ABSTRACT
BACKGROUND: ANG1005 consists of three molecules of paclitaxel conjugated via ester bonds to the 19-amino-acid peptide Angiopep-2. The new chemical agent has been shown to cross the blood-brain barrier (BBB) by receptor-mediated transcytosis via low-density lipoprotein receptor-related protein 1 (LRP1). The experiments here examined the role of LRP1 in the subsequent endocytosis of drug into cancer cells. METHODS: Localisation of ANG1005 and Angiopep-2 was examined by immunohistochemistry and in-vivo near-infrared fluorescence imaging in mice carrying orthotopic glioma tumours. Transport of ANG1005 and Angiopep-2 was examined in U87 glioblastoma cell lines. RESULTS: Systemically administered ANG1005 and Cy5.5Angiopep-2 localised to orthotopic glioma tumours in mice. The glioma transplants correlated with high expression levels of LRP1. Decreasing LRP1 activity, by RNA silencing or LRP1 competitors, decreased uptake of ANG1005 and Angiopep-2 into U87 glioblastoma cells. Conversely, LRP1 expression and endocytosis rates for ANG1005 and Angiopep-2 increased in U87 cells under conditions that mimicked the microenvironment near aggressive tumours, that is, hypoxic and acidic conditions. CONCLUSION: ANG1005 might be a particularly effective chemotherapeutic agent for the wide array of known LRP1-expressing brain and non-brain cancers, in particular those with an aggressive phenotype.
Subject(s)
Brain Neoplasms/metabolism , Glioma/metabolism , Paclitaxel/pharmacokinetics , Receptors, LDL/metabolism , Tumor Suppressor Proteins/metabolism , Animals , Biological Transport , Blood-Brain Barrier/metabolism , Brain Neoplasms/drug therapy , Brain Neoplasms/pathology , Cell Line, Tumor , Endocytosis , Glioma/drug therapy , Glioma/pathology , Hep G2 Cells , Humans , Low Density Lipoprotein Receptor-Related Protein-1 , Male , Mice , Mice, Nude , Paclitaxel/pharmacology , Peptides/pharmacokinetics , Peptides/pharmacology , Phenotype , RNA Interference , Receptors, LDL/genetics , Tumor Microenvironment , Tumor Suppressor Proteins/geneticsABSTRACT
The effect of supplementing postoperative patient-controlled analgesia (PCA) with a mandatory fixed-rate infusion was studied using alfentanil. Patients were assigned by lottery to receive alfentanil PCA with a bolus of 200 or 300 mcg or alfentanil PCA with a bolus of 100 or 200 mcg plus an infusion of 900 mcg/hr, such that ten patients received each treatment. Seven patients receiving PCA only, compared to two in the groups receiving infusion, were withdrawn due to inadequate pain relief (0.1 greater than P greater than 0.05). One patient receiving PCA only was withdrawn because of a low respiratory rate, whereas three patients receiving PCA plus infusion developed respiratory depression. Patients prescribed PCA plus infusion received significantly more alfentanil but did not describe less pain than patients prescribed PCA only. The blood alfentanil concentration immediately prior to demands was significantly higher in the PCA plus infusion groups. These results suggest that during PCA therapy the drug prescription influences the blood concentration associated with satisfactory analgesia.
Subject(s)
Alfentanil/blood , Alfentanil/therapeutic use , Analgesia, Patient-Controlled , Pain, Postoperative/prevention & control , Abdomen/surgery , Adult , Alfentanil/administration & dosage , Consciousness/drug effects , Dose-Response Relationship, Drug , Humans , Infusions, Intravenous , Injections, Intravenous , Middle Aged , Pain Measurement , Sleep/drug effectsABSTRACT
Newborn female Albino Swiss rats received testosterone propionate, dihydrotestosterone benzoate or oestradiol benzoate for 4 days after birth. The neonatal administration of all three hormones maintained neurones of the spinal nucleus of bulbocavernosus (SNB) complex in adulthood at levels intermediate between those found in normal females (approximately 40 neurones) and those found in normal males (approximately 220 neurones). Dihydrotestosterone benzoate was the most effective treatment. Oestradiol benzoate, while as potent as testosterone propionate in maintaining SNB neurone numbers, could not maintain the perineal muscles which are their normal target. Dihydrotestosterone benzoate and testosterone propionate maintained both neurones and muscles. Newborn male Albino Swiss rats received either the aromatase inhibitor 4-OH-androstenedione, or the 5 alpha-reductase inhibitor aza-steroid 17 beta-N,N-diethylcarbamoyl-4-methyl-4-aza-5 alpha-androstan-3-one(4-MA). Only neonatal treatment with 4-MA led to reduced SNB neurone numbers in adulthood, but the reduction was modest (-16%). The results of the two experiments suggest that several hormones can maintain SNB neurone numbers in Albino Swiss rats, but that 5 alpha-reduced metabolites of testosterone may be particularly effective.
