Stimulatory effect of antidepressants on the production of IL-6

A body of evidence indicates that the therapeutic activity of antidepressants is connected with their modulatory effect on the inflammatory response system and cell-mediated immunity. The present study was carried out to examine the effects of antidepressant agents, such as imipramne, venlafaxine, l-5-hydroxytryptophan, fluoxetine and a combination of l-5-hydroxytryptophan and fluoxetine, on the production of the pleotrophic cytokines TNF-alpha and IL-6. Diluted whole blood from fluoxetine-treated patients with treatment-resistant depression (TRD) (mean age: 50.6+/-3.9 years), age-matched healthy controls (mean age: 51.6+/-1.7 years) and younger healthy volunteers (mean age: 35.4+/-1.7 years) was stimulated with phytohemagglutinin (PHA) and lipopolysaccharide (LPS) for 48 h with or without incubation with the antidepressants at 10(-6) and 10(-5) M. The major findings of this study are: (1). imipramine and venlafaxine (at the higher concentration), 5-HTP (at lower and higher concentrations) and a combination of 5-HTP and fluoxetine (both at the lower concentration) increased the production of IL-6; (2). all drugs used did not affect TNF-alpha production. IL-6 production was significantly higher in depressed patients than in age-matched volunteers, whereas TNF-alpha production was significantly higher in older volunteers than in younger ones. We speculate that the therapeutic activity of these antidepressants is at least partly connected with their effect on the cytokine network and IL-6 production.     

Potential health risks of complementary alternative medicines in cancer patients

Many cancer patients use complementary alternative medicines (CAMs) but may not be aware of the potential risks. There are no studies quantifying such risks, but there is some evidence of patient risk from case reports in the literature. A cross-sectional survey of patients attending the outpatient department at a specialist cancer centre was carried out to establish a pattern of herbal remedy or supplement use and to identify potential adverse side effects or drug interactions with conventional medicines. If potential risks were identified, a health warning was issued by a pharmacist. A total of 318 patients participated in the study. Of these, 164 (51.6%) took CAMs, and 133 different combinations were recorded. Of these, 10.4% only took herbal remedies, 42.1% only supplements and 47.6% a combination of both. In all, 18 (11.0%) reported supplements in higher than recommended doses. Health warnings were issued to 20 (12.2%) patients. Most warnings concerned echinacea in patients with lymphoma. Further warnings were issued for cod liver/fish oil, evening primrose oil, gingko, garlic, ginseng, kava kava and beta-carotene. In conclusion, medical practitioners need to be able to identify the potential risks of CAMs. Equally, patients should be encouraged to disclose their use. Also, more research is needed to quantify the actual health risks.     

Expression of the pro-apoptotic protein ARTS in astrocytic tumors: correlation with malignancy grade and survival rate

BACKGROUND: Apoptosis (i.e., programmed cell death) plays a major role in the development of astrocytic tumors, which are the most common tumors of the central nervous system. ARTS, a proapoptotic protein that is localized in the mitochondria, promotes apoptosis by functioning as an XIAP antagonist and a caspase activator. METHODS: To investigate the role of ARTS in astrocytoma, the authors examined protein expression and apoptotic activity in 72 astrocytic tumors, which included low-grade astrocytomas, anaplastic astrocytomas, and glioblastomas. RESULTS: Whereas normal astrocytes did not express the ARTS protein, astrocytoma cells strongly expressed ARTS, and the expression of this protein increased with increasing tumor grade. Furthermore, increased levels of ARTS were significantly associated with higher rates of apoptosis (as measured using the terminal deoxynucleotidyltransferase-mediated deoxyuridine triphosphate nick end-labeling [TUNEL] assay as well as an immunohistochemical staining assay for active caspase-3) in these tumors. Levels of two other apoptosis-related proteins, p53 and Bcl-2, also were examined using immunohistochemical methods; ARTS expression was found to be positively correlated with expression of the former and negatively correlated with expression of the latter, which is known to possess antiapoptotic activity. CONCLUSIONS: The results of the current study suggest that ARTS levels reliably reflect the ability of cells to undergo apoptosis, which serves as a defense mechanism against the development and progression of astrocytoma. Furthermore, ARTS expression, when taken into consideration in combination with tumor grade, was the only independent predictor of survival identified in the current analysis. Thus, the authors conclude that ARTS may possess utility as a prognostic marker, as well as a therapeutic tool, for patients with astrocytoma.     

Ovarian carcinoma expresses the NKG2D ligand Letal and promotes the survival and expansion of CD28- antitumor T cells

The role of the NKG2D immunoreceptor and its ligands in antitumor immune response is incompletely understood. Here, we report that effector immune cells infiltrating ovarian carcinoma are mostly CD8+ lymphocytes lacking CD28 but expressing the NKG2D costimulatory receptor. Human ovarian carcinoma expresses the novel NKG2D ligand lymphocyte effector cell toxicity-activating ligand (Letal). Letal was found to be an independent prognosticator of improved survival in advanced ovarian cancer. Higher levels of tumor-derived Letal were associated with stronger lymphocyte infiltration. Letal exerted marked costimulatory effects and induced type-1 polarization in CD8+CD28- tumor-infiltrating lymphocytes ex vivo. Letal engagement increased the expression of the glucose transporter Glut-1, enhanced glucose up-take, and protected CD8+ lymphocytes from cisplatin-induced killing. Letal also down-regulated the expression of Fas in CD8+ cells and rendered them resistant to Fas ligand-induced apoptosis. Our results indicate that Letal promotes tumor immune surveillance by promoting the survival and intratumoral expansion of antitumor cytotoxic lymphocytes. We propose that Letal could be used for the ex vivo expansion of apoptosis-resistant tumor-reactive cytotoxic lymphocytes for adoptive transfer.     

Increased expression of metallothionein is associated with irinotecan resistance in gastric cancer

To gain insight into clinically relevant mechanisms of irinotecan resistance, we undertook oligonucleotide microarray analyses on paired malignant effusion samples obtained from eight gastric cancer patients treated with weekly irinotecan. Pretreatment and posttreatment (48 h) effusion samples were obtained for each patient, and the change in expression profile was compared between clinical responders and nonresponders. When differences in the expression of genes were examined using SAM (Significance Analysis of Microarrays) software, five isoforms of the metallothionein family were identified to have significantly higher signal log ratios in five nonresponders, compared with three responders. Compared with control cells, metallothionein 1X (MT1X)-transfected AGS cells showed a 1.4-fold higher irinotecan IC(50) by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and tended to form more colonies. These findings collectively suggest that irinotecan-induced up-regulation of metallothionein might be associated with irinotecan resistance in patients with gastric cancer, although it remains to be confirmed in a larger data set.     

Results of a Phase II study of carboplatin plus gemcitabine in patients with untreated extensive small cell lung cancer

PURPOSE: To determine the response rate (RR) and survival produced by carboplatin + gemcitabine therapy in patients with untreated extensive small cell lung cancer (ESCLC). PATIENTS AND METHODS: Treatment consisted of carboplatin (AUC = 5) on day 1 and gemcitabine (1100 mg/m(2)) on days 1 and 8 of each 21-day cycle for 4 planned cycles (additional cycles allowed as per treating physician). ECOG performance status 0/1/2 was 29, 58, and 13%. Median age was 66.5 years (range: 41.3-83.1), 94% were white, and 50.7% were female. RESULTS: Between August 2000 and February 2002, 69 patients with ESCLC were enrolled. All 69 patients were included in the safety analysis, and 66 patients were evaluable for response. There were 2 CR (3.0%), 26 PR (39.5%), 23 SD (34.8%), and 15 PD (22.7%) resulting in a RR of 42.5%. The median survival was 9.2 months (range: <1-22.6), and the estimated 1-year survival was 33%. The median TTP was 3.9 months (range: <1-12.8), and the estimated 6-month progression free survival was 24%. The median duration of response was 3.8 months (range: 1.0-9.9). Out of 69 patients, 29, 3, and 16 received 4, 5, and 6 cycles of therapy, respectively. The major Grade 3, 4 toxicities included neutropenia (39.1%), thrombocytopenia (31.9%), anemia (13.0%), and fatigue (4.3%). CONCLUSION: This regimen resulted in survival data that was similar to other regimens for ESCLC and treatment appeared to be well tolerated. Gemcitabine in combination with carboplatin or other active drugs in ESCLC may be worth further investigation.     

Chkl binds and phosphorylates BAD protein

Chk1 (checkpoint kinase 1) is a serine-threonine kinase that is critical for G2/M arrest in response to DNA damage. Chk1 phosphorylates Cdc25C at serine-216, a major regulatory site, in response to DNA damage. Furthermore, Chk1 also phosphorylates Cdc25A on serine 123 which accelerates its degradation through the ubiquitin-proteasome pathway and arrests cells in late G2-phase after DNA damage. In the present study, we demonstrated that Chk1 phosphorylates pro-apoptotic protein BAD (Bcl-2/Bcl-XL-Antagonist, causing cell Death) in vitro. In vitro phosphorylation analysis with various mouse BAD peptides has revealed two phosphorylation sites for Chk1 at serine-155 and serine-170. When wild-type and mutant BAD (S155A) constructs were transfected into 293T cells, an association between BAD and Chk1 was observed by co-immunoprecipitation. In addition, there was an increase in the phosphorylation of serine-155 following DNA damage by adriamycin treatment. Our results suggest that Chk1 associates with BAD and phosphorylates the BAD protein at serine-155. Taken together, our results suggest that Chk1 may inactivate BAD by associating with and phosphorylating residues critical for BAD function in response to DNA damage.     

Dysphagia and aspiration after chemoradiotherapy for head-and-neck cancer: which anatomic structures are affected and can they be spared by IMRT?

PURPOSE: To identify the anatomic structures whose damage or malfunction cause late dysphagia and aspiration after intensive chemotherapy and radiotherapy (RT) for head-and-neck cancer, and to explore whether they can be spared by intensity-modulated RT (IMRT) without compromising target RT. METHODS AND MATERIALS: A total of 26 patients receiving RT concurrent with gemcitabine, a regimen associated with a high rate of late dysphagia and aspiration, underwent prospective evaluation of swallowing with videofluoroscopy (VF), direct endoscopy, and CT. To assess whether the VF abnormalities were regimen specific, they were compared with the VF findings of 6 patients presenting with dysphagia after RT concurrent with high-dose intra-arterial cisplatin. The anatomic structures whose malfunction was likely to cause each of the VF abnormalities common to both regimens were determined by literature review. Pre- and posttherapy CT scans were reviewed for evidence of posttherapy damage to each of these structures, and those demonstrating posttherapy changes were deemed dysphagia/aspiration-related structures (DARS). Standard three-dimensional (3D) RT, standard IMRT (stIMRT), and dysphagia-optimized IMRT (doIMRT) plans in which sparing of the DARS was included in the optimization cost function, were produced for each of 20 consecutive patients with advanced head-and-neck cancer. RESULTS: The posttherapy VF abnormalities common to both regimens included weakness of the posterior motion of the base of tongue, prolonged pharyngeal transit time, lack of coordination between the swallowing phases, reduced elevation of the larynx, and reduced laryngeal closure and epiglottic inversion, contributing to a high rate of aspiration. The anatomic structures whose malfunction was the likely cause of each of these abnormalities, and that also demonstrated anatomic changes after RT concurrent with gemcitabine doses associated with dysphagia and aspiration, were the pharyngeal constrictor muscles (median thickness near midline 2.5 mm before therapy vs. 7 mm after therapy; p = 0.001), the supraglottic larynx (median thickness, 2 mm before therapy vs. 4 mm after therapy; p < 0.001), and, similarly, the glottic larynx. The constrictors and the glottic and supraglottic larynx were, therefore, deemed the DARS. The lowest maximal dose delivered to a stricture volume was 50 Gy. Reducing the volumes of the DARS receiving > or =50 Gy (V(50)) was, therefore, a planning and evaluation goal. Compared with the 3D plans, stIMRT reduced the V(50) of the pharyngeal constrictors by 10% on average (range, 0-36%, p < 0.001), and doIMRT reduced these volumes further, by an additional 10% on average (range, 0-38%; p <0.001). The V(50) of the larynx (glottic + supraglottic) was reduced marginally by stIMRT compared with 3D (by 7% on average, range, 0-56%; p = 0.054), and doIMRT reduced these volumes by an additional 11%, on average (range, 0-41%; p = 0.002). doIMRT reduced laryngeal V(50) compared with 3D, by 18% on average (range 0-61%; p = 0.001). Certain target delineation rules facilitated sparing of the DARS by IMRT. The maximal DARS doses were not reduced by IMRT because of their partial overlap with the targets. stIMRT and doIMRT did not differ in target doses, parotid gland mean dose, spinal cord, or nonspecified tissue maximal dose. CONCLUSIONS: The structures whose damage may cause dysphagia and aspiration after intensive chemotherapy and RT are the pharyngeal constrictors and the glottic and supraglottic larynx. Compared with 3D-RT, moderate sparing of these structures was achieved by stIMRT, and an additional benefit, whose extent varied among the patients, was gained by doIMRT, without compromising target doses. Clinical validation is required to determine whether the dosimetric gains are translated into clinical ones.     

Simultaneous integrated boost for breast cancer using IMRT: a radiobiological and treatment planning study

PURPOSE: The purpose of this work is to explore the possibility of using intensity-modulated radiation therapy (IMRT) to deliver the boost dose to the tumor bed simultaneously with the whole-breast IMRT to reduce the radiation treatment time by 1-2 weeks. METHODS AND MATERIALS: The biologically effective dose (BED) for different treatments was calculated using the linear-quadratic (LQ) model with parameters previously derived for breast cancer from clinical data (alpha/beta = 10Gy, alpha = 0.3Gy(-1)). A potential doubling time of 15 days (from in vitro measurements) for breast cancer and a generic alpha/beta ratio of 3 Gy for normal tissues were used. A series of regimens that use IMRT as initial treatment and an IMRT simultaneous integrated boost (SIB) were derived using biologic equivalence to conventional schedules. Possible treatment plans with IMRT SIB to the tumor bed were generated for 2 selected breast patients, 1 with a shallow tumor and 1 with a deep-seated tumor. Plans with a simultaneous integrated electron boost were also generated for comparison. Dosimetric merits of these plans were evaluated based on dose volume histograms. RESULTS: A commonly used conventional treatment of 45 Gy (1.8 Gy x 25) to the whole breast and then a boost of 20 Gy (2 Gy x 10) is biologically equivalent to an alternative plan of 1.8 Gy x 25 to the whole breast with a 2.4 Gy x 25 SIB to the tumor bed. The new regime reduces treatment time from 7 to 5 weeks. For the patient with a deep-seated tumor, the IMRT plans reduce the volume of the breast that receives high doses (compared with the conventional photon boost plan) and provides good coverage of the target volumes. CONCLUSION: It is biologically and dosimetrically feasible to reduce the overall treatment time for breast radiotherapy by using an IMRT simultaneous integrated boost. For selected patient groups, IMRT plans with a new regimen can be equal to or better than conventional plans.