Absolute and relative activities of platinum-complexes on human tumors as evaluated by an antimetabolic in vitro assay

An in vitro assay, which evaluates drug effect on ³H-thymidine incorporation, was used to investigate the absolute and relative activities of cisplatin (DDP), carboplatin (CBDCA) and iproplatin (CHIP) on 317 specimens from untreated tumors, including breast and ovarian cancers and malignant melanomas. Similar activities were generally observed for DDP and CHIP, whereas CBDCA exhibited a lower, although not significantly different cytotoxicity on breast and ovarian cancers. The relative activities of Platinum analogues were analyzed on 239 two-way drug sensitivity comparisons. The overall agreement rates ranged from 80.2 to 83.9% for the different comparisons. High coresistance, from 61.1 to 93.8%, was observed for all the comparisons, regardless of the tumor type. Cosensitivity rates were poor for breast and ovarian cancers, from 0 to 37.5%, whereas for melanomas an association in sensitivity was observed in 80% of the cases.     

Schedule-dependent modulation of idarubicin cytotoxicity by lonidamine in human lymphoma cell lines

The ability of lonidamine (LND), an energolytic derivative of indazol-carboxylic acid, to modulate the cytotoxic activity of idarubicin (IDA) and doxorubicin (DX) was investigated in two human lymphoma cell lines (H9 and U937). A different pattern of interaction between the drugs was observed as a function of treatment sequence. Specifically, a 24-h postincubation with a non-cytotoxic concentration of LND (75 mu M) increased the activity of a 1-h anthracycline treatment in both cell lines. However, the extent of potentiation for IDA was more than twofold that of DX. No enhancement of anthracycline activity was observed when LND preceded IDA. For comparative purposes, the modulating effect of all-trans-retinoic acid (ATRA) on the cytotoxicity of IDA was evaluated according to different treatment schemes in both lymphoma cell lines. In U937 cells, which undergo monocytic differentiation after exposure to retinoids, a marked increase in LDA activity was obtained following a 48-h postincubation with 1.5 mu M ATRA. No potentiation of anthracycline activity was obtained using the opposite drug sequence. In H9 cells, no significant interference between ATRA and IDA was observed independent of the modality of drug administration. The ability of LND to potentiate IDA activity, and the consideration that LND causes side effects different from those caused by anthracyclines, make this compound an attractive candidate for multidrug combination therapy in hematological neoplasms.     

Regional heterogeneity for the intracranial self-administration of ethanol and acetaldehyde within the ventral tegmental area of alcohol-preferring (P) rats: involvement of dopamine and serotonin.

The meso-limbic dopamine (DA) system has an important role in regulating alcohol drinking. Previous findings from our laboratory indicated that Wistar rats self-administered ethanol (EtOH) directly into the posterior, but not anterior, ventral tegmental area (VTA), and that coadministration of a DA D(2,3) receptor agonist or a serotonin-3 (5-HT3) receptor antagonist blocked EtOH self-administration. In addition, we reported that alcohol-preferring (P) rats self-administered acetaldehyde (ACD), the first metabolite of EtOH, into the posterior VTA. The objectives of this study were to compare the reinforcing effects of EtOH and ACD within the VTA of P rats to examine the possibility that the reinforcing effects of EtOH within the VTA may be mediated by its conversion to ACD. Adult female P rats were stereotaxically implanted with guide cannulae aimed at either the posterior or anterior VTA. At 1 week after surgery, rats were placed in standard two-lever (active and inactive) experimental chambers for a total of seven to eight sessions. The 4-h sessions were conducted every other day. The results indicated that (a) 75-300 mg% (17-66 mM) EtOH and 6-90 microM ACD were self-administered into the posterior, but not anterior, VTA; (b) the self-administration of 150 mg% EtOH was not altered by coinfusion of a catalase inhibitor; (c) coadministration of the D(2/3) agonist quinpirole (100 microM) blocked the self-infusions of 150 mg% EtOH and 23 microM ACD into the posterior VTA; and (d) coadministration of 200 microM ICS205,930 (5-HT3 receptor antagonist) prevented the self-infusion of 150 mg% EtOH, whereas concentrations of ICS 205,930 up to 400 microM had no effect on the self-infusion of 23 microM ACD into the posterior VTA. Overall, the results of this study indicate that EtOH and ACD can independently produce reinforcing effects within the posterior VTA, and that activation of DA neurons mediates these effects. Furthermore, activation of 5-HT3 receptors within the posterior VTA is involved in the self-infusion of EtOH, but not ACD.     

Biologic response of B lymphoma cells to anti-CD20 monoclonal antibody rituximab in vitro: CD55 and CD59 regulate complement-mediated cell lysis

The chimeric anti-CD20 MAb rituximab has recently become a treatment of choice for low-grade or follicular non-Hodgkin's lymphomas (FL) with a response rate of about 50%. In this report, we have investigated the mechanism of action of rituximab on 4 FL and 1 Burkitt's lymphoma (BL) cell lines, 3 fresh FL samples and normal B cells in vitro. Rituximab efficiently blocks the proliferation of normal B cells, but not that of the lymphoma lines. We did not detect significant apoptosis of the cell lines in response to rituximab alone. All cell lines were targets of antibody-dependent cellular cytotoxicity (ADCC). On the other hand, human complement-mediated lysis was highly variable between cell lines, ranging from 100% lysis to complete resistance. Investigation of the role of the complement inhibitors CD35, CD46, CD55, and CD59 showed that CD55, and to a lesser extent CD59, are important regulators of complement-mediated cytotoxicity (CDC) in FL cell lines as well as in fresh cases of FL: Blocking CD55 and/or CD59 function with specific antibodies significantly increased CDC in FL cells. We conclude that CDC and ADCC are major mechanisms of action of rituximab on B-cell lymphomas and that a heterogeneous susceptibility of different lymphoma cells to complement may be at least in part responsible for the heterogeneity of the response of different patients to rituximab in vivo. Furthermore, we suggest that the relative levels of CD55 and CD59 may become useful markers to predict the clinical response. (Blood. 2000;95:3900-3908)     

Real world experience with teriflunomide in multiple sclerosis: the TER-Italy study

Journal of Neurology - To identify baseline factors associated with disease activity in patients with relapsing–remitting multiple sclerosis (RRMS) under teriflunomide treatment. This was an...     

JAK inhibitors and psoriatic arthritis: A systematic review and meta-analysis

BackgroundDespite the therapeutic armamentarium for the treatment of psoriatic arthritis (PsA) has considerably expanded over the last thirty years, additional drugs are needed to improve care of this disease. JAK inhibitors (JAKinhibs) are small molecules able to interfere with the JAK/STAT pathway, involved in the pathogenesis of PsA. Tofacitinib and Upadacitinib were recently approved for the treatment of PsA. Our aim was to assess the efficacy and safety of JAKinhibs for the treatment of PsA.MethodsA systematic review of the literature was performed to identify RCTs by electronic search of MEDLINE and EMBASE database until April 2021. RCTs were considered eligible if included only patients with PsA treated with JAKinhibs. The pooled efficacy and safety outcomes were calculated by meta-analysis and expressed as odds ratio (OR) and 95% confidence intervals (95% CI). Statistical heterogeneity was assessed with the I² statistic.ResultsFive RCTs for a total of 3293 PsA patients treated with different JAKinhibs or placebo were included (2 phase III studies on Tofacitinib, 1 phase II study on Filgotinib and 2 phase III studies on Upadacitinib). All the studies were judged at low risk of bias according to Cochrane criteria. JAKinhibs showed a significantly higher ACR20 response rate compared to placebo (OR 3.78, 95% CI 2.72–5.24, I^2 = 57%, random effect model).and were associated with a non-statistically significant higher risk of serious adverse events (OR 1.12, 95% CI 0.14–2.82, I^2 = 46%, random effect model).ConclusionsThis is the first systematic review that performed a comprehensive evaluation of the efficacy and safety of JAKinhibs for PsA in RCTs. Our analysis suggests a statistically significant benefit of JAKinhibs that appear to be effective and safe over placebo for the treatment of PsA.     

Risk of multiple sclerosis relapses when switching from fingolimod to cell-depleting agents: the role of washout duration

Journal of Neurology - Fingolimod (FTY) induces sequestration of lymphocytes in secondary lymphoid organs and the average lymphocyte recovery following discontinuation takes...     

Multiple mechanisms of telomere maintenance exist and differentially affect clinical outcome in diffuse malignant peritoneal mesothelioma

PURPOSE: This study aims to investigate the prevalence of the two known telomere maintenance mechanisms, telomerase activity (TA) and alternative lengthening of telomeres (ALT), and to assess their prognostic relevance in diffuse malignant peritoneal mesothelioma (DMPM). EXPERIMENTAL DESIGN: In 44 DMPM specimens obtained from 38 patients, TA was determined using the telomeric repeat amplification protocol and ALT was detected by assaying ALT-associated promyelocytic leukemia nuclear bodies. The prognostic significance of telomere maintenance mechanisms was analyzed by Cox regression in the overall series and in a subset of 29 patients who underwent a uniform treatment regimen consisting of cytoreductive surgery and hyperthermic i.p. chemotherapy. RESULTS: Telomere maintenance mechanisms were detectable in 86.4% of DMPM: ALT or TA alone was found in 18.2% or 63.6% of lesions, respectively, whereas two cases (4.6%) were ALT+/TA+. TA and ALT proved to be inversely associated (P = 0.002). In the overall series, TA was prognostic for 4-year relapse (TA+ versus TA-, hazard ratio, 3.30; 95% confidence interval, 1.23-8.86; P = 0.018) and cancer-related death (TA+ versus TA-, hazard ratio, 3.56; 95% confidence interval, 1.03-12.51; P = 0.045), whereas ALT failed to significantly affect clinical outcome. These results held true also in the subset of patients submitted to uniform treatment with cytoreductive surgery and hyperthermic i.p. chemotherapy. CONCLUSIONS: Our results indicate that both known telomere maintenance mechanisms, TA and ALT, are present in DMPM and differentially affect patient prognosis.