Ten years of marketing approvals of anticancer drugs in Europe: regulatory policy and guidance documents need to find a balance between different pressures

Despite important progress in understanding the molecular factors underlying the development of cancer and the improvement in response rates with new drugs, long-term survival is still disappointing for most common solid tumours. This might be because very little of the modest gain for patients is the result of the new compounds discovered and marketed recently. An assessment of the regulatory agencies' performance may suggest improvements. The present analysis summarizes and evaluates the type of studies and end points used by the EMEA to approve new anticancer drugs, and discusses the application of current regulations. This report is based on the information available on the EMEA web site. We identified current regulatory requirements for anticancer drugs promulgated by the agency and retrieved them in the relevant directory; information about empirical evidence supporting the approval of drugs for solid cancers through the centralised procedure were retrieved from the European Public Assessment Report (EPAR). We surveyed documents for drug applications and later extensions from January 1995, when EMEA was set up, to December 2004. We identified 14 anticancer drugs for 27 different indications (14 new applications and 13 extensions). Overall, 48 clinical studies were used as the basis for approval; randomised comparative (clinical) trial (RCT) and Response Rate were the study design and end points most frequently adopted (respectively, 25 out of 48 and 30 out of 48). In 13 cases, the EPAR explicitly reported differences between arms in terms of survival: the range was 0–3.7 months, and the mean and median differences were 1.5 and 1.2 months. The majority of studies (13 out of 27, 48%) involved the evaluation of complete and/or partial tumour responses, with regard to the end points supporting the 27 indications. Despite the recommendations of the current EMEA guidance documents, new anticancer agents are still often approved on the basis of small single arm trials that do not allow any assessment of an ‘acceptable and extensively documented toxicity profile' and of end points such as response rate, time to progression or progression-free survival which at best can be considered indicators of anticancer activity and are not ‘justified surrogate markers for clinical benefit'. Anticipating an earlier than ideal point along the drug approval path and the use of not fully validated surrogate end points in nonrandomised trials looks like a dangerous shortcut that might jeopardise consumers' health, leading to unsafe and ineffective drugs being marketed and prescribed. The present Note for Guidance for new anticancer agents needs revising. Drugs must be rapidly released for patients who need them but not be at the expense of adequate knowledge about the real benefit of the drugs

Glucose Transporter 1 and Monocarboxylate Transporters 1, 2, and 4 Localization within the Glial Cells of Shark Blood-Brain-Barriers

Although previous studies showed that glucose is used to support the metabolic activity of the cartilaginous fish brain, the distribution and expression levels of glucose transporter (GLUT) isoforms remained undetermined. Optic/ultrastructural immunohistochemistry approaches were used to determine the expression of GLUT1 in the glial blood-brain barrier (gBBB). GLUT1 was observed solely in glial cells; it was primarily located in end-feet processes of the gBBB. Western blot analysis showed a protein with a molecular mass of 50 kDa, and partial sequencing confirmed GLUT1 identity. Similar approaches were used to demonstrate increased GLUT1 polarization to both apical and basolateral membranes in choroid plexus epithelial cells. To explore monocarboxylate transporter (MCT) involvement in shark brain metabolism, the expression of MCTs was analyzed. MCT1, 2 and 4 were expressed in endothelial cells; however, only MCT1 and MCT4 were present in glial cells. In neurons, MCT2 was localized at the cell membrane whereas MCT1 was detected within mitochondria. Previous studies demonstrated that hypoxia modified GLUT and MCT expression in mammalian brain cells, which was mediated by the transcription factor, hypoxia inducible factor-1. Similarly, we observed that hypoxia modified MCT1 cellular distribution and MCT4 expression in shark telencephalic area and brain stem, confirming the role of these transporters in hypoxia adaptation. Finally, using three-dimensional ultrastructural microscopy, the interaction between glial end-feet and leaky blood vessels of shark brain was assessed in the present study. These data suggested that the brains of shark may take up glucose from blood using a different mechanism than that used by mammalian brains, which may induce astrocyte-neuron lactate shuttling and metabolic coupling as observed in mammalian brain. Our data suggested that the structural conditions and expression patterns of GLUT1, MCT1, MCT2 and MCT4 in shark brain may establish the molecular foundation of metabolic coupling between glia and neurons

REDUCTION OF CISPLATIN NEPHROTOXICITY BY SODIUM SELENITE - LACK OF INTERACTION AT THE PHARMACOKINETIC LEVEL OF BOTH COMPOUNDS

Administration of sodium selenite (Na2SeO3) 1 hr before cis-diamminedichloroplatinum(II) (referred to herein as cisplatin) can protect against the nephrotoxicity of cisplatin. The pharmacokinetic aspects of this interaction were studied in rodents with radiolabeled selenite and cisplatin. Total [75Se]selenium in plasma consisted of [75Se] selenium in plasma proteins and [75Se]selenite in plasma ultrafiltrate. After a short distribution phase, the elimination of [75Se]selenite and total [75Se]selenium proceeded biphasically in the rat, with an initial plasma elimination half-life of [75Se]selenite of 22 +/- 2 min. Coadministration of cisplatin had no effect on the initial nor on the much slower terminal elimination phase of [75Se]selenite nor of total [75Se] selenium. Sodium selenite, in doses protecting against the nephrotoxicity of cisplatin, did not significantly affect areas under the plasma concentration time curve from 0-6 hr nor the initial plasma half-lives of [195mPt]cisplatin (t1/2, 28 +/- 2 min) and total [195mPt]platinum (t1/2, 30 +/- 3 min) in plasma. The much slower terminal elimination phases in plasma and the cumulative urinary excretion of [195mPt] cisplatin and total [195mPt]platinum were neither influenced by sodium selenite. Sodium selenite does not react chemically with cisplatin in vitro. Apparently, bioactivation of selenite is required for its protective effect in vivo. Distribution studies in a mice tumor model indicated that [75Se]selenium is concentrated strongly in the kidney and that the bioactivation of selenite also most likely occurs primarily in the kidneys. We conclude that sodium selenite protects rodents against cisplatin-induced nephrotoxicity without influencing the systemic availability of cisplatin and total platinum.(ABSTRACT TRUNCATED AT 250 WORDS