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Cutting hair loss
112
News & Comment
productivity of its R&D by creating an internal market – combining the advantages of one of the industry’s biggest R&D budgets with the flexibility of smaller competitive research units. The quest for new molecules will be the responsibility of separate Centres for Excellence in Drug Discovery, each of which will be measured and rewarded according to its output. It is hoped that the entrepreneurial spirit fostered by this ‘biotech’ culture will pay dividends. Meanwhile, GlaxoSmithKline’s Chief Executive Jean-Pierre Garnier has guaranteed that any savings made as a result of job cuts will be reinvested in the company’s R&D activities. RC
Gender studies In the UK, women in research apply for fewer grants than men. This discrepancy was the focus of a recent survey commissioned by the UK’s Wellcome Trust and the six UK research councils. The results indicate that although women were found to be as successful as men in securing the grants they applied for, they were less likely to apply for funding because of their status in academic institutions. Women were more likely to occupy junior positions, to work part-time, and to be employed on fixed-term contracts. These factors were all found to influence application activities, not least because they affected the eligibility of researchers to apply for grants. Clare Matterson, head of the Wellcome Trust’s Policy Unit, hopes that the study ‘will act as a catalyst and contribute to the broader debate on the equality of women in higher education’. RC
Cutting hair loss An important breakthrough in the search for a drug to prevent chemotherapy-induced hair loss has been reported by Stephen Davis and colleagues (Science 2001, Vol. 291, 134–137). Many anti-tumour agents cause hair loss because they target rapidly dividing cells, including those of the hair follicle. Davis and co-workers showed that an inhibitor of cyclin-dependent kinase 2, which drives the cell cycle, blocked hair follicle cell division and prevented chemotherapy-induced hair loss in neonatal rats. These results offer the hope of a treatment for one of the distressing sideeffects of anti-cancer therapies. RC
TRENDS in Pharmacological Sciences Vol.22 No.3 March 2001
Shell shock The recent row surrounding the use of antitank shells containing depleted uranium (DU) has highlighted important gaps in our understanding of the health risks posed by DU. First deployed during the Gulf War, DU weapons have since been used by NATO during the Balkans conflict. Uncertainty about the hazards of DU, believed by some to cause cancer or renal damage, has led the World Health Organization to push for clean-up operations in impact zones where significant amounts of debris remain. Because DU is only weakly radioactive, the concerns about DU appear related more to its properties as a heavy metal and resultant toxicity. DU also easily enters the brain – which has a large capacity to concentrate metal ions – and although a link between DU and neurotoxicity remains to be established, other metallochemical reactions that give rise to oxygen and protein radicals are thought to underpin neurological disorders. RC and DC
Redesigned kinases Protein phosphorylation by kinases represents a key component of the intracellular machinery necessary for the transmission of information within and between cells, whereas kinase dysfunction underlies a host of disease conditions. A technique patented by Vertex Pharmaceuticals is designed to aid the discovery of kinase inhibitors of potential therapeutic use. Based on the substitution of molecular components in the ATPbinding site of well described kinases to create hybrid kinases, it is hoped that engineering ‘surrogate’ targets might lead to more effective compound design and screening. The putative advantages of this technique are not limited to protein kinase research, and might be applied more generally to study receptors and other targets. DC
This month’s In Brief articles were written by Rebecca Craven ([email protected]) and David Cutler ([email protected]).
Letters
Carnosine as a modulator of endogenous Zn2+ effects A positive role for Zn2+ in the regulation of the immune system, modulation of synaptic processes in the CNS and activation of several hundred enzymes is widely known. However, two recent TiPS articles have illustrated the toxic effects of Zn2+ in the nervous and immune systems1,2. Moreover, on the basis of the selective inhibitory effect of Zn2+ ions on NMDA receptors3 and their stimulatory effect on the generation of reactive oxygen species (ROS) within the neurons1, Zn2+-mediated injury was suggested to be more dangerous than Ca2+-mediated injury4. This suggestion is compatible with the presence of low concentrations of Zn2+ in the whole brain (usually <0.5 µM) but contradicts the well known presence of almost millimolar concentrations of Zn2+ in presynaptic (glutamate-containing) terminals. Weiss et al. suggested that metallothioneines, low molecular weight cysteine-rich peptides, serve as Zn2+ buffers to protect cells from Zn2+ neurotoxicity2. However, the normal concentration of these peptides in brain is very low and increases only in response to heavy metal poisoning. I would like to propose the involvement of another low molecular weight compound, carnosine (β-alanyl-histidine), which is constantly present in brain in millimolar concentrations (1.7–2.5 mM in whole brain, 0.15–0.25 mM in medulla oblongata and ≥10 mM in olfactory bulb)5,6, in the buffering of Zn2+. The concentration of this dipeptide is regulated by two enzymes, carnosine synthase and carnosinase, both of which are present in brain6. Carnosine has been shown to possess a potent antioxidant effect, preventing neuronal cell death both in vitro6,7 and in vivo8,9. However, its biological effects were found to be more sophisticated than only ROS scavenging7,10. Carnosine is colocalized with glutamate in olfactory neuronal terminals11 and protects neurons against excitotoxic effects of glutamate and its agonists7. In water solutions, carnosine forms complexes with heavy metals such as Cu2+, Co2+, Ni2+, Cd2+ and Zn2+ ions6,12,
http://tips.trends.com 0165-6147/01/$ – see front matter © 2001 Elsevier Science Ltd. All rights reserved.
News & Comment
productivity of its R&D by creating an internal market – combining the advantages of one of the industry’s biggest R&D budgets with the flexibility of smaller competitive research units. The quest for new molecules will be the responsibility of separate Centres for Excellence in Drug Discovery, each of which will be measured and rewarded according to its output. It is hoped that the entrepreneurial spirit fostered by this ‘biotech’ culture will pay dividends. Meanwhile, GlaxoSmithKline’s Chief Executive Jean-Pierre Garnier has guaranteed that any savings made as a result of job cuts will be reinvested in the company’s R&D activities. RC
Gender studies In the UK, women in research apply for fewer grants than men. This discrepancy was the focus of a recent survey commissioned by the UK’s Wellcome Trust and the six UK research councils. The results indicate that although women were found to be as successful as men in securing the grants they applied for, they were less likely to apply for funding because of their status in academic institutions. Women were more likely to occupy junior positions, to work part-time, and to be employed on fixed-term contracts. These factors were all found to influence application activities, not least because they affected the eligibility of researchers to apply for grants. Clare Matterson, head of the Wellcome Trust’s Policy Unit, hopes that the study ‘will act as a catalyst and contribute to the broader debate on the equality of women in higher education’. RC
Cutting hair loss An important breakthrough in the search for a drug to prevent chemotherapy-induced hair loss has been reported by Stephen Davis and colleagues (Science 2001, Vol. 291, 134–137). Many anti-tumour agents cause hair loss because they target rapidly dividing cells, including those of the hair follicle. Davis and co-workers showed that an inhibitor of cyclin-dependent kinase 2, which drives the cell cycle, blocked hair follicle cell division and prevented chemotherapy-induced hair loss in neonatal rats. These results offer the hope of a treatment for one of the distressing sideeffects of anti-cancer therapies. RC
TRENDS in Pharmacological Sciences Vol.22 No.3 March 2001
Shell shock The recent row surrounding the use of antitank shells containing depleted uranium (DU) has highlighted important gaps in our understanding of the health risks posed by DU. First deployed during the Gulf War, DU weapons have since been used by NATO during the Balkans conflict. Uncertainty about the hazards of DU, believed by some to cause cancer or renal damage, has led the World Health Organization to push for clean-up operations in impact zones where significant amounts of debris remain. Because DU is only weakly radioactive, the concerns about DU appear related more to its properties as a heavy metal and resultant toxicity. DU also easily enters the brain – which has a large capacity to concentrate metal ions – and although a link between DU and neurotoxicity remains to be established, other metallochemical reactions that give rise to oxygen and protein radicals are thought to underpin neurological disorders. RC and DC
Redesigned kinases Protein phosphorylation by kinases represents a key component of the intracellular machinery necessary for the transmission of information within and between cells, whereas kinase dysfunction underlies a host of disease conditions. A technique patented by Vertex Pharmaceuticals is designed to aid the discovery of kinase inhibitors of potential therapeutic use. Based on the substitution of molecular components in the ATPbinding site of well described kinases to create hybrid kinases, it is hoped that engineering ‘surrogate’ targets might lead to more effective compound design and screening. The putative advantages of this technique are not limited to protein kinase research, and might be applied more generally to study receptors and other targets. DC
This month’s In Brief articles were written by Rebecca Craven ([email protected]) and David Cutler ([email protected]).
Letters
Carnosine as a modulator of endogenous Zn2+ effects A positive role for Zn2+ in the regulation of the immune system, modulation of synaptic processes in the CNS and activation of several hundred enzymes is widely known. However, two recent TiPS articles have illustrated the toxic effects of Zn2+ in the nervous and immune systems1,2. Moreover, on the basis of the selective inhibitory effect of Zn2+ ions on NMDA receptors3 and their stimulatory effect on the generation of reactive oxygen species (ROS) within the neurons1, Zn2+-mediated injury was suggested to be more dangerous than Ca2+-mediated injury4. This suggestion is compatible with the presence of low concentrations of Zn2+ in the whole brain (usually <0.5 µM) but contradicts the well known presence of almost millimolar concentrations of Zn2+ in presynaptic (glutamate-containing) terminals. Weiss et al. suggested that metallothioneines, low molecular weight cysteine-rich peptides, serve as Zn2+ buffers to protect cells from Zn2+ neurotoxicity2. However, the normal concentration of these peptides in brain is very low and increases only in response to heavy metal poisoning. I would like to propose the involvement of another low molecular weight compound, carnosine (β-alanyl-histidine), which is constantly present in brain in millimolar concentrations (1.7–2.5 mM in whole brain, 0.15–0.25 mM in medulla oblongata and ≥10 mM in olfactory bulb)5,6, in the buffering of Zn2+. The concentration of this dipeptide is regulated by two enzymes, carnosine synthase and carnosinase, both of which are present in brain6. Carnosine has been shown to possess a potent antioxidant effect, preventing neuronal cell death both in vitro6,7 and in vivo8,9. However, its biological effects were found to be more sophisticated than only ROS scavenging7,10. Carnosine is colocalized with glutamate in olfactory neuronal terminals11 and protects neurons against excitotoxic effects of glutamate and its agonists7. In water solutions, carnosine forms complexes with heavy metals such as Cu2+, Co2+, Ni2+, Cd2+ and Zn2+ ions6,12,
http://tips.trends.com 0165-6147/01/$ – see front matter © 2001 Elsevier Science Ltd. All rights reserved.