Dietary supplementation with n-3-fatty acids in patients with pancreatic cancer and cachexia: marine phospholipids versus fish oil - a randomized controlled double-blind trial.

BACKGROUND: Like many other cancer patients, most pancreatic carcinoma patients suffer from severe weight loss. As shown in numerous studies with fish oil (FO) supplementation, a minimum daily intake of 1.5 g n-3-fatty acids (n-3-FA) contributes to weight stabilization and improvement of quality of life (QoL) of cancer patients. Given n-3-FA not as triglycerides (FO), but mainly bound to marine phospholipids (MPL), weight stabilization and improvement of QoL has already been seen at much lower doses of n-3-FA (0,3 g), and MPL were much better tolerated. The objective of this double-blind randomized controlled trial was to compare low dose MPL and FO formulations, which had the same n-3-FA amount and composition, on weight and appetite stabilization, global health enhancement (QoL), and plasma FA-profiles in patients suffering from pancreatic cancer. METHODS: Sixty pancreatic cancer patients were included into the study and randomized to take either FO- or MPL supplementation. Patients were treated with 0.3 g of n-3-fatty acids per day over six weeks. Since the n-3-FA content of FO is usually higher than that of MPL, FO was diluted with 40% of medium chain triglycerides (MCT) to achieve the same capsule size in both intervention groups and therefore assure blinding. Routine blood parameters, lipid profiles, body weight, and appetite were measured before and after intervention. Patient compliance was assessed through a patient diary. Quality of life and nutritional habits were assessed with validated questionnaires (EORTC-QLQ-C30, PAN26). Thirty one patients finalized the study protocol and were analyzed (per-protocol-analysis). RESULTS: Intervention with low dose n-3-FAs, either as FO or MPL supplementation, resulted in similar and promising weight and appetite stabilization in pancreatic cancer patients. MPL capsules were slightly better tolerated and showed fewer side effects, when compared to FO supplementation. CONCLUSION: The similar effects between both interventions were unexpected but reliable, since the MPL and FO formulations caused identical increases of n-3-FAs in plasma lipids of included patients after supplementation. The effects of FO with very low n-3-FA content might be explained by the addition of MCT. The results of this study suggest the need for further investigations of marine phospholipids for the improvement of QoL of cancer patients, optionally in combination with MCT.

A nasal epithelial receptor for Staphylococcus aureus WTA governs adhesion to epithelial cells and modulates nasal colonization.

Nasal colonization is a major risk factor for S. aureus infections. The mechanisms responsible for colonization are still not well understood and involve several factors on the host and the bacterial side. One key factor is the cell wall teichoic acid (WTA) of S. aureus, which governs direct interactions with nasal epithelial surfaces. We report here the first receptor for the cell wall glycopolymer WTA on nasal epithelial cells. In several assay systems this type F-scavenger receptor, termed SREC-I, bound WTA in a charge dependent manner and mediated adhesion to nasal epithelial cells in vitro. The impact of WTA and SREC-I interaction on epithelial adhesion was especially pronounced under shear stress, which resembles the conditions found in the nasal cavity. Most importantly, we demonstrate here a key role of the WTA-receptor interaction in a cotton rat model of nasal colonization. When we inhibited WTA mediated adhesion with a SREC-I antibody, nasal colonization in the animal model was strongly reduced at the early onset of colonization. More importantly, colonization stayed low over an extended period of 6 days. Therefore we propose targeting of this glycopolymer-receptor interaction as a novel strategy to prevent or control S. aureus nasal colonization.

Nutrient limitation governs Staphylococcus aureus metabolism and niche adaptation in the human nose.

Colonization of the human nose by Staphylococcus aureus in one-third of the population represents a major risk factor for invasive infections. The basis for adaptation of S. aureus to this specific habitat and reasons for the human predisposition to become colonized have remained largely unknown. Human nasal secretions were analyzed by metabolomics and found to contain potential nutrients in rather low amounts. No significant differences were found between S. aureus carriers and non-carriers, indicating that carriage is not associated with individual differences in nutrient supply. A synthetic nasal medium (SNM3) was composed based on the metabolomics data that permits consistent growth of S. aureus isolates. Key genes were expressed in SNM3 in a similar way as in the human nose, indicating that SNM3 represents a suitable surrogate environment for in vitro simulation studies. While the majority of S. aureus strains grew well in SNM3, most of the tested coagulase-negative staphylococci (CoNS) had major problems to multiply in SNM3 supporting the notion that CoNS are less well adapted to the nose and colonize preferentially the human skin. Global gene expression analysis revealed that, during growth in SNM3, S. aureus depends heavily on de novo synthesis of methionine. Accordingly, the methionine-biosynthesis enzyme cysteine-γ-synthase (MetI) was indispensable for growth in SNM3, and the MetI inhibitor DL-propargylglycine inhibited S. aureus growth in SNM3 but not in the presence of methionine. Of note, metI was strongly up-regulated by S. aureus in human noses, and metI mutants were strongly abrogated in their capacity to colonize the noses of cotton rats. These findings indicate that the methionine biosynthetic pathway may include promising antimicrobial targets that have previously remained unrecognized. Hence, exploring the environmental conditions facultative pathogens are exposed to during colonization can be useful for understanding niche adaptation and identifying targets for new antimicrobial strategies.

Effects of Marine Phospholipids Extract on the Lipid Levels of Metastatic and Nonmetastatic Prostate Cancer Patients.

High intake of omega-3 fatty acids (n-3 FAs) from fish has shown to reduce metastatic progression of prostate cancer. This clinical trial investigated the influence of high n-3 FA intake (marine phospholipids, MPL) on the FA composition of blood lipids, lysophosphatidylcholine (LPC), and on lipoproteins in prostate cancer patients and elderly men without prostate cancer. MPL supplementation resulted in a significant increase of n-3 FAs (eicosapentaenoic and docosahexaenoic acid) in blood lipids, while arachidonic acid (n-6 FA) decreased significantly. Low density lipoprotein (LDL) and high density lipoprotein (HDL) increased significantly, but the LDL increase was observed only in subjects with an inactive tumour. Similarly, LPC plasma concentration increased significantly only in patients without tumour. The missing increase of LDL and LPC after MPL supplementation in patients with actively growing (metastasizing) prostate cancer suggests that tumour cells have an elevated demand for LDL and LPC. Due to the MPL-induced increase of n-3 FAs in these blood lipids, it can be assumed that especially actively growing and metastasizing prostate cancer cells are provided with elevated amounts of these antimetastatic n-3 FAs. A hypothetic model explaining the lower incidence of metastatic progression in prostate cancer patients with high fish consumption is presented.

Characterization and comparison of 2 distinct epidemic community-associated methicillin-resistant Staphylococcus aureus clones of ST59 lineage.

Sequence type (ST) 59 is an epidemic lineage of community-associated (CA) methicillin-resistant Staphylococcus aureus (MRSA) isolates. Taiwanese CA-MRSA isolates belong to ST59 and can be grouped into 2 distinct clones, a virulent Taiwan clone and a commensal Asian-Pacific clone. The Taiwan clone carries the Panton-Valentine leukocidin (PVL) genes and the staphylococcal chromosomal cassette mec (SCCmec) VT, and is frequently isolated from patients with severe disease. The Asian-Pacific clone is PVL-negative, carries SCCmec IV, and a frequent colonizer of healthy children. Isolates of both clones were characterized by their ability to adhere to respiratory A549 cells, cytotoxicity to human neutrophils, and nasal colonization of a murine and murine sepsis models. Genome variation was determined by polymerase chain reaction of selected virulence factors and by multi-strain whole genome microarray. Additionally, the expression of selected factors was compared between the 2 clones. The Taiwan clone showed a much higher cytotoxicity to the human neutrophils and caused more severe septic infections with a high mortality rate in the murine model. The clones were indistinguishable in their adhesion to A549 cells and persistence of murine nasal colonization. The microarray data revealed that the Taiwan clone had lost the ø3-prophage that integrates into the ß-hemolysin gene and includes staphylokinase- and enterotoxin P-encoding genes, but had retained the genes for human immune evasion, scn and chps. Production of the virulence factors did not differ significantly in the 2 clonal groups, although more α-toxin was expressed in Taiwan clone isolates from pneumonia patients. In conclusion, the Taiwan CA-MRSA clone was distinguished by enhanced virulence in both humans and an animal infection model. The evolutionary acquisition of PVL, the higher expression of α-toxin, and possibly the loss of a large portion of the ß-hemolysin-converting prophage likely contribute to its higher pathogenic potential than the Asian-Pacific clone.

A phase I dose-escalation study of regorafenib (BAY 73-4506), an inhibitor of oncogenic, angiogenic, and stromal kinases, in patients with advanced solid tumors.

PURPOSE: Regorafenib is a novel oral multikinase inhibitor of angiogenic (VEGFR1-3, TIE2), stromal (PDGFR-ß, FGFR), and oncogenic kinases (KIT, RET, and RAF). This first-in-man, phase I dose-escalation study assessed the safety, pharmacokinetic, pharmacodynamic, and efficacy profiles of regorafenib in patients with advanced solid tumors. PATIENTS AND METHODS: Patients aged 18 years or older with advanced solid tumors refractory to standard treatment were recruited. Regorafenib was administered orally for 21 days on/seven days off in repeating cycles, until discontinuation due to toxicity or tumor progression. Adverse events (AE) were assessed using National Cancer Institute Common Terminology Criteria for Adverse Events v3.0. Pharmacokinetic profiles were measured after a single dose and on day 21. Pharmacodynamic and efficacy evaluations included tumor perfusion assessment using dynamic contrast-enhanced MRI, plasma cytokines, and tumor response using RECIST (v1.0). RESULTS: Fifty-three patients were enrolled into eight cohorts at dose levels from 10 to 220 mg daily. The recommended dose for future studies was determined to be 160 mg daily, with a treatment schedule of 21 days on/seven days off in repeating 28-day cycles. The most common drug-related grade 3 or 4 AEs were dermatologic AEs (hand-foot skin reaction, rash), hypertension, and diarrhea. Pharmacokinetic analysis revealed a similar exposure at steady state for the parent compound and two pharmacologically active metabolites. Tumor perfusion and plasma cytokine analysis showed biologic activity of regorafenib. Three of 47 evaluable patients achieved a partial response (renal cell carcinoma, colorectal carcinoma, and osteosarcoma). CONCLUSION: Regorafenib showed an acceptable safety profile and preliminary evidence of antitumor activity in patients with solid tumors.

Development of a novel prodrug of paclitaxel that is cleaved by prostate-specific antigen: an in vitro and in vivo evaluation study.

In developed countries, prostate cancer is the third most common cause of death from cancer in men. Unfortunately, whilst accumulating clinical data have suggested that taxanes may prolong the survival in a subset of men with prostate carcinoma, the dose and duration of administration of these drugs are limited by their significant systemic toxicities due to a lack of tumour selectivity. In an attempt to improve both the water solubility and tumour-targeting properties of paclitaxel (Taxol®), we set out to develop a water soluble paclitaxel prodrug that is activated specifically by prostate-specific antigen (PSA) which is almost exclusively expressed in prostate tissue and prostate carcinoma making it an ideal molecular target for prodrug strategies. Using albumin as a drug carrier, we describe a novel albumin-binding prodrug of paclitaxel, EMC-Arg-Ser-Ser-Tyr-Tyr-Ser-Leu-PABC-paclitaxel [EMC: ε-maleimidocaproyl; PABC: p-aminobenzyloxycarbonyl] that was synthesised by reacting EMC-Arg-Ser-Ser-Tyr-Tyr-Ser-OH with H-Leu-PABC-paclitaxel. This prodrug was water soluble and was bound to endogenous and exogenous albumin. Moreover, incubation studies with PSA demonstrated that the albumin-bound form of the prodrug was cleaved rapidly at the P1-P1' scissile bond releasing the paclitaxel-dipeptide H-Ser-Leu-PABC-paclitaxel. Last but not least, due to the incorporation of a PABC self-eliminating linker, this dipeptide was rapidly degraded to liberate paclitaxel as a final cleavage product within a few hours in prostate tumour tissue homogenates. Of note was that the albumin-bound form of the prodrug was approximately three-fold more active in killing PSA-positive LNCaP cells than paclitaxel. In addition, orientating toxicity studies in mice showed that the maximum tolerated dose of the novel paclitaxel prodrug was twice that of conventional paclitaxel. When tested in vivo in an orthotopic mouse model of human prostate cancer using luciferase-transduced LNCaP LLN cells, both paclitaxel and the new paclitaxel prodrug showed distinct antitumour efficacy on the primary tumour and metastases that was significantly better than the effect of doxorubicin which was used as a comparison and showed no antitumour efficacy. The new paclitaxel prodrug (3 × 24 mg paclitaxel equivalents) showed comparable antitumour activity on the primary tumour to paclitaxel at its maximum-tolerated dose (3 × 12mg/kg), reduced circulating PSA levels and demonstrated a better antitumour effect on lung metastases but not on bone metastases.

A phase IA, open-label, dose-escalating study of PTK787/ZK 222584 administered orally on a continuous dosing schedule in patients with advanced cancer.

BACKGROUND: PTK787/ZK 222584 (PTK/ZK) offers a novel approach to inhibit tumour angiogenesis. PATIENTS AND METHODS: This study characterized the safety, tolerability, biological activity and pharmacokinetic profile of PTK/ZK, while determining the optimum dose. Seventy-one patients with advanced cancer were enrolled to receive once daily dosing. Pharmacokinetic, dynamic contrast enhanced magnetic resonance imaging and safety assessments were performed, along with measurement of soluble markers. Patients were treated until they had unacceptable toxicity and/or disease progression. RESULTS: Twenty-nine patients were assessable for maximum tolerated dose (MTD) determination, but no MTD was established; only two patients experienced dose limiting toxicities. PTK/ZK was well tolerated with only nine patients experiencing serious adverse events suspected to be PTK/ZK related, but no objective tumour response was observed; 34% had stable disease and 48% had progressive disease. In addition, PTK/ZK was rapidly absorbed with a maximum concentration occurring 2 hours post-dosing. Vascular endothelial growth factor and basic fibroblastic growth factor were good predictors of best tumour response, as was the MRI bidirectional transfer constant on day 2 of treatment. CONCLUSION: An MTD was not reached in this study but, based on these data and findings from other studies, 1200 mg was found to be the optimum dose of PTK/ZK for patients with advanced cancer.

c-kit (CD117) expression in human tumors and its prognostic value: an immunohistochemical analysis.

c-kit functions as a tyrosine kinase receptor and represents a target for small molecule kinase inhibitors. The expression pattern for c-kit was studied in different human tumor types to their correlation with prognosis. Paraffin-embedded tumor tissues from 282 patients were analyzed immunohistochemically for c-kit expression. Survival and follow-up data were available from 192/282 (68%) patients. c-kit immunopositivity was found in 62/282 (22%) cases. c-kit expression was found in 14/83 (17%) colorectal cancers, in 13/62 (21%) breast cancers, in 7/20 sarcomas (35%), in 5/14 (36%) renal cell carcinomas, in 2/12 ovarian cancers (17%) and in 2/12 (17%) hepatocellular carcinomas. We found no significant correlation between c-kit expression and prognosis although a trend to a worse prognosis in patients with c-kit positive tumors could be observed. Expression of c-kit was found in tumor samples with varying intensities and infrequently.

First-time-in-man and pharmacokinetic study of weekly oral perifosine in patients with solid tumours.

AIM: To identify the maximum-tolerated dose (MTD) and pharmacokinetics of oral perifosine. METHODS: Patients with solid tumours received perifosine at dosages ranging from 100-800mg/week. Eligibility criteria included life expectancy>12weeks, WHO performance status2, normal blood, liver and renal functions and no recent anticancer treatment. Drug concentrations were analysed by HPLC-MS/MS. RESULTS: Thirty six patients were recruited (75% males, mean age 54.7years, performance status 1 in 72.2%). Adverse events included nausea (69.4%), diarrhoea (55.6%), vomiting (52.8%) and abdominal pain (13.9%). Antiemetic regimens including glucocorticoids, dopamine antagonists and 5-HT3-antagonists were used as treatment and/or prophylaxis in 50% of the patients. Though MTD was formally not reached with 800mg/week, the treatment discontinuation due to diarrhoea and vomiting likely related to perifosine in two cases led to the decision to stop further dose escalation. Pharmacokinetics after a single dose were median t(max)=8.0-24.2h, median t(1/2)=81.0-115.9h and mean(geo) CL/f=0.28-0.43mL/min/kg. Urinary excretion was below 1%. Perifosine slightly accumulated and steady state was nearly reached after 2-3weeks. CONCLUSION: Oral perifosine was tolerable up to 600mg/week in cancer patients when administered with meal and prophylactic antiemetics. Based on its half-life of about 4days, a weekly regimen may be appropriate.

Marine phospholipids--a promising new dietary approach to tumor-associated weight loss.

GOALS OF WORK: Advanced tumor disease very often evokes excessive loss of body weight. Among others, fish oil or marine fatty acid ethyl esters were investigated for treatment of cancer cachexia with controversial results. In this study, a new formulation of marine fatty acids was investigated, the marine phospholipids, with more than 50% of phospholipid-bound fatty acids being eicosapentaenoic and docosahexaenoic acid. MATERIALS AND METHODS: Thirty-one tumor patients with various tumor entities suffering from weight loss were asked to take marine phospholipids (1.5 g/day) as softgel capsules for a period of 6 weeks. Compliance, body weight, appetite, and quality of life as well as the fatty acid profile in plasma and blood cells were monitored; 17 patients could be analyzed. MAIN RESULTS: Marine phospholipids were very well accepted; low-dose supplementation resulted in a significant increase of eicosapentaenoic and docosahexaenoic acid in plasma phospholipids; therefore, significantly reducing the n-6 to n-3 fatty acid ratio. A stabilization of body weight was achieved (median weight change of +0.6% after 6 weeks), while appetite and quality of life improved. CONCLUSIONS: These promising first results encourage further investigation of marine phospholipids in cancer care.

Phase I study of the angiogenesis inhibitor BIBF 1120 in patients with advanced solid tumors.

PURPOSE: BIBF 1120 is an oral, potent angiokinase inhibitor targeting receptors of the vascular endothelial growth factors, platelet-derived growth factors, and fibroblast growth factors. This phase I, accelerated titration study assessed the maximum tolerated dose, safety, pharmacokinetics, and pharmacodynamic effects of BIBF 1120. PATIENTS AND METHODS: Sixty-one patients with advanced cancers received BIBF 1120 in successive cohorts. Twenty-five received 50 to 450 mg once daily and 36 received 150 to 300 mg twice daily in 4-week treatment courses interspersed by 1 week of washout. Dynamic contrast-enhanced magnetic resonance imaging assessed antiangiogenic effect in 42 patients. RESULTS: Most frequent BIBF 1120-related adverse events were mostly mild to moderate (Common Toxicity Criteria grade 1-2) nausea (68.9%), vomiting (45.9%), and diarrhea (44.3%). The majority of dose-limiting adverse events of Common Toxicity Criteria grade 3 or 4 were reversible liver enzyme elevations. The maximum tolerated dose was 250 mg of BIBF 1120 for once and twice daily dosing. BIBF 1120 was absorbed moderately fast (t(max) = 1-3 hours at steady state), with no deviation from dose linearity and no decrease of exposure over time. The gMean terminal half-life was from 13 to 19 hours. One complete and two partial responses occurred in patients with renal cell cancer (n = 2) and colorectal cancer (n = 1). Dynamic contrast-enhanced magnetic resonance imaging showed a significant reduction in tumor blood flow in 55% of evaluable patients. CONCLUSIONS: BIBF 1120 dosed continuously displayed a favorable safety and pharmacokinetics profile, and first efficacy signals were observed. Twice daily dosing permitted increased drug exposure without additional toxicity. Two hundred milligrams BIBF 1120 twice daily is the recommended dose for phase II monotherapy studies.

Optimization of an albumin-binding prodrug of Doxorubicin that is cleaved by prostate-specific antigen.

We have developed a novel albumin-binding prodrug of doxorubicin that incorporates p-aminobenzyloxycarbonyl (PABC) as a 1,6 self-immolative spacer in addition to the heptapeptide, Arg-Ser-Ser-Tyr-Tyr-Ser-Leu, as a substrate for the prostate-specific antigen (PSA) that is overexpressed in prostate carcinoma and represents a molecular target for selectively releasing an anticancer agent from a prodrug formulation. The prodrug exhibited good water solubility and was bound rapidly to the cysteine-34 position of human serum albumin. Incubation studies with PSA demonstrated that the albumin-bound form of the prodrug was cleaved rapidly at the P1-P1' scissile bond, releasing H-Ser-Leu-PABC-DOXO, which was further degraded to release doxorubicin as a final cleavage product within a few hours in prostate tumor tissue homogenates as well as in PSA-positive LNCaP LN cell lysates. Moreover, our prodrug exhibited antiproliferative activity in a low micromolar range against a PSA-expressing prostate cancer cell line (LNCaP).

Tumour Biology: tumour-associated inflammation versus antitumor immunity.

The latest research results suggest that tumour-infiltrating leukocytes and the intra-tumoural cytokine environment play a central role in both the genesis and development of cancer. Over a hundred years ago, Virchow pointed out that numerous immune cells occur in the vicinity of practically all malignant tumours and that the structure of tumour tissue closely resembles the inflamed region of a non-healing wound. With the aid of the latest molecular and cell-biological methods, we are not only able today to closely characterise tumour cells and their immediate vicinity but also the other cell types present in tumour tissue, such as infiltrating immune cells, endothelial cells, connective tissue cells and others, both in terms of phenotype and function. In addition, there is growing understanding of the significance of the composition and functioning of endogenous messenger substances such as cytokines, chemokines and prostaglandins in healthy and malignantly altered tissues. From the immunological point of view, the main characteristics are dysregulated inflammatory conditions caused by the tumour cells themselves or by external factors, depending on the type of tumour event. It is evident that prolonged dysregulated inflammatory conditions favour not only carcinogenesis but also the local infiltration and metastasis of malignantly modified cells and counteract the development of efficient antitumor immunity. On the other hand, there are indications that through the polarisation of immunological reactions, the ability of immunological regulator and effector cells to induce efficient antitumor immunity can be modulated. Within the framework of this summary, the essential immunological aspects of tumour formation and tumour development known at present are presented and possible new therapeutic strategies are discussed.

DCE-MRI assessment of the effect of vandetanib on tumor vasculature in patients with advanced colorectal cancer and liver metastases: a randomized phase I study.

BACKGROUND: Vandetanib is a once-daily oral inhibitor of VEGFR, EGFR and RET signaling pathways. In patients with advanced colorectal cancer and liver metastases, the effect of vandetanib on tumor vasculature was assessed using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). METHODS: Eligible patients received vandetanib 100 or 300 mg/day. DCE-MRI (iAUC(60 )and K(trans)) was used to quantify the primary endpoints of tumor perfusion and vascular permeability. An exploratory assessment of tumor oxygenation was performed using MRI/T2*. All MRI parameters were measured at baseline (twice) and on days 2, 8, 29 and 57. RESULTS: Twenty-two patients received vandetanib (n = 10, 100 mg; n = 12, 300 mg). Baseline measurements of iAUC(60 )and K(trans )were reproducible, with low intrapatient coefficients of variation (11% and 24%, respectively). Estimates of mean % changes from baseline were -3.4% (100 mg) and -4.6% (300 mg) for iAUC(60), and -4.6% (100 mg) and -2.7% (300 mg) for K(trans); these changes were not significantly different between doses. The exploratory T2* measurement showed a significant increase at 300 mg versus 100 mg (P = 0.006). Both doses of vandetanib were generally well tolerated; common toxicities were fatigue, rash and diarrhea (majority CTC grade 1 or 2). The pharmacokinetic profile of vandetanib was similar to that observed previously. There were no RECIST-defined objective responses; five patients experienced stable disease >/=8 weeks. CONCLUSION: In this study in patients with advanced colorectal cancer, vandetanib did not modulate gadolinium uptake in tumor vasculature and tissue measured by the DCE-MRI parameters iAUC(60 )and K(trans). TRIAL REGISTRATION: NCT00496509 (ClinicalTrials.gov); D4200C00050 (AstraZeneca).

Effective strategies for management of hypertension after vascular endothelial growth factor signaling inhibition therapy: results from a phase II randomized, factorial, double-blind study of Cediranib in patients with advanced solid tumors.

PURPOSE Hypertension is a commonly reported adverse effect after administration of vascular endothelial growth factor (VEGF) inhibitors. Cediranib is a highly potent and selective VEGF signaling inhibitor of all three VEGFRs. This study prospectively investigated hypertension management to help minimize dose interruptions/reductions to maximize cediranib dose intensity. PATIENTS AND METHODS Patients (n = 126) with advanced solid tumors were randomly assigned to one of four groups: cediranib 30 or 45 mg/d with or without antihypertensive prophylaxis. All patients developing hypertension on cediranib treatment were treated with a standardized, predefined hypertension management protocol. Results Cediranib was generally well tolerated, and all groups achieved high-dose intensities in the first 12 weeks (> 74% in all groups). Antihypertensive prophylaxis did not result in fewer dose reductions or interruptions. Increases in blood pressure, including moderate and severe readings of hypertension, were seen early in treatment in all groups and successfully managed. Severe hypertension occurred in one patient receiving prophylaxis versus 18 in the nonprophylaxis groups. Overall, there were nine partial responses, and 38 patients experienced stable disease >/= 8 weeks. CONCLUSION To our knowledge, this is the first prospective investigation of hypertension management during administration of a VEGF signaling inhibitor. All four regimens were well tolerated with high-dose intensities and no strategy was clearly superior. The current cediranib hypertension management protocol appears to be effective in managing hypertension compared with previous cediranib studies where no plan was in place, and early recognition and treatment of hypertension is likely to reduce the number of severe hypertension events. This protocol is included in all ongoing cediranib clinical studies.

Anti-metastatic effects of liposomal gemcitabine in a human orthotopic LNCaP prostate cancer xenograft model.

Fatal outcomes of prostate carcinoma (PCa) mostly result from metastatic spread rather than from primary tumor burden. Here, we monitored growth and metastatic spread of an orthotopic luciferase/GFP-expressing LNCaP PCa xenograft model in SCID mice by in vivo imaging and in vitro luciferase assay of tissues homogenates. Although the metastatic spread generally shows a significant correlation to primary tumor volumes, the susceptibility of various tissues to metastatic invasion was different in the number of affected animals as well as in absolute metastatic burden in the individual tissues. Using this xenograft model we showed that treatment with liposomal gemcitabine (GemLip) inhibited growth of the primary tumors (83.9 +/- 6.4%; P = 0.009) as well as metastatic burden in lymph nodes (95.6 +/- 24.0%; P = 0.047), lung (86.5 +/- 10.5%; P = 0.015), kidney (88.4 +/- 9.2%; P = 0.045) and stomach (79.5 +/- 6.6%; P = 0.036) already at very low efficient concentrations (8 mg/kg) as compared to conventional gemcitabine (360 mg/kg). Our data show that this orthotopic LNCaP xenograft PCa model seems to reflect the clinical situation characterized by the fact that at time of diagnosis, prostate neoplasms are biologically heterogeneous and thus, it is a useful model to investigate new anti-metastatic therapies.

Phase II STUdy with 3rd- or 4th-line bendamustine (flat dose) therapy in patients with metastatic breast cancer.

BACKGROUND: Bendamustine is a drug with a favorable side effect spectrum and it offers a chance to overcome tumor resistance in pretreated patients with metastatic breast cancer (MBC). PATIENTS AND METHODS: Bendamustine was given as flat dose with 200 mg at days 1 + 2 in MBC patients pretreated with 2-3 different chemotherapies. Therapy was repeated at day 28 or fully recovered neutrophils. After 2 treatment cycles, a tumor response evaluation was performed. Toxicity was graded according to the National Cancer Institute common toxicity criteria (NCI-CTC) catalogue. RESULTS: 22 patients were evaluated for toxicity. 4 patients dropped out before the first tumor response evaluation; thus, 18 patients were evaluable for anticancer efficacy evaluation. 3/18 patients reached a partial remission (PR), 4 stable disease and 11 showed progression after 2 treatment cycles. The time to progression (TTP) was 5 months in patients with PR and 4 months in patients with no change (NC). In patients with progressive disease (PD), TTP was < 2 months. The main toxicities were nausea, weight loss and fatigue. CONCLUSIONS: Bendamustine can be given with a fixed flat dose, which simplifies the drug preparation. 2/5th of all treated patients responded to this therapy whereas bendamustine showed no anticancer effect in 3/5th of all patients. Bendamustine is definitely a drug with anticancer potential.

Liposomal gemcitabine (GemLip)-efficient drug against hormone-refractory Du145 and PC-3 prostate cancer xenografts.

BACKGROUND: Gemcitabine (Gemc) is an efficient chemotherapeutic drug in various cancer types (e.g., pancreas) but has only limited effects on hormone-refractory prostate cancer (HRPCa). Since HRPCa cells are highly sensitive to even low doses of Gemc in vitro, the lack of clinical effects might be due to rapid degradation of Gemc by deaminases combined with impaired accumulation in tumor tissue and PCa cells. Liposomal formulation (GemLip) is expected to protect the entrapped cytotoxic substance from enzymatic degradation and furthermore augment its accumulation within tumor tissues due to an enhanced permeability of the tumor vessels. METHODS: Anti-tumoral and anti-metastatic activity of GemLip and Gemc were investigated in two luciferase-expressing, human hormone-refractory PC-3 and Du145 HRPCa xenograft models in immunodeficient mice. Tumor growth was monitored by in vivo luminescence imaging (orthotopic) or callipering (subcutaneous). Anti-metastatic effects of treatment were determined by in vitro luciferase assay of the tissues. RESULTS: Tumor growth of subcutaneous Du145 xenografts was significantly inhibited only by GemLip (8 mg/kg: P = 0.014 and 6 mg/kg: P = 0.011) but not by conventional Gemc (360 mg/kg). In contrast, growth of orthotopic PC-3 xenografts was significantly inhibited by both, GemLip (P = 0.041) and Gemc (P = 0.002). The drugs furthermore strongly reduced spleen and liver metastases in this model. CONCLUSIONS: As shown by the very low efficient concentration of GemLip, liposomal entrapment of Gemc greatly enhances its activity. GemLip has, even at very low doses, a significant anti-tumoral and anti-metastatic therapeutic effect in HRPCa xenografts in vivo and was beneficial even when the conventional Gemc failed.

Antimetastatic effects of liposomal gemcitabine and empty liposomes in an orthotopic mouse model of pancreatic cancer.

OBJECTIVES: Test the efficacy of liposomal gemcitabine (GemLip) on primary tumor and metastases using the pancreatic tumor cell line AsPC1 implanted orthotopically into nude mice. METHODS: The efficacy of gemcitabine and GemLip cells was tested on luciferase-transduced AsPC1 cells in vitro as well as implanted orthotopically into the pancreata of nude mice. RESULTS: In vitro, the IC50s for GemLip and gemcitabine were 20 nM and 140 nM, respectively. However, when applied against established tumors, GemLip (8 mg/kg) blocked tumor growth for 5 consecutive weeks according to bioluminescence measurements in vivo. Gemcitabine (240 mg/kg) had no effect on luciferase-monitored tumor growth. When analyzed at the time of necropsy, GemLip strongly reduced tumor size (-64% +/- [SD] 27%; ***P < 0.0001), whereas gemcitabine only weakly (-36% +/- 37%) affected tumor size. Empty liposomes had no effect on the tumor size. GemLip and empty liposomes both significantly interfered with the metastatic spread to the liver, as measured using luciferase assays (GemLip, *P = 0.01; empty liposomes, *P = 0.036). In addition, they showed effects against spleen, as well as peritoneal metastases. CONCLUSIONS: GemLip presents an effective new formulation of gemcitabine, combining the targeting and protective features of the liposomes with their antimetastatic effects to target pancreatic cancer.