event-free survival was 85% (95% confidence interval 72–99%). The overall survival at 3 years was 91% (95% confidence interval 80–100%). No patient died from toxicity. The most common toxicity was febrile neutropenia in 35% of VDC and 26% of El cycles. No nephrotoxicity or cardiac toxicity was seen. No patient progressed prior to week 12 local therapy. Alternating cycles of VDC and EI are an effective treatment for patients with intermediate risk RMS and US. Toxicity is tolerable. Delaying local treatment until week 12 does not compromise outcome.

Adjuvant Therapy of Breast Cancer

This article examines questions about adjuvant systemic therapy, especially in premenopausal and postmenopausal women. The impact of adjuvant therapy on quality of life is addressed, as is the role of doxorubicin in adjuvant chemotherapy. The value of high dose adjuvant chemotherapy and late effects of adjuvant therapy are also examined.