Modest Increase In Survival Research Articles

Immunomodulatory effects of recombinant lactoferrin during MRSA infection

Methicillin-resistant Staphylococcus aureus (MRSA) infection remains a serious hazard to global health. The use of immune modulatory therapy to combat infection is gaining an interest as a novel treatment alternative. Lactoferrin (LF), an iron binding protein with immune modulating properties, has the potential to modify the course of systemic MRSA infection. Specifically, LF is capable of limiting deleterious inflammatory responses while promoting the development of antigen specific T-cell activity. The efficacy of a novel recombinant mouse LF (rmLF) to protect against MRSA infection was examined in a mouse peritonitis model. BALB/c mice were infected with a lethal dose of MRSA and treated at 2h post-infection with rmLF. Effects of rmLF on MRSA-infected primary monocytes and granulocytes were analyzed for inflammatory mediators. The rmLF treated mice demonstrated a modest increase in survival of more than 24h, albeit with reduced bacteremia. Serum cytokines, IL-17 and IL-6, were significantly reduced post-challenge post-rmLF treatment. The rmLF led to a minor decrease in IL-1b, and a slight increase in TNF-a production. Preliminary investigation towards human clinical relevance was accomplished using human blood derived monocytes and granulocytes infected with MRSA and treated with homologous recombinant human LF (rhLF). Treatment with (rhLF) led to increased production of IFN-g and IL-2. The human cell studies also showed a concurrent decrease in TNF-a, IL-6, IL-1b, IL-12p40, and IL-10. These results indicate that the rmLF and rhLF have a high degree of overlap to modify inflammatory responses, although differences in activities were observed between the two heterologous recombinant molecules.

Emerging role of insulin-like growth factor-binding protein 7 in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a vicious and highly vascular cancer with a dismal prognosis. It is a life-threatening illness worldwide that ranks fifth in terms of cancer prevalence and third in cancer deaths. Most patients are diagnosed at an advanced stage by which time conventional therapies are no longer effective. Targeted molecular therapies, such as the multikinase inhibitor sorafenib, provide a modest increase in survival for advanced HCC patients and display significant toxicity. Thus, there is an immense need to identify novel regulators of HCC that might be targeted effectively. The insulin-like growth factor (IGF) axis is commonly abnormal in HCC. Upon activation, the IGF axis controls metabolism, tissue homeostasis, and survival. Insulin-like growth factor-binding protein 7 (IGFBP7) is a secreted protein of a family of low-affinity IGF-binding proteins termed “IGFBP-related proteins” that have been identified as a potential tumor suppressor in HCC. IGFBP7 has been implicated in regulating cellular proliferation, senescence, and angiogenesis. In this review, we provide a comprehensive discussion of the role of IGFBP7 in HCC and the potential use of IGFBP7 as a novel biomarker for drug resistance and as an effective therapeutic strategy.

Therapeutic Perspectives on Pancreatic Cancer

Pancreatic cancer has a poor prognosis, with only 10% survival one year following diagnosis. Despite significant advances in conventional therapies (chemotherapy and radiotherapy), little improvement in patient survival has occurred in the last decade. Therefore, there is a critical need for novel and effective therapeutic approaches for this cancer. This article reviews current concepts in the pathogenesis and treatment of pancreatic cancer, the latter including tumor resection approaches and the current standard of care. We further describe recent advances in new and combination therapies, which result only in modest increases in survival, and discuss challenges in drug delivery and limiting toxicity.

Znu Is the Predominant Zinc Importer in Yersinia pestis during In Vitro Growth but Is Not Essential for Virulence

Little is known about Zn homeostasis in Yersinia pestis, the plague bacillus. The Znu ABC transporter is essential for zinc (Zn) uptake and virulence in a number of bacterial pathogens. Bioinformatics analysis identified ZnuABC as the only apparent high-affinity Zn uptake system in Y. pestis. Mutation of znuACB caused a growth defect in Chelex-100-treated PMH2 growth medium, which was alleviated by supplementation with submicromolar concentrations of Zn. Use of transcriptional reporters confirmed that Zur mediated Zn-dependent repression and that it can repress gene expression in response to Zn even in the absence of Znu. Virulence testing in mouse models of bubonic and pneumonic plague found only a modest increase in survival in low-dose infections by the znuACB mutant. Previous studies of cluster 9 (C9) transporters suggested that Yfe, a well-characterized C9 importer for manganese (Mn) and iron in Y. pestis, might function as a second, high-affinity Zn uptake system. Isothermal titration calorimetry revealed that YfeA, the solute-binding protein component of Yfe, binds Mn and Zn with comparably high affinities (dissociation constants of 17.8 ± 4.4 nM and 6.6 ± 1.2 nM, respectively), although the complete Yfe transporter could not compensate for the loss of Znu in in vitro growth studies. Unexpectedly, overexpression of Yfe interfered with the znu mutant's ability to grow in low concentrations of Zn, while excess Zn interfered with the ability of Yfe to import iron at low concentrations; these results suggest that YfeA can bind Zn in the bacterial cell but that Yfe is incompetent for transport of the metal. In addition to Yfe, we have now eliminated MntH, FetMP, Efe, Feo, a substrate-binding protein, and a putative nickel transporter as the unidentified, secondary Zn transporter in Y. pestis. Unlike other bacterial pathogens, Y. pestis does not require Znu for high-level infectivity and virulence; instead, it appears to possess a novel class of transporter, which can satisfy the bacterium's Zn requirements under in vivo metal-limiting conditions. Our studies also underscore the need for bacterial cells to balance binding and transporter specificities within the periplasm in order to maintain transition metal homeostasis.

The Triterpenoid CDDO-Me Delays Murine Acute Graft-versus-Host Disease with the Preservation of Graft-versus-Tumor Effects after Allogeneic Bone Marrow Transplantation

The occurrence of acute graft-versus-host disease (aGVHD) and tumor relapse represent the two major obstacles impeding the efficacy of allogeneic bone marrow transplantation (BMT) in cancer. We have previously shown that the synthetic triterpenoid 2-cyano-3, 12-dioxooleana-1, 9-dien-28-oic acid (CDDO) can inhibit murine early aGVHD, but antitumor effects were not assessed. In the current study, we found that a new derivative of CDDO, CDDO-Me, had an increased ability to inhibit allogeneic T cell responses and induce cell death of alloreactive T cells in vitro. Administration of CDDO-Me to mice following allogeneic BMT resulted in significant and increased protection from lethal aGVHD compared to CDDO. This correlated with reduced TNF-alpha production, reduced donor T cell proliferation, and decreased adhesion molecule (alpha(4)beta(7) integrin) expression on the donor T cells. CDDO-Me was also superior to CDDO in inhibiting leukemia growth in vitro. When CDDO-Me was administered following an allogeneic BMT to leukemia-bearing mice, significant increases in survival were observed. These findings suggest that CDDO-Me is superior to CDDO in delaying aGVHD, while preserving or possibly even augmenting GVT effects.

Current and emerging treatments for amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a relatively rare neurodegenerative disorder of both upper and lower motoneurons. Currently, the management of ALS is essentially symptoms-based, and riluzole, an antiglutamatergic agent, is the only drug for the treatment of ALS approved by the food and drug administration. We reviewed current literature concerning emerging treatments for amyotrophic lateral sclerosis. A Medline literature search was performed to identify all studies on ALS treatment published from January 1st, 1986 through August 31st, 2009. We selected papers concerning only disease-modifying therapy. Forty-eight compounds were identified and reviewed in this study. Riluzole is the only compound that demonstrated a beneficial effect on ALS patients, but with only modest increase in survival. Although several drugs showed effective results in the animal models for ALS, none of them significantly prolonged survival or improved quality of life of ALS patients. Several factors have been implicated in explaining the predominantly negative results of numerous randomized clinical trials in ALS, including methodological problems in the use of animal-drug screening, the lack of assessment of pharmacokinetic profile of the drugs, and methodological pitfalls of clinical trials in ALS patients.

Shortcomings of current therapies for non-small-cell lung cancer: unmet medical needs

Non-small-cell lung cancer (NSCLC) is a major global health problem and is the leading cause of cancer death worldwide. Current treatment involves nonspecific, nonselective cytotoxic chemotherapy, which results in only a modest increase in survival and causes significant toxicity to the patient. Targeted agents are initially effective in certain small subpopulations of patients, but eventually nearly all patients become resistant to further treatment. The limitations in efficacy and safety associated with available treatments for NSCLC underscore the need for novel agents with improved efficacy and safety profiles. This review discusses the limitations of currently recommended therapies for patients with advanced NSCLC and discusses new agents in clinical development for this disease.

Timing of Therapeutic Intervention Determines Functional and Survival Outcomes in a Mouse Model of Late Infantile Batten Disease

Classical late infantile neuronal ceroid lipofuscinosis (cLINCL) is a monogenic disorder caused by the loss of tripeptidyl peptidase 1 (TPP1) activity as a result of mutations in CLN2. Absence of TPP1 results in lysosomal storage with an accompanying axonal degeneration throughout the central nervous system (CNS), which leads to progressive neurodegeneration and early death. In this study, we compared the efficacies of pre- and post-symptomatic injections of recombinant adeno-associated virus (AAV) for treating the cellular and functional abnormalities of CLN2 mutant mice. Intracranial injection of AAV1-hCLN2 resulted in widespread human TPP1 (hTPP1) activity in the brain that was 10-100-fold above wild-type levels. Injections before disease onset prevented storage and spared neurons from axonal degeneration, reflected by the preservation of motor function. Furthermore, the majority of CLN2 mutant mice treated pre-symptomatically lived for at least 330 days, compared with a median survival of 151 days in untreated CLN2 mutant controls. In contrast, although injection after disease onset ameliorated lysosomal storage, there was evidence of axonal degeneration, motor function showed limited recovery, and the animals had a median lifespan of 216 days. These data illustrate the importance of early intervention for enhanced therapeutic benefit, which may provide guidance in designing novel treatment strategies for cLINCL patients.

Interstitial Docetaxel (Taxotere), Carmustine and Combined Interstitial Therapy: a Novel Treatment for Experimental Malignant Glioma

Docetaxel (Taxotere) is a hemisynthetic, anti-cancer compound with good preclinical and clinical activity in a variety of systemic neoplasms. We tested its activity against malignant gliomas using local delivery methods. Antitumor activity was assessed in vitro against human (U87 and U80 glioma) and rat brain-tumor (9L gliosarcoma and F98 glioma) cell lines. For in vivo evaluation, we incorporated docetaxel into a biodegradable polymer matrix, determined associated toxicity in the rat brain, and measured efficacy at extending survival in a rat model of malignant glioma. Also, we examined the combined local delivery of docetaxel with carmustine (BCNU) against the experimental intracranial glioma. Rats bearing intracranial 9L gliosarcomas were treated 5 days after tumor implantation with various polymers (placebo, 5% docetaxel, 3.8% BCNU, or 5% docetaxel and 3.8% BCNU combination). Animals receiving docetaxel polymers (n=15, median survival 39.1 days) had significantly improved survival over control animals (n=12, median survival 22.5 days, P=0.01). Similarly, animals receiving BCNU polymers (n=15, median survival 39.3 days, 13.3% long-term survivors) demonstrated an increase in survival compared to the controls (P=0.04). Animals receiving the combination polymers demonstrated a modest increase in survival compared to either chemotherapeutic agent alone (n=14, median survival 54.9 days, 28.6% long-term survivors) with markedly improved survival over controls (P=0.003). We conclude that locally delivered docetaxel shows promise as a novel anti-glioma therapy and that the combination of drug regimens via biodegradable polymers may be a great therapeutic benefit to patients with malignant glioma.

Role of adjuvant chemotherapy in the treatment of non-small-cell lung cancer

The role of adjuvant chemotherapy in the treatment of non-small-cell lung cancer (NSCLC) is described. The intrinsic resistance of NSCLC tumors to chemotherapy necessitates the use of complete surgical resection of the malignant growth as the primary modality of treatment; however, only about one third of patients are appropriate candidates for surgical resection. While several cytotoxic combinations have been used to treat metastatic NSCLC, no single regimen is considered the standard of care. Given the poor prognosis of patients with NSCLC, adjuvant chemotherapy has been investigated as a treatment option but has not demonstrated a consistent survival benefit. Several recent studies have sought to clarify the role of adjuvant chemotherapy in the treatment of NSCLC: the Big Lung Trial, the International Adjuvant Lung Cancer Trial (IALT), the Adjuvant Lung Project Italy trial, and a study of the combination of uracil and tegafur, which is not yet available in the United States. The IALT, the largest trial among the four and sufficiently powered to detect a survival benefit, revealed a modest increase in survival. Complicating the issue is the financial cost of adjuvant therapy, especially in light of the small survival benefit gained. The use of adjuvant chemotherapy in patients with NSCLC can lead to a modest increase in survival. Platinum-based regimens are the most studied and should be considered the regimens of choice. However, further studies are needed to determine the optimal regimen and patient population that would derive the most benefit from this treatment.

Priming in the Presence of IL-10 Results in Direct Enhancement of CD8+ T Cell Primary Responses and Inhibition of Secondary Responses

Although IL-10 acts as an inhibitory cytokine for APC and CD4(+) T cell function, its effects on CD8(+) T cells are unclear. Additionally, little is known about whether initial priming in the presence of IL-10 can have long-lasting effects and influence subsequent CD8(+) T cell responses that occur in the absence of the cytokine. In the present study, we clarified the role of IL-10 during primary responses and examined whether exposure to IL-10 during initial priming of CD8(+) T cells impacted secondary responses. To determine the effect of IL-10 on Ag-specific T cell responses, peptide-pulsed IL-10R2(-/-) splenic dendritic cells were used to prime T cells from OT-I CD8(+) TCR transgenic mice. During the primary response, the presence of IL-10 resulted in enhancement of CD8(+) T cell numbers without detectable alterations in the kinetics or percentage of cells that underwent proliferation. A modest increase in survival, not attributable to Bcl-2 or Bcl-x(L), was also observed with IL-10 treatment. Other parameters of CD8(+) T cell function, including IL-2, IFN-gamma, TNF-alpha, and granzyme production, were unaltered. In contrast, initial exposure to IL-10 during the primary response resulted in decreased OT-I expansion during secondary stimulation. This was accompanied by lowered IL-2 levels and reduced percentages of proliferating BrdU(+) cells and OT-I cells that were CD25(high). IFN-gamma, TNF-alpha, and granzyme production were unaltered. These data suggest that initial exposure of CD8(+) T cells to IL-10 may be temporarily stimulatory; however, programming of the cells may be altered, resulting in diminished overall responses.

CHOP activation by photodynamic therapy increases treatment induced photosensitization

C/EBP homologous protein (CHOP) is an endoplasmic reticulum (ER) stress inducible transcription factor involved in the development of apoptosis, growth arrest, and differentiation. CHOP deficient (chop - / - ) mouse embryonic fibroblasts (MEFs) exposed to ER stresses such as tunicamycin exhibit decreased apoptosis and reduced toxicity when compared to chop + / + control cells. Overexpression of the 70 kDa heat shock stress protein (HSP-70) can inhibit apoptotic pathways. The biological significance of photodynamic therapy (PDT) protocols that induce cellular damage resulting in differential CHOP and stress protein expression patterns was examined. Wild type mouse radiation induced fibrosarcoma (RIF) cells as well as MEFs with chop + / + and chop - / - genotypes were used with either a mitochondrial and ER localizing porphyrin (PH) photosensitizer or a lysosomal localizing chlorin (NPe6) photosensitizer. PDT induced cytotoxicity, apoptosis, and stress protein expression patterns were determined as a function of cell type and photosensitizer. PH mediated PDT induced expression of CHOP and 78 kDa glucose regulated protein (GRP-78), but not HSP-70 while NPe6 mediated PDT induced protein expression of HSP-70 but did not activate CHOP or GRP-78 expression. Enhanced apoptosis and toxicity were observed in chop + / + cells following exposure to tunicamycin or PH mediated PDT when compared to identical treatments in chop - / - cells. NPe6 mediated PDT induced minimally detectable apoptosis in both chop + / + and chop - / - cells and only a modest increase in survival for chop - / - cells. These results demonstrate that PDT activation of CHOP, GRP-78, and HSP-70 varied as a function of photosensitizer subcellular localization and that a single oxidative stress response was not observed following PDT. We also show that CHOP expression increased apoptosis following PH mediated PDT and that increased CHOP expression is associated with enhanced PDT photosensitization.

Chemotherapy in stage-IV NSCLC

Since cisplatin-based chemotherapy was proven to increase survival in advanced and metastatic NSCLC various new combinations have been tested. The third generation regimens which showed almost comparable efficacy among each other in randomised trials often proved a better response rate and time to progression combined with a remarkable reduction of toxic side effects compared to "classic" combinations, whereas most studies only noted a modest increase in survival. Two-drug regimens were more effective than monotherapy but at the expense of significantly increased toxicity, while monotherapy compared to BSC improved quality of life and survival. The novel antifolate Pemetrexed proved comparable activity to docetaxel with significantly reduced toxicities.

Acute Myeloid Leukemia in Children: A Review of Risk Factors and Recent Trials

Acute leukemia is the most common malignancy seen in childhood and is comprised mainly by acute lymphoblastic leukemia (ALL). Acute myeloid leukemia (AML) constitutes approximately 15% of childhood leukemia. While treatment for ALL has undergone dramatic improvements in event free survival (EFS) over the past four decades, the treatment for patients with AML has resulted in modest increases in survival during this time. Even the most recent studies in the literature report that about half of the children diagnosed with AML will not survive.

Palliative radiotherapy regimens for non-small cell lung cancer.

Palliative radiotherapy (RT) to the chest is often used in patients with lung cancer, but RT regimens are more often based on tradition than research results. To discover the most effective and least toxic regimens of palliative RT, and whether higher doses increase survival. Electronic databases, reference lists, handsearching of journals and conference proceedings, and discussion with experts were used to identify potentially eligible trials, published and unpublished. Randomised controlled clinical trials comparing different regimens of palliative RT in patients with non-small lung cancer. Ten randomised trials were reviewed. There were important differences in the doses of RT investigated, the patient characteristics and the outcome measures. Because of this heterogeneity no meta-analysis was attempted. There is no strong evidence that any regimen gives greater palliation. Higher dose regimens give more acute toxicity. There is evidence for a modest increase in survival (6% at 1 year and 3% at 2 years) in patients with better performance status (PS) given higher dose RT. The majority of patients should be treated with short courses of palliative RT, of 1 or 2 fractions. Care should be taken with the dose to the spinal cord. The use of high dose palliative regimens should be considered for and discussed with selected patients with good PS. More research is needed into reducing the acute toxicity of large fraction regimens and into the role of radical compared to high dose palliative RT and more homogeneous studies are needed.

A dominant-negative mutant of the platelet-derived growth factor A-chain increases survival of hamsters implanted intracerebrally with the highly invasive CxT24-neo3 glioblastoma cell.

Evidence is accumulating to suggest a role for PDGF in stimulating malignant growth in astrocytoma, although it has been obtained using model systems (growth in 2-dimensional cell culture, athymic nude mice) that do not assess the complex interactions of these tumors with normal brain tissue. In the current study, the highly invasive hamster glioblastoma cell line CxT24-neo3 was used as a model to study the role of platelet-derived growth factor (PDGF) in mediating malignant growth both in vitro and in vivo when implanted directly into the right lateral ventricle of the brain. Co-expression of PDGF B-chain mRNA and PDGF alpha-receptors was detected in these cells, indicating potential for autocrine activation of their growth. CxT24-neo3 cells transfected with wild-type and receptor binding-deficient forms of the PDGF A- and B-chains displayed alterations in their abilities to grow as three-dimensional spheroids, with overexpression of wild-type B-chain resulting in increased spheroid formation, but a decreased rate of spheroid growth. Influence of these PDGF polypeptides on tumor invasion and survival time in vivo was evaluated following implantation of these spheroids in the brain. While all hamsters implanted with control spheroids died within 21 d (average 17 d), those implanted with cells expressing the receptor binding-deficient A-chain survived for much greater periods of time (average 80 d). Modest increases in survival were also seen in cells stably expressing wild-type A-chain (25 d) and mutant B-chain (26 d) proteins. The present study suggests an important role of PDGF in mediating the malignant growth of the CxT24-neo3 cell line in cerebral cortex, possibly via paracrine interactions with normal cortical cell types (i.e., glia, neurons).

The effect of gemcitabine in non-small cell lung cancer

Even though chemotherapy in non-resectable non-small cell lung cancer (NSCLC) lee& to a modest increase in survival, the therapeutic results of chemotherapy in this disease is far from satisfactory. More effective chemotherapy is needed and the development of new active cytostatic agents is a mean in achieving this goal. NSCLC is rather chemoresistant and only relatively few cytostatic drugs are active in this disease. Among the most active older drugs are ifosfamide, vindesine, vinblastine, mitomycinG and cisplatin; all with an average response rate of 20% when used as a single agents. Usually, only partial responses are seen in the patients treated and the duration of response is short; 3-5 months. Combination chemotherapy has improved the response rate with a significant impact on survival in metaanalyses. Identification on new drugs with significant activity against NSCLC is therefore sorely needed in order to improve the response rate, the fraction of complete responses and the duration of response with the ultimate aim of increasing the quality-of-life and survival of the patients treated. Among the most promising new agents are the taxanes (paclitaxel and docetaxel), topotecan, (Hycamtin) CPT-11 (irinotecan), vinorelbine and gemcitabine (gemzar). Gemcitabine (2’2’-difluorodeoxycitidine) is a new pyrimidine analog with both novel metabolic properties and mechanisms of action. Although it is structurally similar to the antimetabolite cytarabine (AraC), its cellular pharmacology and mechanism of action differ markedly, which may explain why gemcitabine has a much wider spectrum of antitumour activity against several solid tumours than AraC (1). Extensive data generated from early phase I trials demonstrated that the clinical toxicity profile of gemcitabine is schedule dependent. The current accepted best schedule from the phase I studies is once weekly x 3 i.v. every 28 days, which provides a combination of activity and acceptable tolerability with minimal non-haematologic toxicity and manageable neutropenia and thrombocytopenia. The non-haematologic toxicity includes mild nausea and vomiting, lethargy, reversible skin rash and occasional mild peripheral oedema. Alopecia and mucositis are rare events. In addition, elevation of hepatic transaminase as well as varying degrees of dyspnoea have been reported. Activity in gemcitabine in NSCLC was already noted in the initial phase I trials. It has since been confirmed in a number of phase II trials performed both in Europe, the US and South Africa (2). The selection of patients was quite similar in all the studies and included patients with inoperable TNM stage Illa, Illb, or IV, adeno-, squamousor large cell carcinoma with bidimensionally measured disease, and the World Health Organisation performance status 0 to 2. None of the patients had received prior chemotherapy. A majority of the trials applied a schedule of gemcitabine given i.v. day 1, 8 and 15 every 4 weeks with a dose of 800 mg/m* in the initial trials, later on increased to 1200-l 500 mg/m* in subsequent trials, when toxicity secundary to gemcitabine was observed to be very modest. Alltogether, 438 patients with NSCLC have been treated with gemcitabine using dosage between 800-1250 mg/m* giving an overall response rate of 21% (95% Cl, 16-25). The median response varies from study to study being 2549 weeks, while the medians survivals in the trials are between 26-46 weeks. In some of the studies more detailed data are available concerning changes in the clinical symptomatology. From Gatzemeier and al.‘s study (3) it is noteworthy that of 10 patients with performance status 2 on entry, 3 improved on performance status 1. 27% of the 65 eligible patients reduced their analgesic requirements. Of 83 eligible patients who experienced pain at study entry, these symptoms improved in 31%. Other disease-related symptom improvements included: cough (35%) dyspnoea (22%), and haemoptysis (68%). Similar results have also been reported by Thatcher et al. (4) With respect to response among the various histological cell types cumulated data show no significant difference when comparing squamous-, adeno-, and large cell carcinoma with the response rates being 16%, 19%, and 27%, respectively (2). In other phase II trials gemcitabine has been combined with various cytostatic compounds as doublets such as cisplatin, carboplatin, iphosphamide, etoposide, vindesine, taxol, and taxotere (5, 6, 7) and also in triplets using for instance gemcitabine together with cisplatin or carboplatin together with taxol or vinorelbine. The response rate has varied between 38-58% based on published abstracts with the majority being between 3552% thus achieving substantially higher response rate compaired to single-agent chemotherapy. Various phase Ill trials are at present ongoing comparing various 2-drug combinations including gemcitabine vs. combinations without gemcitabine. Noteworthy is in a European study that gemcitabine when compared to etoposide and cisplatin resulted in considerably less toxicity and similar survival (8). Other studies explore the combination of gemcitabine with radiotherapy in stage Ill non-small cell lung cancer (9).

Therapeutic advances: riluzole for the treatment of motor neurone disease.

Amyotrophic laterial sclerosis is a fatal neurogenerative disorder, for which only symptomatic treatment was previously available. Riluzole was recently launched in the U.S.A. and Europe. This is the first drug to produce a modest increase in survival (approximately 3 months) in patients with this disease. Unfortunately, treatment causes a number of side-effects of which asthenia is particularly troublesome. Between 10 and 20 per cent of patients can be expected to withdraw from treatment due to these adverse effects. Data on the real time survival advantage and quality of life that can be expected whilst on treatment are needed to identify the place of riluzole in the management of this distressing disease.

Advances in Chemotherapy for Brain Tumors

Malignant brain tumors, particularly those of glial origin, carry a dismal prognosis despite decades of therapeutic maneuvers. Surgery and radiotherapy have not been curative, and adjunctive chemotherapy has resulted only in modest increases in survival. This article discusses the current status of chemotherapy, the problems encountered with the interpretation of chemotherapeutic trials, and some of the new approaches currently being evaluated.

Selection of Arabidopsis cDNAs that partially correct phenotypes of Escherichia coli DNA-damage-sensitive mutants and analysis of two plant cDNAs that appear to express UV-specific dark repair activities.

To resist terrestrial UV radiation, plants employ DNA-damage-repair/toleration (DRT) activities, as well as shielding mechanisms. Little is known about the structure and regulation of plant DRT genes. We isolated DRT cDNAs from Arabidopsis thaliana, by selecting for complementation of Escherichia coli mutants lacking all bacterial defenses against UV-light damage to DNA. These mutants are phenotypically deficient in recombinational and mutagenic toleration (RecA-), excision repair (Uvr-) and photoreactivation (Phr-). Among 840 survivors of heavily UV-irradiated (10(-7) survival) mutants harboring plasmids derived from an Arabidopsis cDNA library in the vector lambda YES, we identified four unique plant cDNAs, designated DRT100, DRT101, DRT102, and DRT103. Drt101 and Drt102 activity were specific for UV-light damage, and complemented both UvrB- and UvrC- phenotypes in the dark. Apparent Uvr- correction efficiencies were 1 to 40% for Drt101, and 0.2 to 15% for Drt102, depending on the UV fluence. Drt101 and Drt102 showed no extensive amino-acid homology with any known DNA-repair proteins. Drt100 appeared to correct RecA-, rather than Uvr-, phenotypes. Although the light dependence of Drt103 activity was consistent with its identification as a photoreactivating enzyme, its predicted amino-acid sequence did not resemble known photolyase sequences. The N-terminal coding sequence of Drt101 suggests that it is targeted to chloroplasts, as reported for Drt100. These cDNAs afforded only modest increases in survival during the original selection procedure. The fact that they were readily isolated nevertheless suggests that selections may be made powerful enough to overcome barriers to expression and function in bacteria, at least for cDNAs of reasonable abundance.