Effect of Panax ginseng combined with Angelica sinensis on the dissolution of ginsenosides and in chemotherapy mice hematopoietic function

ObjectiveTo study the changes of ginsenoside content in different proportion of Panax ginseng-Angelica sinensis (GA) co-decoction, and to explore the amelioration of hematopoietic function in mice after combined use of the two drugs. The active ingredient profiles in P. ginseng single decoction and co-decoction of GA were determined by high performance liquid chromatography (HPLC). The experimental pharmacology method was used to explore the effect of GA co-decoction on the hematopoietic function of chemotherapy mice.ResultsThe active ingredient profiles of the co-decoction of GA significantly changed compared with those of the single decoction. Compared with GA1:0 (single decoction of Panax ginseng), the routine ginsenosides of all proportions of GA decreased significantly, but the proportion of rare ginsenosides increased significantly. The changes of contents of rare ginsenosides of GA were basically consistent with the trends of effects on the myelosuppression induced by CY. Compared with the model group, GA significantly increased the number of bone marrow nucleated cells, thymus index, peripheral blood leukocytes and platelets, and significantly reduced the spleen index. Moreover, GA could promote G1 phase bone marrow cells to enter the cell cycle, increase the proportion of S phase cells and G2/M phase cells, and increase the cell proliferation index.ConclusionGA can ameliorate the hematopoietic function of mice after chemotherapy, and GA2:3, GA3:2 were the best, which may be due to the changes of the pharmacodynamic material basis of GA after compatibility. All these results implied that GA may be an ideal drug and food supplement for the treatment of toxic and side effects of chemotherapeutic drugs.     

Introduction of Z-GP scaffold into procarbazine reduces spermatoxicity and myelosuppression

Incorporation of carbobenzoxy-glycylprolyl (Z-GP) to either α or β position of the hydrazine moiety in procarbazine (Pcb) has been carried on in 5-steps process. The overall yield was 32.7%. The new entity Z-GP-Pcb was confirmed targeting to fibroblast activation protein-α (FAPα). Z-GP-Pcb may be hydrolyzed by either isolated rhFAPα or tumor homogenate. It was shown far less cytotoxicity against NCI-H460 cell line than Pcb. Z-GP-Pcb was displayed the potency to reduce spermatoxcity in H22-bearing mice. The mechanism may be ascribed to the blockade of dehydrogenation by α-glycerolphosphate dehydrogenase. This candidate was further proved equal antitumor activity to Pcb. However, the introduction of Z-GP scaffold decreased myelosuppression. All the evidences support that Z-GP-Pcb is a better antitumor agent than Pcb.     

Topotecan Treatment and Its Toxic Effects on Hematologic Parameters and Trace Elements

The aim of this study was to investigate the effects of topotecan, a topoisomerase I-inhibiting anticancer agent, on hematologic parameters and serum levels of trace elements. The study was conducted on three groups consisting of 16 and 18 rabbits in the study groups and 15 rabbits in the control group. Rabbits in group I (n = 16) received high-dose topotecan intravenously (i.v.; 0.5 mg/kg once daily), while rabbits in group II (n = 18) received low-dose topotecan i.v. (0.25 mg/kg once daily) for 3 days. The 15 rabbits comprising the control group did not receive topotecan. Serum samples were collected from each rabbit on the first day, before the treatment, and on the 15th day of treatment. Erithrocytes, hemoglobin, white blood cell count, thrombocyte count, and trace elements such as selenium, copper, lead, zinc, and cobalt were analyzed. Hemoglobin levels and erythrocyte counts were lower in both study groups than in the control group. However, thrombocyte and leukocyte counts were similar in all three groups (p > 0.005). Serum trace element levels (copper, lead, zinc, and cobalt) did not differ significantly between groups. However, serum selenium levels were significantly lower in both study groups than the control group (p < 0.001). The results revealed that topotecan treatment causes a decrease in erythrocyte counts and hemoglobin levels due to bone marrow suppression, and these effects must be taken into account during treatment. In addition, selenium supplementation might be helpful in cancer patients receiving topotecan to increase the effect of the chemotherapeutic agent.     

六君子汤加当归补血汤防治化疗后骨髓抑制的疗效研究

目的：观察六君子汤加当归补血汤对化疗后患者骨髓抑制的疗效。方法：选择来本院就诊并于肿瘤科住院的患者60 例,经病理学检查确诊为恶性肿瘤,并且使用TP 方案化疗。患者随机分为治疗组和对照组,治疗组为TP方案化疗＋ 中药组,对照组为TP 方案化疗组。对照组常规化疗,治疗组在对照组的基础上予以六君子汤加当归补血汤,观察患者的临床症状、骨髓抑制程度以及生活质量等指标。结果：治疗组在临床症状改善程度、白细胞数量、血小板数量以及血红蛋白含量以及生活质量等情况均优于对照组（P＜0.05）。结论：六君子汤加当归补血汤可以有效地改善化疗后患者骨髓抑制的情况。     

Mast cell growth factor (C-Kit Ligand) in combination with granulocyte-macrophage colony-stimulating factor and interleukin-3:in vivo hemopoietic effects in irradiated mice compared toin vitro effects

In the presence of hemopoietic cytokines such as granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-3 (IL-3), mast cell growth factor (MGF; also known as steel factor, stem cell factor, and c-kit ligand) has proven to be a potent hemopoietic regulatorin vitro. In these studies, we examined thein vivo effects of MGF in combination with GM-CSF or GM-CSF plus IL-3. Effects were based on the ability of these cytokines to stimulate recovery from radiation-induced hemopoietic aplasia. Female B6D2F1 mice were exposed to a sublethal 7.75-Gy dose of⁶⁰Co radiation followed by subcutaneous administration of either saline, recombinant murine (rm) MGF (100g/kg/day), rmGM-CSF (100g/kg/day), rmIL-3 (100g/kg/day), or combinations of these cytokines on days 1–17 postirradiation. Recoveries of bone marrow and splenic spleen colony-forming units (CFU-s), granulocyte macrophage colony-forming cells (GM-CFC), and peripheral white blood cells (WBC), red blood cells (RBC) and platelets (PLT) were determined on days 14 and 17 during the postirradiation recovery period. MGF administered in combination with GM-CSF or in combination with GM-CSF plus IL-3 either produced no greater response than GM-CSF alone or down-regulated the GM-CSF-induced recovery. These results sharply contrasted results ofin vitro studies evaluating the effects of these cytokines on induction of GM-CFC colony formation from bone marrow cells obtained from normal or irradiated B6D2F1 mice, in which MGF synergized with GM-CSF or GM-CSF plus IL-3 to increase both GM-CFC colony numbers and colony size. These studies demonstrate a dichotomy between MGF-induced effectsin vivo andin vitro and emphasize that caution should be taken in attempting to predict cytokine interactionsin vivo in hemopoietically injured animals based onin vitro cytokine effects.Abbreviations GM-CSF Granulocyte-Macrophage Colonly-Stimulating Factor - IL-3 Interleukin-3 - MGF Mast Cell Growth Factor - SCF Stem Cell Factor - rm Recombinant Murine - CFU-s Colony Forming Unit-Spleen - GM-CFC Granulocyte Macrophage Colony-Forming Cell - WBC White Blood Cells - RBC Red Blood Cells - PLT Platelets - SLF Steel Factor - G-CSF Granulocyte Colonly-Stimulating Factor - IL-1 Interleukin-1 - IL-6 Interleukin-6 - Epo Erythropoietin - CFC Colony-Forming Cell - Sl Steel - BFU-e Erythroid Burst Forming Units - s.c Subcutaneous - PEG Polyethyleneglycol - PIXY321 GM-CSF/IL-3 Fusion Protein     

Hematopoietic augmentation by a β-(1,4)-linked mannan

 CARN 750 (injectable acemannan) is a polydispersed β-(1,4)-linked acetylated mannan isolated from the Aloe barbadensis plant. It has multiple therapeutic properties including activity in wound repair and as a biological agent for the treatment of neoplasia in animals as well as the ability to activate macrophages. We report herein that CARN 750 directly or indirectly has significant hematoaugmenting properties. We observed that the subcutaneous administration of CARN 750 significantly increases splenic and peripheral blood cellularity, as well as hematopoietic progenitors in the spleen and bone marrow as determined by the interleukin-3-responsive colony-forming unit culture assay and the high-proliferative-potential colony-forming-cell (HPP-CFC) assay (a measure of primitive hematopoietic precursors) in myelosuppressed (7 Gy) C₅₇BL/6 mice. The greatest hematopoietic effect was observed following sublethal irradiation in mice receiving 1 mg CARN 750/animal, with less activity observed at higher or lower doses. Further, CARN 750, following daily injection, has activity equal to or greater than the injection of an optimal dose of granulocyte-colony-stimulating factor (G-CSF) in myelosuppressed mice. In this comparison, significantly greater activity was observed in the splenic and peripheral blood cellularity, and in the frequency and absolute number of splenic HPP-CFC as compared to the mice receiving G-CSF at 3 μg/animal. CARN 750, when administered to myelosuppressed animals. decreased the frequency of lymphocytes with a concomitant significant increase in the frequency of polymorphonuclear leukocytes (PMN). However, owing to the increased cellularity, a significant increase in the absolute number of PMN, lymphocytes, monocytes and platelets was observed, suggesting activity on multiple cell lineages. The latter is the primary difference in activity as compared to G-CSF which has activity predominantly on PMN. Received: 21 November 1995 / Accepted: 13 September 1996     

六君子汤加当归补血汤防治化疗后骨髓抑制的疗效研究

目的:观察六君子汤加当归补血汤对化疗后患者骨髓抑制的疗效。方法:选择来本院就诊并于肿瘤科住院的患者60例,经病理学检查确诊为恶性肿瘤,并且使用TP方案化疗。患者随机分为治疗组和对照组,治疗组为TP方案化疗+中药组,对照组为TP方案化疗组。对照组常规化疗,治疗组在对照组的基础上予以六君子汤加当归补血汤,观察患者的临床症状、骨髓抑制程度以及生活质量等指标。结果:治疗组在临床症状改善程度、白细胞数量、血小板数量以及血红蛋白含量以及生活质量等情况均优于对照组(P0.05)。结论:六君子汤加当归补血汤可以有效地改善化疗后患者骨髓抑制的情况。     

A mechanistic mathematical model of temozolomide myelosuppression in children with high-grade gliomas

Temozolomide (TMZ) is currently being evaluated for the treatment of high-grade gliomas in children. Myelosuppression (the suppression of bone marrow activity) is the dose-limiting toxicity for TMZ in adults and children. Empirical methods (i.e. relations between the percent change in absolute neutrophil count (ANC) and the area under the plasma concentration curve (AUC) of TMZ or its active metabolite MTIC) showed poor results when attempting to describe myelosuppression from serial data derived during TMZ therapy in a Phase II study of children with high-grade glioma. Therefore, to improve our understanding of the myelosuppressive effects of TMZ and MTIC in children we developed a mechanistic mathematical model. The model describes the progression of neutrophils from their production in the bone marrow to their release in the plasma. Included in the model are the feedback effects of granulocyte colony stimulating factor (G-CSF), which stimulates neutrophil production when there is a decrease in circulating neutrophils. The model is fit to serial ANC measurements obtained after TMZ dosing and it is able to explain, among other things, the lag in ANC reduction following a dose of TMZ, the ANC nadir, and the 'rebound effect' observed where the ANC recovers to levels greater than that observed pre-TMZ dose. This model will be useful for the prospective design of clinical trials of TMZ in children with cancer.     

The effects of Arctigenin-Valine ester on chemotherapy-induced myelosuppression in mice

ObjectiveTo explore whether Arctigenin-Valine ester (ARG-V) can treat myelosuppression caused by chemotherapy.MethodsThe number of peripheral blood cells of the mice was measured by an automatic blood analyzer, and the hematopoietic progenitor colonies CFU-GM, CFU-E, BFU-E, and CFU-Meg were cultured in vitro. Hematopoietic progenitor colonies and BMNCs were counted under an inverted microscope. The expressions of cytokines GM-CSF, EPO and TPO were detected by ELISA. The cell cycle was measured by flow cytometry. The expressions of related proteins MEK and p-ERK were quantitated by western blots, and the thymus index and spleen index were quantitated.ResultsAfter taking ARG-V, the peripheral blood cells of the mice gradually returned to normal, the number of nucleated cells in the bone marrow increased, the thymus index increased, the spleen index decreased, the number of hematopoietic progenitor cells increased, and the hematopoietic cytokines decreased. And ARG-V promoted the transformation of myelosuppression cells from G0/G1 to S and from S to G2/M. ARG-V could up-regulate the expression of MEK and p-ERK, and low dose ARG-V is not as effective in all aspects as high dose ARG-V.ConclusionARG-V can effectively alleviate the myelosuppression that caused by intraperitoneal injection of CTX in 100mg/kg, and ARG-V can promote the proliferation and differentiation of hematopoietic progenitor cells and improve immunity, and the effect of high-dose Arctigenin-Valine ester is more significant to some extent.     

Type I interferons and limitin: a comparison of structures, receptors, and functions

The type I interferon (IFN) family includes IFN-, IFN-β, IFN-, and IFN-τ. These molecules are clustered according to sequence homologies, use of the same cell surface receptor, and similar functions. IFN- and IFN-β have a globular structure composed of five a-helices. Their receptors, IFNAR1 and IFNAR2, belong to the class II cytokine receptor family for a-helical cytokines. Information about structure-function relationships between these and other IFNs is being provided by comparative sequence analysis, reference to a prototypic three-dimensional structure, analysis with monoclonal antibodies, construction of hybrid molecules and site directed mutagenesis. While much remains to be done, it should someday be possible to understand differences among IFNs in terms of how they interact with their corresponding receptors. Our recently identified IFN-like molecule, limitin, has weak sequence homology to IFN-, IFN-β, and IFN-ω and displays its biological functions through the same IFN-/β receptors. While limitin has antiproliferative, immunomodulatory, and antiviral effects like IFN- and IFN-β, it is unique in lacking influence on myeloid and erythroid progenitors. Further analysis of this functionally unique cytokine should be informative about complex IFN–receptor interactions. Furthermore, a human homologue or synthetic variant might be superior for clinical applications as an IFN without myelosuppressive properties.