'Iron-saturated' lactoferrin is a potent natural adjuvant for augmenting cancer chemotherapy

Bovine lactoferrin (bLf), an iron-containing natural defence protein found in bodily secretions, has been reported to inhibit carcinogenesis and the growth of tumours. Here, we investigated whether natural bLf and iron-saturated forms of bLf differ in their ability to augment cancer chemotherapy. bLf was supplemented into the diet of C57BL/6 mice that were subsequently challenged subcutaneously with tumour cells, and treated by chemotherapy. Chemotherapy eradicated large (0.6 cm diameter) EL-4 lymphomas in mice that had been fed iron-saturated bLf (here designated Lf(+)) for 6 weeks prior to chemotherapy, but surprisingly not in mice that were fed lesser iron-saturated forms of bLf, including apo-bLf (4% iron saturated), natural bLf (approximately 15% iron saturated) and 50% iron-saturated bLf. Lf(+)-fed mice bearing either EL-4, Lewis lung carcinoma or B16 melanoma tumours completely rejected their tumours within 3 weeks following a single injection of either paclitaxel, doxorubicin, epirubicin or fluorouracil, whereas mice fed the control diet were resistant to chemotherapy. Lf(+) had to be fed to mice for more than 2 weeks prior to chemotherapy to be wholly effective in eradicating tumours from all mice, suggesting that it acts as a competence factor. It significantly reduced tumour vascularity and blood flow, and increased antitumour cytotoxicity, tumour apoptosis and the infiltration of tumours by leukocytes. Lf(+) bound to the intestinal epithelium and was preferentially taken up within Peyer's patches. It increased the production of Th1 and Th2 cytokines within the intestine and tumour, including TNF, IFN-gamma, as well as nitric oxide that have been reported to sensitize tumours to chemotherapy. Importantly, it restored both red and white peripheral blood cell numbers depleted by chemotherapy, potentially fortifying the mice against cancer. In summary, bLf is a potent natural adjuvant and fortifying agent for augmenting cancer chemotherapy, but needs to be saturated with iron to be effective.

A prospective cohort study of the effects of adjuvant breast cancer chemotherapy on taste function, food liking, appetite and associated nutritional outcomes

'Taste' changes are commonly reported during chemotherapy. It is unclear to what extent this relates to actual changes in taste function or to changes in appetite and food liking and how these changes affect dietary intake and nutritional status.

Review of the role of emergency nurses in management of chemotherapy-related complications

Aims and objectives : To examine the role of emergency nurses in caring for patients who receive chemotherapy in ambulatory oncology settings. Reasons for emergency department presentations are examined, specific sources of clinical risk for patients receiving chemotherapy who require emergency care are discussed and cost implications of emergency department presentations related to chemotherapy are analysed.

Background : Given the increased administration of chemotherapy in ambulatory settings, emergency nurses play an important role in the management of patients undergoing adjuvant chemotherapy. Emergency departments are the major entry point for acute inpatient hospital care of complications arising from chemotherapy.

Design : Systematic review.

Results : Chemotherapy-related emergency department presentations have considerable clinical and cost implications for patients and the healthcare system. Strategies to improve emergency department management of chemotherapy complications and reduction in preventable emergency department presentations has significant implications for improving cancer patients' quality of life and reducing the cost of cancer care.

Conclusions : Nurses are well placed to play a pivotal role in chemotherapy management and lead interventions such as a specialist oncology nursing roles that provide information and support to guide patients through their chemotherapy cycles. These interventions may prevent emergency department presentations for patients receiving chemotherapy in ambulatory settings.

Relevance to clinical practice : Patients receiving chemotherapy require access to specialised care to manage distressing symptoms, as they are at significant clinical risk because of immunosuppression and may not exhibit the usual signs of critical illness. A team approach both within and across nursing specialities may improve care for patients receiving chemotherapy and increase effective use of healthcare resources.

Immune thrombocytopenic purpura (ITP) and breast cancer. Does adjuvant therapy for breast cancer improve platelet counts in ITP?

Although both breast cancer and immune thrombocytopenic purpura (ITP) are common conditions, the simultaneous coexistence of these two diseases is rare. ITP is an autoimmune disease in which the presence of autoantibodies against platelets results in splenic sequestration and thrombocytopenia that may be associated with lymphoid neoplasms [1]. Except for an observational case series of 10 patients [2], only a few individual case reports of ITP coinciding with breast cancer have been reported [3–8]. We are reporting two cases with simultaneous confirmed ITP and breast cancer. The platelet counts in both women have improved during adjuvant breast cancer chemotherapy.

Using lithium as a neuroprotective agent in patients with cancer

Neurocognitive impairment is being increasingly recognized as an important issue in patients with cancer who develop cognitive difficulties either as part of direct or indirect involvement of the nervous system or as a consequence of either chemotherapy-related or radiotherapy-related complications. Brain radiotherapy in particular can lead to significant cognitive defects. Neurocognitive decline adversely affects quality of life, meaningful employment, and even simple daily activities. Neuroprotection may be a viable and realistic goal in preventing neurocognitive sequelae in these patients, especially in the setting of cranial irradiation. Lithium is an agent that has been in use for psychiatric disorders for decades, but recently there has been emerging evidence that it can have a neuroprotective effect.

This review discusses neurocognitive impairment in patients with cancer and the potential for investigating the use of lithium as a neuroprotectant in such patients.

Use of targeted therapy in cancer patients in the end-of-life period: results from an Australian centre

PURPOSE: Data on the use of targeted therapies at the end of life are scarce. This study reviews the pattern of use of targeted and potentially futile, toxic, or costly therapies at an Australian cancer centre. METHODS: This retrospective single-centre review of data from patients who died within 3 months of having targeted therapy examined demographic characteristics, types of cancers, types of therapy, age, and lines of prior therapy. RESULTS: Over 24 months, two groups were analysed. Firstly, 889 patients died with 107 patients who were prescribed targeted therapy. Secondly, 457 patients were treated with targeted therapies with 52 patients, (11 %) dying within 3 months. To focus on the 52 patients: median age was 69 years, 65 % were men and 35 % were women, 50 % had haematologic cancers and 50 % had solid tumours. Ten therapeutic agents were represented: a higher total number of deaths among those prescribed erlotinib, bevacizumab, and rituximab. There were no deaths within 3 months of treatment with trastuzumab, ipilimumab, or vemurafenib. The targeted therapy was the first-line treatment in 54 %, second in 15 %, and third and beyond in 15 %. The patient's sex and type of cancer had no statistically significant influence on death within 3 months of targeted treatment. CONCLUSIONS: The use of targeted therapy at the end of life in this single-centre descriptive study was lower than documented in other studies. There is a need to prospectively document the factors leading to this prescribing behaviour to guide future protocols.

Metabolism and transport of oxazphosphorines and the clinical implications

The oxazaphosphorines including cyclophosphamide (CPA), ifosfamide (IFO), and trofosfamide represent an important group of therapeutic agents due to their substantial antitumor and immuno-modulating activity. CPA is widely used as an anticancer drug, an immunosuppressant, and for the mobilization of hematopoetic progenitor cells from the bone marrow into peripheral blood prior to bone marrow transplantation for aplastic anemia, leukemia, and other malignancies. New oxazaphosphorines derivatives have been developed in an attempt to improve selectivity and response with reduced toxicity. These derivatives include mafosfamide (NSC 345842), glufosfamide (D19575, β-D-glucosylisophosphoramide mustard), NSC 612567 (aldophosphamide perhydrothiazine), and NSC 613060 (aldophosphamide thiazolidine). This review highlights the metabolism and transport of these oxazaphosphorines (mainly CPA and IFO, as these two oxazaphosphorine drugs are the most widely used alkylating agents) and the clinical implications. Both CPA and IFO are prodrugs that require activation by hepatic cytochrome P450 (CYP)-catalyzed 4-hydroxylation, yielding cytotoxic nitrogen mustards capable of reacting with DNA molecules to form crosslinks and lead to cell apoptosis and/or necrosis. Such prodrug activation can be enhanced within tumor cells by the CYP-based gene directed-enzyme prodrug therapy (GDEPT) approach. However, those newly synthesized oxazaphosphorine derivatives such as glufosfamide, NSC 612567 and NSC 613060, do not need hepatic activation. They are activated through other enzymatic and/or non-enzymatic pathways. For example, both NSC 612567 and NSC 613060 can be activated by plain phosphodiesterase (PDEs) in plasma and other tissues or by the high-affinity nuclear 3'-5' exonucleases associated with DNA polymerases, such as DNA polymerases and ε. The alternative CYP-catalyzed inactivation pathway by N-dechloroethylation generates the neurotoxic and nephrotoxic byproduct chloroacetaldehyde (CAA). Various aldehyde dehydrogenases (ALDHs) and glutathione S-transferases (GSTs) are involved in the detoxification of oxazaphosphorine metabolites. The metabolism of oxazaphosphorines is auto-inducible, with the activation of the orphan nuclear receptor pregnane X receptor (PXR) being the major mechanism. Oxazaphosphorine metabolism is affected by a number of factors associated with the drugs (e.g., dosage, route of administration, chirality, and drug combination) and patients (e.g., age, gender, renal and hepatic function). Several drug transporters, such as breast cancer resistance protein (BCRP), multidrug resistance associated proteins (MRP1, MRP2, and MRP4) are involved in the active uptake and efflux of parental oxazaphosphorines, their cytotoxic mustards and conjugates in hepatocytes and tumor cells. Oxazaphosphorine metabolism and transport have a major impact on pharmacokinetic variability, pharmacokinetic-pharmacodynamic relationship, toxicity, resistance, and drug interactions since the drug-metabolizing enzymes and drug transporters involved are key determinants of the pharmacokinetics and pharmacodynamics of oxazaphosphorines. A better understanding of the factors that affect the metabolism and transport of oxazaphosphorines is important for their optional use in cancer chemotherapy.

St. Johns wort attenuates irinotecan-induced diarhea via down-regulation of intestinal pro-inflammatory cytokines and inhibition of intestinal epithelial apoptosis

Diarrhea is a common dose-limiting toxicity associated with cancer chemotherapy, in particular for drugs such as irinotecan (CPT-11), 5-fluouracil, oxaliplatin, capecitabine and raltitrexed. St. John's wort (Hypericum perforatum, SJW) has anti-inflammatory activity, and our preliminary study in the rat and a pilot study in cancer patients found that treatment of SJW alleviated irinotecan-induced diarrhea. In the present study, we investigated whether SJW modulated various pro-inflammatory cytokines including interleukins (IL-1β, IL-2, IL-6), interferon (IFN-γ) and tumor necrosis factor-α (TNF-α) and intestinal epithelium apoptosis in rats. The rats were treated with irinotecan at 60 mg/kg for 4 days in combination with oral SJW or SJW-free control vehicle at 400 mg/kg for 8 days. Diarrhea, tissue damage, body weight loss, various cytokines including IL-1β, IL-2, IL-6, IFN-γ and TNF-α and intestinal epithelial apoptosis were monitored over 11 days. Our studies demonstrated that combined SJW markedly reduced CPT-11-induced diarrhea and intestinal lesions. The production of pro-inflammatory cytokines such as IL-1β, IFN-γ and TNF-α was significantly up-regulated in intestine. In the mean time, combined SJW significantly suppressed the intestinal epithelial apoptosis induced by CPT-11 over days 5–11. In particular, combination of SJW significantly inhibited the expression of TNF-α mRNA in the intestine over days 5–11. In conclusion, inhibition of pro-inflammatory cytokines and intestinal epithelium apoptosis partly explained the protective effect of SJW against the intestinal toxicities induced by irinotecan. Further studies are warranted to explore the potential for STW as an agent in combination with chemotherapeutic drugs to lower their dose-limiting toxicities.

Substrates and inhibitors of human multidrug resistance associated proteins and the implications in drug development

Human contains 49 ATP-binding cassette (ABC) transporter genes and the multidrug resistance associated proteins (MRP1/ABCC1, MRP2/ABCC2, MRP3/ABCC3, MRP4/ABCC4, MRP5/ABCC5, MRP6/ABCC6, MRP7/ABCC10, MRP8/ABCC11 and MRP9/ABCC12) belong to the ABCC family which contains 13 members. ABCC7 is cystic fibrosis transmembrane conductance regulator; ABCC8 and ABCC9 are the sulfonylurea receptors which constitute the ATP-sensing subunits of a complex potassium channel. MRP10/ABCC13 is clearly a pseudo-gene which encodes a truncated protein that is highly expressed in fetal human liver with the highest similarity to MRP2/ABCC2 but without transporting activity. These transporters are localized to the apical and/or basolateral membrane of the hepatocytes, enterocytes, renal proximal tubule cells and endothelial cells of the blood-brain barrier. MRP/ABCC members transport a structurally diverse array of important endogenous substances and xenobiotics and their metabolites (in particular conjugates) with different substrate specificity and transport kinetics. The human MRP/ABCC transporters except MRP9/ABCC12 are all able to transport organic anions, such as drugs conjugated to glutathione, sulphate or glucuronate. In addition, selected MRP/ABCC members may transport a variety of endogenous compounds, such as leukotriene C(4) (LTC(4) by MRP1/ABCC1), bilirubin glucuronides (MRP2/ABCC2, and MRP3/ABCC3), prostaglandins E1 and E2 (MRP4/ABCC4), cGMP (MRP4/ABCC4, MRP5/ABCC5, and MRP8/ABCC11), and several glucuronosyl-, or sulfatidyl steroids. In vitro, the MRP/ABCC transporters can collectively confer resistance to natural product anticancer drugs and their conjugated metabolites, platinum compounds, folate antimetabolites, nucleoside and nucleotide analogs, arsenical and antimonial oxyanions, peptide-based agents, and in concert with alterations in phase II conjugating or biosynthetic enzymes, classical alkylating agents, alkylating agents. Several MRP/ABCC members (MRPs 1-3) are associated with tumor resistance which is often caused by an increased efflux and decreased intracellular accumulation of natural product anticancer drugs and other anticancer agents. Drug targeting of these transporters to overcome MRP/ABCC-mediated multidrug resistance may play a role in cancer chemotherapy. Most MRP/ABCC transporters are subject to inhibition by a variety of compounds. Based on currently available preclinical and limited clinical data, it can be expected that modulation of MRP members may represent a useful approach in the management of anticancer and antimicrobial drug resistance and possibly of inflammatory diseases and other diseases. A better understanding of their substrates and inhibitors has important implications in development of drugs for treatment of cancer and inflammation.

Effect of selenium-saturated bovine lactoferrin (Se-bLF) on antioxidant enzyme activities in human gut epithelial cells under oxidative stress

Cancer and many chronic inflammatory diseases are associated with increased amounts of reactive oxygen species (ROS). The potential cellular and tissue damage created by ROS has significant impact on many disease and cancer states and natural therapeutics are becoming essential in regulating altered redox states. We have shown recently that iron content is a critical determinant in the antitumour activity of bovine milk lactoferrin (bLF). We found that 100% iron-saturated bLF (Fe-bLF) acts as a potent natural adjuvant and fortifying agent for augmenting cancer chemotherapy and thus has a broad utility in the treatment of cancer. Furthermore, we also studied the effects of iron saturated bLF's ability as an antioxidant in the human epithelial colon cancer cell line HT29, giving insights into the potential of bLF in its different states. Thus, metal saturated bLF could be implemented as anti-cancer neutraceutical. In this regard, we have recently been able to prepare a selenium (Se) saturated form of bLF, being up to 98% saturated. Therefore, the objectives of this study were to determine how oxidative stress induced by hydrogen peroxide (H₂O₂) alters antioxidant enzyme activity within HT29 epithelial colon cancer cells, and observe changes in this activity by treatments with different antioxidants ascorbic acid (AA), Apo (iron free)-bLF and selenium (Se)-bLF. The states of all antioxidant enzymes (glutathione peroxidase (GPx), glutathione reductase (GR), glutathione-s-transferase (GsT), catalase and superoxide dismutase (SOD)) demonstrated high levels within untreated HT29 cells compared to the majority of other treatments being used, even prior to H₂O₂ exposure. All enzymes showed significant alterations in activity when cells were treated with antioxidants AA, Apo-bLF or Se-bLF, with and/or without H₂O₂ exposure. Obvious indications that the Se content of the bLF potentially interacted with the glutathione (GSH)/GPx/GR/GsT associated redox system could be observed immediately, showing capability of Se-bLF being highly beneficial in helping to maintain a balance between the oxidant/antioxidant systems within cells and tissues, especially in selenium deficient systems. In conclusion, the antioxidative defence activity of Se-bLf, investigated in this study for the first time, shows dynamic adaptations that may allow for essential protection from the imbalanced oxidative conditions. Because of its lack of toxicity and the availability of both selenium and bLF in whole milk, Se-bLF offers a promise for a prospective natural dietary supplement, in addition to being an immune system enhancement, or a potential chemopreventive agent for cancers.

Clinical and economic burden of emergency department presentations for neutropenia following outpatient chemotherapy for cancer in Victoria, Australia

Objective. To examine the clinical characteristics and financial charges associated with treating adult cancer patients receiving chemotherapy in outpatient clinics who presented to the emergency department (ED) with neutropenia.
Design and Setting. A retrospective audit was conducted across two health services involving ED episodes and subsequent hospital admissions of patients who received chemotherapy through day oncology from January 1 to December 31, 2007 and presented to the ED with neutropenia. ED data were collected from the Victorian Emergency Minimum Dataset and charges were collected from Health Information Services. Descriptive and bivariate statistics were used to describe the patient and clinical characteristics and financial outcomes, and to explore associations between these factors.
Results. In total, 200 neutropenic episodes in 159 outpatients were seen in the ED over the survey period. The mean patient age was 56.6 years (standard deviation, 13.2 years) and 47.2% were male. Overall, 70.0% of ED episodes were triaged as Australasian Triage Scale 2 (emergency). The median ED wait time was 10 minutes and the median ED length of stay was 6.8 hours. The median charge for each ED episode was $764.08 Australian dollars. The total combined ED and inpatient charge per episode was in the range of $144.27-$174,732.68, with a median charge of $5,640.87.
Conclusions. This study provides important insights into the clinical and economic burden of neutropenia from both the ED and inpatient perspectives. Alternative treatment models, such as outpatient treatment, early discharge programs or prophylactic interventions to reduce the clinical and economic burden of neutropenia on our health system, must be explored.

The role of informal caregivers during cancer patients’ recovery from chemotherapy

Aims:  (i) To investigate the availability, perceived importance and roles of informal caregivers in the recovery of patients treated at day oncology centres and (ii) identify differences between patients with and without informal caregivers in the extent to which they experienced symptoms, and the level of bother symptoms caused.

Method:  Patients from three Australian hospitals (n = 122) were recruited during cycles 1 or 2 of adjuvant chemotherapy. Participants completed a modified version of the Rotterdam Symptom Checklist (RSCL) each day for 5 days after chemotherapy. A telephone interview conducted 10 days post-treatment explored the availability, importance and roles of caregivers. During the interview, participants also completed the modified RSCL in which they were asked about the extent to which they experienced, and were bothered by, each symptom over the prior 5 days combined.

Results:  Overall, 71% of participants had an informal caregiver in the 5 days postchemotherapy, commonly a partner. More women (71%) than men (48%) had a caregiver (p < 0.05). Caregivers were perceived to be highly important; they were more important for women than men (U = 213.50, p < 0.01). The most common assistance caregivers provided was meal preparation and emotional support and companionship. On days 6–10 postchemotherapy, the extent to which overall physical symptoms were experienced was higher for patients with a caregiver than without (U = 987.50, p < 0.05); similarly their symptoms caused more bother (U = 966.00, p < 0.01).

Conclusions:  These findings highlighted the importance of informal caregivers to patients postchemotherapy. It is imperative that patients are informed of the importance of this support so a caregiver can be arranged, if possible. Understanding the needs of patients following chemotherapy would enable health professionals to advise patients, with or without caregivers, how to best prepare for and manage their recovery at home.