salicylates and Lymphoma

This phase I first-in-human trial evaluated salirasib, an S-prenyl derivative of thiosalicylic acid that competitively blocks RAS signaling.. Patients with advanced cancers received salirasib twice daily for 21 days every 4 weeks. Doses were escalated from 100 to 200, 400, 600, and 800 mg.. The most common toxicity was dose-related diarrhea (Grade 1-2, 79% of 24 patients). Other toxicities included abdominal pain, nausea, and vomiting. No Grade 3-4 toxicity was noted. Nineteen (79%) patients had no drug-related toxicity >Grade 1. Dose-limiting toxicity (DLT) was not reached, but all three patients treated with 800 mg experienced Grade 1-2 diarrhea, brogating dose escalation. Six patients were treated at a dose of 600 mg with no DLTs. Seven (29%) patients had stable disease on salirasib for ≥4 months (range 4-23+). The salirasib pharmacokinetic profile was characterized by slow absorption and a rapid elimination phase following oral administration. Salirasib exposure (C(max); day 1 AUC(inf) vs. day 15 AUC(0-12 h)) was similar between days 1 and 15 (P > 0.05). The T(1/2) (mean ± SD) was 3.6 ± 2.2 h on day 1.. Salirasib therapy was well tolerated. The recommended dose for phase II studies is 600 mg twice daily.

Topics: Adult; Aged; Antineoplastic Agents; Farnesol; Female; Humans; Lymphoma; Male; Middle Aged; Neoplasms; Salicylates; Stereoisomerism

We report on our preclinical findings of a simple salicylic diamine compound (THG 1213) which has yielded exceptional results as a potential chemotherapeutic drug. THG 1213 is an easy to synthesize chiral and metal-free salan compound.. THG 1213 was tested on several leukemia, lymphoma and solid tumor cell lines in vitro. The effects have been studied by LDH release essay, FACS flow cytometry, photometric cell count, immunoblotting, and NMR spectroscopy.. THG 1213 selectively inhibits proliferation and induces apoptosis in leukemia, lymphoma and solid tumor cell lines. Necrosis or effects on healthy leucocytes could not be detected. Apoptosis is induced via the intrinsic and extrinsic pathways. The salan THG 1213 overcomes multidrug resistance in tumor cells and acts synergistically with vincristine and daunorubicin.. THG 1213 displays remarkable antitumor properties. In particular, the lack of metallic components of THG 1213 could prove to be beneficial in future clinical trials, as metal-containing drugs are known to show severe side effects.

Topics: Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cell Line, Tumor; Daunorubicin; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Drug Synergism; Humans; Leukemia; Lymphoma; Neoplasms; Phenylenediamines; Salicylates; Vincristine

We demonstrate the cytotoxic potential of the Schiff base iron complex [Fe(III)(salophene)Cl] in vitro and ex vivo and illustrate its ability to overcome multiple drug resistance in vincristine and daunorubicine resistant leukemic cells (Nalm-6). Treatment of lymphoma cells (BJAB) with [Fe(III)(salophene)Cl] led to the exclusion of unspecific necrosis, a concentration-dependent inhibition of proliferation and a specific apoptotic cell death. We further detected a significant loss of the mitochondrial membrane potential in lymphoma cells and an up- and downregulation of various apoptosis relevant genes, respectively, indicating the involvement of the intrinsic mitochondrial pathway.

Topics: Apoptosis; Biomarkers, Tumor; Blotting, Western; Cell Line, Tumor; Cell Proliferation; Daunorubicin; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Ferric Compounds; Humans; Leukemia; Lymphoma; Membrane Potential, Mitochondrial; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Salicylates; Vincristine

Schiff base transition metal complexes are an important class of compounds with great potential for therapeutic interventions. However, data on antileukemic and antilymphoma effects of these complexes are limited. The activity of N,N'-bis(salicylidene)-1,2-phenylenediamine (salophene, 1), its iron(II/III) and manganese(II/III) complexes as well as rac-trans-N,N'-bis(salicylidene)-1,2-cyclohexanediamine (saldach, 2) and its respective iron(II/III) complexes was evaluated against U-937 non-Hodgkin's lymphoma and the HL-60, SUP-B15, and K-562 leukemia cell lines. The free ligands induced in all cell lines, if at all, only marginal, concentration-dependent growth inhibitory effects, and did not trigger Cu/Zn superoxide dismutase (Cu/Zn SOD) release or induce apoptosis. [Fe(II) (salophene)] (3) and [Fe(III) (salophene)Cl] (4) blocked cellular growth, caused a strong release of Cu/Zn SOD and induced apoptosis. In contrast, the manganese analogs [Mn(II) (salophene)] (5) and [Mn(III) (salophene)OAc] (6) inhibited cell growth, caused the programmed cell death only at higher concentrations and did not provoke release of Cu/Zn SOD in any of the four cell lines. Weaker cell death-promoting effects were observed when the salophene moiety of 3 and 4 was replaced with saldach (complexes 7 and 8), indicating the influence exerted by the ligand structure. In conclusion, Schiff base transition metal complexes induce strong inhibitory effects on human lymphoma and leukemia cells.

Topics: Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Proliferation; Cyclohexylamines; Dose-Response Relationship, Drug; Humans; Iron; Leukemia; Ligands; Lymphoma; Manganese; Molecular Structure; Organometallic Compounds; Salicylates; Schiff Bases; Superoxide Dismutase

The practical importance of BSR and blood cell changes for the early recognition should not be overestimated. But every symptomless person with raised BSR should be examined very carefully, especially for occult hepatic diseases (active hepatitis, liver cirrhosis), for anaemias, leukaemias, malignant lymphomas and other malignant diseases. The practical use of the diagnosis of blood cell changes is the possible recognition of anaemias, leukaemias and malignant lymphomas.

Topics: Adrenal Cortex Hormones; Anemia; Blood Cell Count; Blood Sedimentation; Eosinophilia; Humans; Hyperlipidemias; Leukemia; Liver Diseases; Lymphoma; Multiple Myeloma; Parasitic Diseases; Salicylates

Topics: Aged; Cell Transformation, Neoplastic; Female; Hodgkin Disease; Humans; Lymphoma; Polymyalgia Rheumatica; Prednisolone; Salicylates; Synovitis