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1.
Eur J Cancer ; 45(8): 1370-80, 2009 May.
Article in English | MEDLINE | ID: mdl-19201599

ABSTRACT

The aim of this paper is to identify the major barriers hindering adequate pain management and critically review interventions aiming to overcome them. We searched relevant literature on PubMed published between January 1986 and April 2007. The most frequently mentioned barriers for both patients and professionals were knowledge deficits, inadequate pain assessment and misconceptions regarding pain. Four interventions were identified: patient education, professional education, pain assessment and pain consultation. These interventions were never combined in multidisciplinary study protocols. Most RCTs included small groups of patients and reported no power analysis. Studies on professional education and pain assessment did not evaluate patients' outcomes. In 5 of 11 RCTs on patient education, pain intensity decreased statistically significantly. In two RCTs on pain consultation, patients' pain decreased statistically significantly, although the adequacy of pain treatment did not change. In conclusion, international guidelines on multidisciplinary interventions in pain management are partly substantiated by clinical trials.


Subject(s)
Analgesia/methods , Evidence-Based Medicine , Neoplasms/psychology , Humans , Pain Measurement/methods , Patient Care Planning , Patient Education as Topic , Patient-Centered Care , Randomized Controlled Trials as Topic
2.
Amino Acids ; 37(4): 703-8, 2009 Oct.
Article in English | MEDLINE | ID: mdl-18953681

ABSTRACT

Both increased and decreased nitric oxide (NO) synthesis have been reported in patients treated with interferon-alpha (IFN-alpha). Animal studies showed that IFN-alpha administration results in increased levels of biogenic amines, subsequent activation of monoamine oxidases (MAOs), and finally in a change in NO production due to the H(2)O(2) generated by MAOs. We examined the potential relationship between NO production in plasma and MAO-B activity in platelets of 43 cancer patients during 8 weeks of treatment with IFN-alpha. NO synthesis was quantitated by measuring both the ratio of citrulline and arginine (CIT/ARG-ratio) and total nitrite/nitrate (NOx) levels. Compared to baseline, MAO activity and NOx increased, while the CIT/ARG-ratio decreased. No associations were found between NOx, MAO and CIT/ARG-ratio. Only few associations were observed between changes in the biochemical parameters and changes in psychopathology induced by IFN-alpha, of which the association between changes in CIT and lassitude was the most consistent. The results suggest that peripheral NO production and MAO activity are unrelated to each other, and that peripheral changes in these biochemical parameters induced by IFN-alpha are unlikely to contribute to definite psychiatric disturbance.


Subject(s)
Carcinoma, Renal Cell/drug therapy , Interferon-alpha/therapeutic use , Kidney Neoplasms/drug therapy , Melanoma/drug therapy , Monoamine Oxidase/biosynthesis , Nitric Oxide/biosynthesis , Skin Neoplasms/drug therapy , Adult , Aged , Arginine/blood , Arginine/metabolism , Blood Platelets/metabolism , Carcinoma, Renal Cell/metabolism , Citrulline/blood , Citrulline/metabolism , Female , Humans , Interferon-alpha/administration & dosage , Kidney Neoplasms/metabolism , Male , Melanoma/metabolism , Middle Aged , Monoamine Oxidase/blood , Nitrates/blood , Nitrates/metabolism , Nitric Oxide/blood , Nitrites/blood , Nitrites/metabolism , Prospective Studies , Skin Neoplasms/metabolism
3.
Psychiatry Clin Neurosci ; 62(5): 597-602, 2008 Oct.
Article in English | MEDLINE | ID: mdl-18950381

ABSTRACT

AIMS: Immunotherapy with interferon-alpha (IFN-alpha) is associated with psychiatric side-effects, including depression. One of the putative pathways underlying these psychiatric side-effects involves tryptophan (TRP) metabolism. Cytokines including IFN-alpha induce the enzyme indoleamine 2,3-dioxygenase (IDO), which converts TRP to kynurenine (KYN), leading to a shortage of serotonin (5-HT). In addition, the production of neurotoxic metabolites of KYN such as 3-hydroxykynurenine and quinolinic acid (QA) might increase and contribute to IFN-alpha-induced psychopathology. In contrast, other catabolites of KYN, such as kynurenic acid (KA), are thought to have neuroprotective properties. METHODS: In a group of 24 patients treated with standard IFN-alpha for metastatic renal cell carcinoma (RCC), combined psychiatric and laboratory assessments were performed at baseline, 4 and 8 weeks, and at 6 months. RESULTS: No psychopathology was observed, despite an increase in neurotoxic challenge as reflected in indices for the balance between neurotoxic and neuroprotective metabolites of KYN. CONCLUSIONS: The present hypothesis that a shift in the balance between neurotoxic and neuroprotective metabolites of KYN underlies the neuropsychiatric side-effects of IFN-alpha-based immunotherapy, is neither supported nor rejected.


Subject(s)
Carcinoma, Renal Cell/drug therapy , Depressive Disorder, Major/chemically induced , Immunologic Factors/toxicity , Immunologic Factors/therapeutic use , Interferon-alpha/toxicity , Interferon-alpha/therapeutic use , Kidney Neoplasms/drug therapy , Kynurenine/analogs & derivatives , Kynurenine/blood , Neuroprotective Agents/blood , Neurotoxins/blood , Quinolinic Acid/blood , Adult , Aged , Brain/drug effects , Brain/metabolism , Carcinoma, Renal Cell/blood , Depressive Disorder, Major/blood , Dose-Response Relationship, Drug , Drug Administration Schedule , Female , Humans , Immunologic Factors/pharmacokinetics , Injections, Subcutaneous , Interferon-alpha/pharmacokinetics , Kidney Neoplasms/blood , Male , Middle Aged , Neuropsychological Tests
4.
Psychosomatics ; 49(1): 56-63, 2008.
Article in English | MEDLINE | ID: mdl-18212177

ABSTRACT

Interferon-alpha (IFN-alpha) treatment in both oncological and hepatological settings is associated with depression. If IFN-alpha treatment induces depression in high numbers, it could serve as a model for studying the pathophysiology of depression, in general. The authors therefore studied 43 oncology patients treated with standard or pegylated IFN-alpha with baseline psychiatric assessment and at regular time-points in the first 6 months of treatment. Apart from a severe depression because of brain metastases, authors observed only two clinically relevant depressive states. Contrary to findings in most of the literature, most depressive episodes in this study were self-limiting and short-lasting and were associated with either episodes of flu-like symptoms common at the start of the treatment or with concurrent psychosocial events. In the group as a whole, scores on both observer-based and self-report rating scales did not show clinically relevant changes. The results of this study indicate that IFN-alpha treatment is not suitable as a study model for depression in general.


Subject(s)
Antineoplastic Agents/adverse effects , Anxiety Disorders/chemically induced , Carcinoma, Renal Cell/drug therapy , Depressive Disorder, Major/chemically induced , Interferon-alpha/adverse effects , Kidney Neoplasms/drug therapy , Melanoma/drug therapy , Polyethylene Glycols/adverse effects , Skin Neoplasms/drug therapy , Adult , Aged , Antineoplastic Agents/therapeutic use , Anxiety Disorders/diagnosis , Anxiety Disorders/epidemiology , Carcinoma, Renal Cell/psychology , Cross-Sectional Studies , Depressive Disorder, Major/diagnosis , Depressive Disorder, Major/epidemiology , Dose-Response Relationship, Drug , Drug Administration Schedule , Female , Follow-Up Studies , Humans , Injections, Subcutaneous , Interferon alpha-2 , Interferon-alpha/therapeutic use , Kidney Neoplasms/psychology , Male , Melanoma/psychology , Middle Aged , Personality Inventory , Polyethylene Glycols/therapeutic use , Recombinant Proteins , Risk Factors , Skin Neoplasms/psychology
6.
Neuropsychobiology ; 55(3-4): 225-31, 2007.
Article in English | MEDLINE | ID: mdl-17873497

ABSTRACT

BACKGROUND: Interferon-alpha (IFN-alpha) treatment is often associated with psychiatric side effects and has been found to lower the amount of tryptophan (TRP) available to the brain. The alterations in tryptophan metabolism might underlie the psychiatric side effects during treatment with IFN-alpha. METHODS: In this study, 43 oncology patients treated with IFN-alpha were included. In order to study de novo depressions, depressed patients at baseline were excluded. Psychiatric evaluation comprising clinical judgment combined with a structured psychiatric interview and observer-based and self-report rating scales was performed at baseline and at 4 weeks, 8 weeks and 6 months after the start of treatment with IFN-alpha, and in the case of emerging psychopathology. Blood samples were drawn at the same evaluation times and assessed for concentrations of TRP, large neutral amino acids, kynurenine, 5-hydroxyindole acetic acid, neopterin and biopterin. RESULTS: During treatment with IFN-alpha, several alterations in laboratory parameters occurred that were consistent with an increased degradation of peripheral TRP. Psychometric ratings revealed hardly any psychiatric changes. No consistent associations were found between changes in the laboratory assessments determined and the diverse psychiatric measures. CONCLUSION: In this study, IFN-alpha was found to alter TRP metabolism without inducing psychiatric side effects. Therefore, a possible relationship between TRP metabolism and depression was not substantiated by this study.


Subject(s)
Behavioral Symptoms/chemically induced , Immunologic Factors/adverse effects , Interferon-alpha/adverse effects , Melanoma/blood , Tryptophan/blood , Adult , Aged , Female , Humans , Male , Melanoma/drug therapy , Middle Aged , Psychiatric Status Rating Scales , Statistics, Nonparametric , Time Factors
7.
J Pain Symptom Manage ; 34(6): 639-47, 2007 Dec.
Article in English | MEDLINE | ID: mdl-17703909

ABSTRACT

Adherence to analgesics in cancer patients has scarcely been studied. In this study, the Medication Event Monitoring System (MEMS) and medication diaries were compared with respect to feasibility and adherence measurements. Forty-six outpatients with nociceptive pain caused by cancer were asked to use MEMS for their analgesics and to record their medication usage in a diary for four weeks. Seventy-nine percent of the patients used MEMS for the full four-week period; 70% did so for the diary. The majority of patients were satisfied with both MEMS and diary. Adherence data assessed by MEMS and diary were comparable. Patients used the amount of analgesics adequately (taking adherence: 87%) but took them irregularly (timing adherence: 53%). Subgroup analyses in patients using single and multiple analgesic regimens confirmed the comparable suitability of both methods. MEMS and a medication diary are equally useful for analgesic adherence measurement in cancer patients with pain.


Subject(s)
Analgesics/administration & dosage , Drug Monitoring/methods , Neoplasms/complications , Pain/drug therapy , Patient Compliance , Adult , Aged , Female , Humans , Male , Medical Records , Middle Aged , Pain/etiology , Self Administration
8.
BMC Cancer ; 6: 201, 2006 Jul 31.
Article in English | MEDLINE | ID: mdl-16879751

ABSTRACT

BACKGROUND: The treatment of ovarian cancer is hindered by intrinsic or acquired resistance to platinum-based chemotherapy. The aim of this study is to determine the frequency of mismatch repair (MMR) inactivation in ovarian cancer and its association with resistance to platinum-based chemotherapy. METHODS: We determined, microsatellite instability (MSI) as a marker for MMR inactivation (analysis of BAT25 and BAT26), MLH1 promoter methylation status (methylation specific PCR on bisulfite treated DNA) and mRNA expression of MLH1, MSH2, MSH3, MSH6 and PMS2 (quantitative RT-PCR) in 75 ovarian carcinomas and eight ovarian cancer cell lines RESULTS: MSI was detected in three of the eight cell lines i.e. A2780 (no MLH1 mRNA expression due to promoter methylation), SKOV3 (no MLH1 mRNA expression) and 2774 (no altered expression of MMR genes). Overall, there was no association between cisplatin response and MMR status in these eight cell lines. Seven of the 75 ovarian carcinomas showed MLH1 promoter methylation, however, none of these showed MSI. Forty-six of these patients received platinum-based chemotherapy (11 non-responders, 34 responders, one unknown response). The resistance seen in the eleven non-responders was not related to MSI and therefore also not to MMR inactivation. CONCLUSION: No MMR inactivation was detected in 75 ovarian carcinoma specimens and no association was seen between MMR inactivation and resistance in the ovarian cancer cell lines as well as the ovarian carcinomas. In the discussion, the results were compared to that of twenty similar studies in the literature including in total 1315 ovarian cancer patients. Although no association between response and MMR status was seen in the primary tumor the possible role of MMR inactivation in acquired resistance deserves further investigation.


Subject(s)
DNA Repair/genetics , DNA, Neoplasm/genetics , Drug Resistance, Neoplasm , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/genetics , Adaptor Proteins, Signal Transducing , Adenosine Triphosphatases/genetics , Carrier Proteins/genetics , Carrier Proteins/metabolism , Cell Line, Tumor , DNA Methylation , DNA Repair Enzymes/genetics , DNA-Binding Proteins/genetics , Female , Gene Expression Profiling , Gene Expression Regulation, Neoplastic , Humans , Mismatch Repair Endonuclease PMS2 , MutL Protein Homolog 1 , MutS Homolog 2 Protein/classification , MutS Homolog 2 Protein/genetics , Nuclear Proteins/genetics , Nuclear Proteins/metabolism , Ovarian Neoplasms/pathology , Promoter Regions, Genetic/genetics
9.
Cancer Biol Ther ; 5(8): 943-9, 2006 Aug.
Article in English | MEDLINE | ID: mdl-16775422

ABSTRACT

The effectiveness of platinum drugs in the treatment of cancer is hindered by intrinsic and acquired resistance. The cause of clinical resistance to platinum compounds is still unknown. In an attempt to identify new cellular mechanisms of cisplatin resistance, a one-step cisplatin-selection procedure was used to generate resistant sublines of the platinum sensitive A2780 ovarian cancer cell line. In the present study we selected an A2780 subline, A2780-Pt, that has a significantly reduced ability to accumulate cisplatin (36% of the parent A2780 cell line) and consequently shows a clear cisplatin-resistant phenotype (resistance factor, i.e., RF: 8.6). The A2780-Pt cell line was specifically cross-resistant to carboplatin (RF: 12.0), tetraplatin (RF: 8.1) and oxaliplatin (RF: 6.1) which was associated with a reduced cellular platinum accumulation (50%, 54% and 58% of A2780, respectively). No cross-resistance was found for a variety of other anticancer agents. Further experiments to determine the cause of the platinum resistance of the A2780-Pt cell line revealed that: (1) impaired cellular platinum accumulation could not be attributed to aberrant expression of MRP2 (ABCC2), CTR1 (SLC31A1), ATP7A or ATP7B, (2) resistance was not associated with platinum inactivation by metallothionein and glutathione, (3) the platinum efflux rate was similar to that of A2780, (4) the defect in cellular accumulation and the resistance could be overcome by treatment with cisplatin nanocapsules, consistent with impaired influx, and (5) the defect in accumulation is specific for platinum compounds in the cis-configuration, since A2780-Pt cells did not show reduced accumulation of transplatin. This specificity suggests that not passive diffusion but an inward transporter is impaired in A2780-Pt. In conclusion, we generated an A2780 subline that showed a uniquely stable platinum resistance phenotype, which could theoretically be caused by an impaired inward transporter specific for cis-configurated platinum compounds.


Subject(s)
Antineoplastic Agents/pharmacokinetics , Cation Transport Proteins/physiology , Cisplatin/pharmacokinetics , Drug Resistance, Neoplasm , Ovarian Neoplasms/drug therapy , Carboplatin/pharmacokinetics , Female , Glutathione/metabolism , Humans , Multidrug Resistance-Associated Protein 2 , Nanotechnology , Neoplasm Proteins/genetics , Neoplasm Proteins/metabolism , Organoplatinum Compounds/pharmacokinetics , Ovarian Neoplasms/metabolism , Ovarian Neoplasms/pathology , Oxaliplatin , RNA, Messenger/genetics , RNA, Messenger/metabolism , RNA, Neoplasm/genetics , RNA, Neoplasm/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Tumor Cells, Cultured/drug effects , Tumor Cells, Cultured/metabolism
11.
J Clin Oncol ; 24(10): 1499-506, 2006 Apr 01.
Article in English | MEDLINE | ID: mdl-16574999

ABSTRACT

PURPOSE: The majority of cytotoxic drugs for adults are dosed based on body surface area (BSA), aiming to reduce interpatient variability in drug exposure. We prospectively studied the usefulness of BSA-based dosing of cisplatin in patients at extremes of BSA values. PATIENTS AND METHODS: Patients were randomly assigned to receive a fixed dose of cisplatin in course 1, and a BSA-adjusted dose in course 2, or vice versa. The fixed dose was based on the average BSA for males and females, while extremes were set at BSA values exceeding the average +/- 1 standard deviation. Subsequently, we retrospectively analyzed data from a normal population. RESULTS: In 25 patients assessable for both courses, the use of a fixed dose of cisplatin resulted in reduced exposure to unbound platinum in patients at the upper extremes of BSA (P = .003) and higher exposures in patients at the lower extremes (P = .009), as compared with exposures following the BSA-adjusted dose. Although clearance was related to BSA (R2 = 0.44; P < .001), only a small reduction in interpatient variability in clearance after correction for BSA was achieved (20.8% v 17.1%). In the retrospective analysis, compared with the average patient, the clearance of unbound platinum in patients with a BSA value < or = 1.65 m2 was 16% slower (P < .001), while an 18% faster clearance (P < .001) was observed in patients with a BSA value > or = 2.05 m2. CONCLUSION Unless better predictors for platinum clearance are identified, fixed-dose regimens per BSA cluster (< or = 1.65 m2; 1.66 m2 to 2.04 m2; > or = 2.05 m2) are recommended.


Subject(s)
Antineoplastic Agents/administration & dosage , Body Surface Area , Cisplatin/administration & dosage , Adult , Aged , Cisplatin/pharmacokinetics , Female , Humans , Male , Metabolic Clearance Rate , Middle Aged , Platinum/pharmacokinetics
12.
Ophthalmology ; 113(6): 1040-4, 2006 Jun.
Article in English | MEDLINE | ID: mdl-16631255

ABSTRACT

PURPOSE: To describe the documented growth, clinical course, and histopathology of retinoblastomas in an untreated and otherwise normal right eye of a 27-year-old white male with a g.153211T>A (p.Tyr606X) mutation in the retinoblastoma 1 gene, whose left eye was enucleated at age 2 years for 2 retinoblastomas. DESIGN AND PARTICIPANTS: Retrospective interventional case report. INTERVENTIONS: Over the years, the right eye was irradiated twice and underwent trans-pars plana vitrectomy, transscleral cryocoagulation, argon laser photocoagulation of tumors and their feeder vessels, extracapsular cataract extraction with posterior chamber lens implantation, and neodymium:yttrium-aluminum-garnet laser treatment of after-cataract in the form of Elschnig's pearls. Finally, the patient received combination chemotherapy with etoposide, methotrexate, actinomycin D, cisplatin, and vincristine. RESULTS: The eye finally had to be removed 12 years later due to tumor recurrences and seeding, pseudohypopyon, and elevated intraocular pressure. Histopathology showed microcellular retinoblastoma cells in the anterior chamber angle and trabecular meshwork without subconjunctival extension and in the nasal ciliary body, pars plana, internal limiting membrane, and optic nerve head anterior to the cribriform plate. The patient is without local or systemic recurrences at age 50, 11 years after the last eye was enucleated. CONCLUSIONS: This report shows that retinoblastoma patients may have tumor growth in their fellow eye 25 years after the first eye and also that Elschnig's after-cataract pearls still can arise after irradiation of a lens with 45 Gy.


Subject(s)
Retinal Neoplasms/pathology , Retinoblastoma/pathology , Adult , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Cataract Extraction , Cryotherapy , Eye Enucleation , Functional Laterality , Humans , Laser Coagulation , Male , Point Mutation , Retinal Neoplasms/genetics , Retinal Neoplasms/therapy , Retinoblastoma/genetics , Retinoblastoma/therapy , Retinoblastoma Protein/genetics , Retrospective Studies , Tyrosine/genetics , Vitrectomy
13.
Int J Cancer ; 118(8): 1963-71, 2006 Apr 15.
Article in English | MEDLINE | ID: mdl-16287073

ABSTRACT

The aim of this study is to discover a gene set that can predict resistance to platinum-based chemotherapy in ovarian cancer. The study was performed on 96 primary ovarian adenocarcinoma specimens from 2 hospitals all treated with platinum-based chemotherapy. In our search for genes, 24 specimens of the discovery set (5 nonresponders and 19 responders) were profiled in duplicate with 18K cDNA microarrays. Confirmation was done using quantitative RT-PCR on 72 independent specimens (9 nonresponders and 63 responders). Sixty-nine genes were differentially expressed between the nonresponders (n=5) and the responders (n=19) in the discovery phase. An algorithm was constructed to identify predictive genes in this discovery set. This resulted in 9 genes (FN1, TOP2A, LBR, ASS, COL3A1, STK6, SGPP1, ITGAE, PCNA), which were confirmed with qRT-PCR. This gene set predicted platinum resistance in an independent validation set of 72 tumours with a sensitivity of 89% (95% CI: 0.68-1.09) and a specificity of 59% (95% CI: 0.47-0.71)(OR=0.09, p=0.026). Multivariable analysis including patient and tumour characteristics demonstrated that this set of 9 genes is independent for the prediction of resistance (p<0.01). The findings of this study are the discovery of a gene signature that classifies the tumours, according to their response, and a 9-gene set that determines resistance in an independent validation set that outperforms patient and tumour characteristics. A larger independent multicentre study should further confirm whether this 9-gene set can identify the patients who will not respond to platinum-based chemotherapy and could benefit from other therapies.


Subject(s)
Antineoplastic Agents/pharmacology , Cisplatin/pharmacology , Gene Expression Profiling , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/genetics , Adult , Aged , Antineoplastic Agents/therapeutic use , Cisplatin/therapeutic use , Drug Resistance, Neoplasm , Female , Gene Expression Regulation, Neoplastic , Genes, Neoplasm , Humans , Middle Aged , Ovarian Neoplasms/pathology , Predictive Value of Tests , Prognosis , Reverse Transcriptase Polymerase Chain Reaction , Sensitivity and Specificity , Treatment Outcome
14.
Pharm World Sci ; 27(6): 423-31, 2005 Dec.
Article in English | MEDLINE | ID: mdl-16341948

ABSTRACT

AIM: Interferon-alpha (IFN-alpha) has been extensively explored for its efficacy in various disease conditions and is currently used as a standard treatment in several of these. Its use is accompanied by a wide variety of possible side effects. These side-effects may hamper reaching and maintaining the dose needed for maximal therapeutic effect while their occurrence can outweigh clinical benefit of IFN-alpha treatment. This review addresses the toxicity profile of IFN-alpha, the presumed pathophysiology of the different side effects and the strategies to handle these. METHODS: Computerized searches were used and cross-references of articles and books were checked. RESULTS: Adverse effects due to IFN-alpha have been described in almost every organ system. Many side-effects are clearly dose-dependent. Taken together, occurrence of flu-like symptoms, hematological toxicity, elevated transaminases, nausea, fatigue, and psychiatric sequelae are the most frequently encountered. Although insight in the mechanisms accounting for IFN-alpha-related toxicities has improved in recent years, much remains to be elucidated. Guidelines on the management of these untoward sequelae are mostly based on clinical experience, while many side-effects can only be adequately handled by dose adjustment or cessation of treatment. CONCLUSION: Further research on the mechanisms underlying both therapeutic effects and adverse events is warranted. Hopefully, this will lead to better identification of those patients who are likely to benefit from treatment without experiencing severe toxicities.


Subject(s)
Antineoplastic Agents/adverse effects , Antiviral Agents/adverse effects , Interferon-alpha/adverse effects , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/chemistry , Antiviral Agents/administration & dosage , Antiviral Agents/chemistry , Autoimmune Diseases/etiology , Chemistry, Pharmaceutical , Dose-Response Relationship, Drug , Drug Administration Schedule , Fever/etiology , Gastrointestinal Diseases/etiology , Hematologic Diseases/etiology , Humans , Interferon-alpha/administration & dosage , Interferon-alpha/chemistry , Liver Diseases/etiology , Randomized Controlled Trials as Topic
16.
Eur J Cancer ; 41(4): 516-22, 2005 Mar.
Article in English | MEDLINE | ID: mdl-15737555

ABSTRACT

Statins are known to reduce mortality related to cardiovascular diseases. In recent years, evidence has accumulated that statins also exert anti-tumour activity for which numerous potential underlying mechanisms of action have been suggested. Accordingly, several case-control studies showed a reduction in cancer incidence in patients treated with statins. Furthermore, statins interact synergistically with several anti-tumour treatments in preclinical studies. Until now, only a few clinical studies are available that explore the optimal dose, feasibility, and efficacy of statins applied as single agents to control the growth of existing tumours. Studies investigating statins as part of a multi-drug regimen are completely lacking. Nevertheless, the interesting pre-clinical anti-tumour activity of statins combined with a favourable toxicity profile warrant their further development as anti-tumour agents, in particular as part of multi-drug regimens.


Subject(s)
Antineoplastic Agents/therapeutic use , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Neoplasms/drug therapy , Drug Combinations , Drug Synergism , GTP-Binding Proteins/metabolism , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Randomized Controlled Trials as Topic
17.
Cancer Immunol Immunother ; 54(1): 37-43, 2005 Jan.
Article in English | MEDLINE | ID: mdl-15693137

ABSTRACT

Interleukin 12 (IL-12) is a cytokine with important regulatory functions bridging innate and adaptive immunity. It has been proposed as an immune adjuvant for vaccination therapy of infectious diseases and malignancies. The inflammatory properties of IL-12 play an important role in the adjuvant effect. We studied the effect of s.c. injections of recombinant human IL-12 (rHuIL-12) in 26 patients with renal cell cancer and demonstrated dose-dependent systemic activation of multiple inflammatory mediator systems in humans. rHuIL-12 at a dose of 0.5 microg/kg induced degranulation of neutrophils with a significant increase in the plasma levels of elastase (p < 0.05) and lactoferrin (p = 0.01) at 24 h. Additionally, rHuIL-12 injection mediated the release of lipid mediators, as demonstrated by a sharp increase in the plasma secretory phospholipase A2 (sPLA2) level (p = 0.003). rHuIL-12, when administered at a dose of 0.1 microg/kg, showed minimal systemic effects. In conclusion, when IL-12 is used as an adjuvant, doses should not exceed 0.1 microg/kg, in order to avoid severe systemic inflammatory responses.


Subject(s)
Adjuvants, Immunologic/adverse effects , Interleukin-12/adverse effects , Systemic Inflammatory Response Syndrome/chemically induced , Adjuvants, Immunologic/administration & dosage , Dose-Response Relationship, Drug , Humans , Injections, Subcutaneous , Interleukin-12/administration & dosage , Leukocyte Count , Neutrophils/cytology , Neutrophils/drug effects , Neutrophils/metabolism , Phospholipases A/blood , Phospholipases A2 , Systemic Inflammatory Response Syndrome/drug therapy , Time Factors
18.
Article in English | MEDLINE | ID: mdl-15610952

ABSTRACT

Depression and cognitive disturbance are well-known neuropsychiatric side effects of therapy with interferon-alfa (IFN-alfa). Aggression and irritability are also reported as side effects. Probably, central nervous system (CNS) serotonergic dysfunction is one of the underlying pathophysiological mechanisms of IFN-alfa-induced neuropsychiatric toxicity. Platelet activity of monoamine oxidase-B (MAO; EC1.4.3.4) is a possible indicator of central serotonergic function. Moreover, low platelet MAO activity is linked to impulsiveness, addiction and personality disorder. In this exploratory study in 17 high-risk melanoma patients, platelet counts, whole blood MAO, and platelet MAO activity were measured before and during therapy with IFN-alfa. Patients were randomized to treatment either with pegylated IFN-alfa (PEG-IFN-alfa) once a week at a dose of 6 microg/kg/week subcuteanously (s.c.) during 8 weeks, followed by a maintenance treatment of 3 microg/kg/week s.c. for a total of 5 years, or to observation only. Blood samples were taken at baseline, 4 and 8 weeks and 3 months. During treatment with IFN-alfa, platelet counts decreased at 4 and 8 weeks and 3 months, while platelet MAO activity increased, both compared to baseline and compared to non-treated controls. Compared to non-treated controls, platelet MAO activity increased with 86.4% (95 CI: 52.9-127.2). No significant changes in platelet MAO activity were observed in the control group. This indicates that platelet MAO activity is influenced by IFN-alfa. Since platelet MAO activity is a model for CNS MAO-B activity, it may be speculated that CNS MAO-B activity will also be increased. This could influence serotonin (5-HT) metabolism and thereby contribute to the development of psychiatric disturbance. However, a preferential inhibition of platelet production cannot be ruled out. Hypothetically, the antiproliferative effects of IFN-alfa could interfere more strongly with the synthesis of platelets than with the synthesis of mitochondria. In that case, increased platelet MAO activity reflects an increased number of mitochondria per platelet.


Subject(s)
Antineoplastic Agents/therapeutic use , Blood Platelets/enzymology , Interferon-alpha/therapeutic use , Melanoma/drug therapy , Melanoma/enzymology , Monoamine Oxidase/blood , Adult , Aged , Antineoplastic Agents/administration & dosage , Female , Humans , Injections, Subcutaneous , Interferon-alpha/administration & dosage , Male , Middle Aged , Mitochondria/drug effects , Mitochondria/enzymology , Platelet Count , Polyethylene Glycols
19.
Eur J Cancer ; 40(16): 2377-82, 2004 Nov.
Article in English | MEDLINE | ID: mdl-15519508

ABSTRACT

Following reports of its teratogenicity, thalidomide was banned from the market in the 1960s. Later, the elucidation that the inhibition of angiogenesis underlies this teratogenicity and the recognition of the importance of angiogenesis in malignancies has raised interest in thalidomide as an anti-tumour agent. Since then, numerous other mechanisms accounting for the anti-tumour effect of thalidomide have been revealed and many studies exploring the efficacy of thalidomide in tumours have been initiated. This Review focuses on the application of thalidomide and its derivatives in solid tumours, the mechanisms underlying their anti-tumour effects, and their potential to be applied in combination with other anti-tumour agents.


Subject(s)
Angiogenesis Inhibitors/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Neoplasms/drug therapy , Thalidomide/therapeutic use , Humans
20.
Neoplasia ; 6(4): 297-301, 2004.
Article in English | MEDLINE | ID: mdl-15256051

ABSTRACT

Male germ cell tumors (GCTs) are extremely sensitive to platinum-containing chemotherapy, with only 10% of patients showing therapy resistance. However, the biological basis of the high curability of disseminated GCTs by chemotherapy is still unknown. Recently, we demonstrated that the mammalian serine/arginine-rich protein-specific kinase 1 (SRPK1) is a cisplatin-sensitive gene, inactivation of which leads to cisplatin resistance. Because, in mammalians, the expression of SRPK1 is preferentially high in testicular tissues, cisplatin responsiveness of male GCTs might be associated with SRPK1 levels. In the present study, we monitored SRPK1 protein expression in a unique series of nonseminomatous GCTs by immunohistochemistry. Randomly selected GCTs (n = 70) and tumors from patients responding to standard chemotherapy (n = 20) generally showed strong SRPK1 staining. In contrast, expression in refractory GCTs (n = 20) as well as in GCTs from poor-prognosis patients responding to high-dose chemotherapy only (n = 11) was significantly lower (two-sided Wilcoxon rank sum test: P < .001). In conclusion, our data suggest that SRPK1 expression might be an important prognostic indicator for the chemoresponsiveness of nonseminomatous GCTs.


Subject(s)
Germinoma/enzymology , Platinum Compounds/therapeutic use , Protein Serine-Threonine Kinases/genetics , Testicular Neoplasms/enzymology , Adolescent , Adult , Drug Resistance, Neoplasm , Gene Expression Regulation, Neoplastic , Germinoma/drug therapy , Germinoma/mortality , Germinoma/pathology , Humans , Immunohistochemistry , Male , Middle Aged , Protein Serine-Threonine Kinases/metabolism , RNA Splicing , Survival Analysis , Testicular Neoplasms/drug therapy , Testicular Neoplasms/mortality , Testicular Neoplasms/pathology
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