白术挥发油抗实体瘤的作用研究

目的　研究白术挥发油对动物移植性肿瘤的作用。方法　以动物移植性肿瘤肝癌H2 2 、肉瘤S180 为模型 ,以环磷酰胺为阳性对照 ,观察白术挥发油的抗肿瘤作用。结果　白术挥发油 2 5 0mg/kg对小鼠肝癌H2 2 、肉瘤S180 的抑制率分别为 5 1 6 %、5 3 2 %。结论　白术挥发油对小鼠移植性肿瘤肝癌H2 2 及肉瘤S180 有显著抑制作用     

Thioredoxin reductase inactivation as a pivotal mechanism of ifosfamide in cancer therapy

Thioredoxin reductase reduces thioredoxin, thereby contributing to multiple cellular events related to carcinogenesis including cell proliferation, apoptosis, and cell signaling. This selenium-containing oxidoreductase is over-expressed in many malignant cells and has been proposed as a target for cancer therapy. Ifosfamide is an oxazaphosphorine alkylating agent with a broad spectrum of antineoplastic activity. The purpose of this study is to test the hypothesis that anticancer efficacy of ifosfamide may rely on its ability to inhibit thioredoxin reductase in tumor. To inspect the consequence of thioredoxin reductase inhibition by ifosfamide on tumor cell proliferation, mice bearing hepatoma 22 (H22) cells in ascites were injected with 350 mg/kg ifosfamide. Thioredoxin reductase activity was maximally inhibited by half at 6 h, and a subsequent pronounced cellular proliferation inhibition due to cell cycle arrest in G(1) phase was found. Moreover, at 6 h, except thioredoxin reductase inhibition, ifosfamide did not affect cell cycle or other measured antioxidant enzymes activity in the tumor cells. Intriguingly, when these cells were injected into healthy mice, they totally lost the capacity of causing either ascitic or solid tumors. Thioredoxin reductase inhibition could also be found in solid H22 tumor by 62%, bladder by 74% and kidney by 37% at 6 h. Overall, these observations provide direct evidence that inhibition of thioredoxin reductase activity in malignant cells by ifosfamide is highly associated with its anticancer effect and the mechanism of ifosfamide systemic toxicity may be related to multi-organ inhibition of thioredoxin reductase activity.     

Distinction between the in vitro and in vivo inhibitory effects of morphine on lymphocyte proliferation based on agonist sensitivity and naltrexone reversibility.

We have previously reported that administration of a single dose of morphine (25 mg/kg) to rats results in a naltrexone-sensitive suppression of mitogen-stimulated lymphocyte proliferation. To further delineate the site of action of this inhibitory effect, the in vitro and in vivo effects of morphine on mitogen-stimulated lymphocyte proliferation were examined. In vitro, concentrations of morphine exceeding 0.1 mM exhibited a dose-dependent inhibition of Concanavalin A-induced proliferation of both whole blood and splenic lymphocytes. This inhibitory effect of morphine on lymphocyte proliferation was not attenuated by co-incubation with the opioid antagonist naltrexone (0.25 mM). These data indicate that the in vitro inhibitory effects of morphine occur at only high concentrations and are not opioid receptor mediated. In vivo, a dose-dependent inhibition of blood lymphocyte proliferation was also observed 2 h following the subcutaneous injection of morphine. In contrast to these effects, proliferation of splenic lymphocyte cultures was not significantly inhibited by morphine at doses of up to 40 mg/kg. However, following morphine administration, a greater than 90% inhibition of proliferation was obtained in cultures containing either whole blood or Ficoll-separated lymphocytes, indicating that plasma was not a contributory factor in the differential sensitivity of blood and splenic lymphocyte responses to morphine. Moreover, in these experiments, significant inhibition of lymphocyte proliferation occurred at plasma concentrations that were two orders of magnitude less than those required to produce inhibition in vitro. The in vivo inhibition of lymphocyte proliferation by morphine (10 mg/kg) was completely antagonized by pretreatment with naltrexone (5 mg/kg).(ABSTRACT TRUNCATED AT 250 WORDS)     

糙苏素的抗肿瘤作用及机制研究

目的:研究糙苏素的抗肿瘤作用及其对端粒酶活性和细胞周期的影响。方法:采用血清药理学与体内、外抑瘤实验相结合的方法,MTT法检测糙苏素含药血清对体外培养的人白血病K562细胞增殖的抑制作用,聚合酶链反应-酶联免疫吸附法检测K562细胞在糙苏素作用后端粒酶活性的变化,流式细胞仪分析细胞周期的改变;体内实验采用小鼠肝癌H22细胞株接种小鼠,连续给药14d,计算抑瘤率。结果:糙苏素含药血清在10%～50%剂量范围内对K562细胞有抑制作用,且呈剂量依赖关系(P<0.05);糙苏素作用后端粒酶活性出现抑制,且各给药组随糙苏素浓度增加抑制作用显著增强(P<0.01),同一浓度随作用时间延长,抑制作用逐渐增强(P<0.05);K562细胞的DNA合成后期/分裂期(G2/M)细胞含量显著增高(P<0.01);糙苏素(2.5、5、10mg·kg-1)灌胃能显著抑制小鼠移植性肝癌H22细胞的生长。结论:糙苏素具有抗肿瘤作用,其作用是通过抑制肿瘤细胞的端粒酶活性而实现的。     

A long-form α-neurotoxin from cobra venom produces potent opioidindependent analgesia

AIM: In light of the antinociceptive activity of the short-chain neurotoxin, cobrotoxin, and other acetylcholine antagonists, the antinociceptive activity and mechanisms of cobratoxin (CTX), a long-chain postsynaptic alpha-neurotoxin, was investigated in rodent pain models. METHODS: CTX was administered intraperitoneally (30, 45, 68 microg/kg), intra-cerebral ventricularly (4.5 microg/kg) or microinjected into periaqueductal gray (PAG; 4.5 microg/kg). The antinociceptive action was tested using the hot-plate and acetic acid writhing tests in mice and rats. The involvement of the cholinergic system and opioid system in CTX-induced analgesia was examined by pretreatment of animals with atropine (0.5 mg/kg, im; or 10 mg/kg, ip) or naloxone (1 and 5 mg/kg, ip). The effect of CTX on motor activity was tested using the Animex test. RESULTS: CTX exhibited a dose-dependent analgesic action in mice as determined by both the hot-plate and acetic acid writhing tests. The peak effect of analgesia was seen 3 h after administration. In the mouse acetic acid writhing test, the intra-cerebral ventricular administration of CTX at 4.5 microg/kg (1/12th of a systemic dose) produced marked analgesic effects. Microinjection of CTX (4.5 microg/kg) into the PAG region did not elicit an analgesic action in rats in the hot-plate test. Atropine at 0.5 mg/kg (im) and naloxone at 1 and 5 mg/kg (ip) both failed to block the analgesic effects of CTX, but atropine at 10 mg/kg (ip) did antagonize the analgesia mediated by CTX in the mouse acetic acid writhing test. Acetylsalicylic acid (300 mg/kg) did not enhance the analgesic effects of CTX. At the highest effective dose of 68 microg/kg the neurotoxin did not change the spontaneous mobility of mice. CONCLUSION: CTX has analgesic effects, which are mediated in the central nervous system though not through the PAG. The central cholinergic system but not opioid system appears to be involved in the antinociceptive action of CTX.     

Role of intracellular calcium in histamine release from rat mast cells

An aqueous extract of Panax Ginseng C.A. Meyer (G.S.) was prepared by boiling crushed G.S. roots in water. The extract obtained was adjusted to 125 mg G.S. per ml and was administered orally to mice for 5 to 6 days at the daily dose of 10, 50 and 250 mg G.S. per kg or was added to cultures of mouse spleen cells at concentrations varying between 0.25 and 8 mg G.S. per ml. The average total ginsenoside content of the G.S. roots used was determined by HPLC analysis and found to be 0.58% (w/w). Treated mice responded with enhanced antibody formation to either a primary or a secondary challenge with sheep red cells. The effects were dose-dependent. At the highest dose regimen, the primary IgM response was increased by 50% and the secondary IgG and IgM responses were increased by 50 and 100%, respectively. An even more pronounced effect was obtained with natural killer cell activity which was enhanced between 44 and 150% depending on the effector-to-target cell ratios used in the assay. In vitro, G.S. showed two main effects, an inhibition of stimulated and spontaneous lymphocyte proliferation at high, but not cytotoxic concentrations and an enhancement of interferon production particularly in non-stimulated spleen cells. The immunostimulating effects obtained in vivo are in agreement with the stimulation of interferon production observed in vitro. The inhibition of lymphocyte proliferation, however, cannot be reconciled with the immunostimulatory action of G.S. observed in vivo.     

多肽ND100的抗肿瘤活性研究

目的　研究多肽ND100的抗肿瘤活性。方法　用液相法人工合成了抗肿瘤八肽ND100,分子量为 846 9。测定了ND100对 3种小鼠移植性肿瘤的抑制作用,并研究了ND100对小鼠红细胞和白细胞数量的影响。结果　体内抑瘤试验表明,ND100对小鼠H22肝癌、小鼠Lewis肺癌和小鼠S180肉瘤的生长均有明显抑制作用,有效剂量为 2 5mg·kg-1,当使用高剂量时(15mg·kg-1 )时,对 3种小鼠移植性肿瘤的抑制率达 0 70以上,且具有剂效关系。ND100对小鼠红细胞和白细胞的数量均无影响。结论　ND100具有明显的体内抗肿瘤活性。     

赖氨酰谷氨酸二肽的抗肿瘤活性研究

目的研究二肽Lys-Glu(Vilon)的抗肿瘤活性。方法用液相法人工合成了抗肿瘤二肽Vilon,分子量为275.3。用细胞计数法和MTT法测定Vilon对人肠癌LOVO,人胃癌MKN45和人肝癌QGY77033种肿瘤细胞生长的抑制作用,以及对人体正常细胞生长的影响;并对其进行了体内实验。结果Vilon对体外培养的LOVO,MKN45和QGY7703细胞具有剂量依赖性抑制作用,但对人正常白细胞无明显抑制作用。体内抑瘤实验表明,Vilon对小鼠肝癌H22的生长有抑制作用,有效剂量为15mg.kg-1,当使用高剂量30mg.kg-1时,对小鼠移植性肿瘤肝癌H22的抑瘤率达0.60以上,且具有剂效关系。结论Vilon具有明显的体外、体内抗肿瘤活性。     

力达霉素诱导人胃癌BGC823细胞凋亡和抑制裸鼠移植瘤生长

观察力达霉素(LDM)对人胃癌BGC823细胞的诱导凋亡作用及体内抗肿瘤活性。采用MTT法观察LDM对人胃癌BGC823细胞增殖的抑制作用。利用Annexin V-FITC/PI双染结合流式细胞仪和脱氧核糖核酸末端转移酶介导的缺口末端标记技术检测细胞凋亡的改变。采用Western blotting法检测细胞中VEGF蛋白的表达情况。建立裸鼠胃癌皮下移植瘤模型，观察LDM的体内抗肿瘤活性。LDM能够明显抑制BGC823细胞增殖，诱导细胞凋亡，降低细胞VEGF蛋白的表达，抑制胃癌裸鼠移植瘤的生长。LDM剂量0.02和0.04 mg·kg^-1的抑瘤率分别为57%和72%(P<0.01)。LDM可诱导胃癌细胞凋亡并抑制裸鼠移植肿瘤的生长。     

Characterization and immunostimulatory activity of an (1-->6)-a-D-glucan from the root of Ipomoea batatas

The polysaccharide PSPP (purified sweet potato polysaccharide), isolated and purified from the roots of Ipomoea batatas, was found to be a glucan with a molecular weight of 53.2 kDa and specific rotation of +115.0 degrees (ca. 0.80, H(2)O). On the basis of methylation analysis, periodate oxidation, Smith degradation, infra-red spectroscopy, and (13)C NMR, the polysaccharide was confirmed as a (1-->6)-alpha-D-glucan. We evaluated the effects of polysaccharide PSPP on the in vivo immune function of mouse. Mice were treated with the polysaccharide PSPP (50, 150, and 250 mg/kg body weight) for 7 days. Phagocytic function, proliferation of lymphocytes, natural killer cell activity, hemolytic activity, and serum IgG concentration of the mice were studied. At the dose of 50 mg/kg, significant increments in proliferation of lymphocytes (P<0.05) and serum IgG concentration (P<0.05) were observed. At the dose of 150 and 250 mg/kg, significant increments (P<0.01 or P<0.05) were observed in all tested immunological indexes. A dose-dependent manner was demonstrated in phagocytic function, hemolytic activity, and serum IgG concentration, but not in proliferation of lymphocytes and natural killer cell activity. This suggests that PSPP improve the immune system and could be regarded as a biological response modifier.     

Immunosuppressive effect of cyclophosphamide on white blood cells and lymphocyte subpopulations from peripheral blood of Balb/c mice

There has been lack of the uniform standard for establishment of animal immunodepressive models induced by cyclophosphamide (CTX), and the information about the immunosuppressive effect of CTX on peripheral blood lymphocyte subsets in rodents. Here we describe a CTX-induced mouse model and try to establish a feasible immunosuppressive model for studying the fungal pathogenicity. Balb/c mice received two intraperitoneal injections of different CTX doses (50-200 mg/kg) at 2-day intervals. Peripheral whole blood collected at different time-points before and after CTX injection was used to detect white blood cells (WBCs), lymphocytes and their subsets by automated hematology analyzer and flow cytometry, respectively. WBCs and lymphocytes in all groups except CTX50 (50 mg/kg CTX) group commenced to decrease in a dose-dependent manner on day 1, reached the nadir on day 4, rebounded on day 10, and declined again on day 17 after CTX treatment. Low dose (50 mg/kg) CTX produced no obvious change of percentage of CD3(+), CD4(+) and CD8(+) T cells and CD19(+) cells, but high doses (100 or 150 mg/kg) yielded a significant decrease of CD3(+) and CD4(+) cells on day 4 and CD19(+) cells on day 10, and increase of CD8(+) cells on day 4. The CD4(+)/CD8(+) ratio decreased on day 4, followed by a rebound thereafter when treated with 3 different doses of CTX. The results indicate that two intraperitoneal injections of CTX at 150 mg/kg at 2-day intervals may establish good immunosuppressive models of Balb/c mice for studying the fungal pathogenicity.     

蛇毒心脏毒素诱导肺癌A549细胞的凋亡机制研究

目的:研究眼镜蛇心脏毒素(CTX)诱导肺癌A549细胞凋亡的机制。方法:MTT法测定CTX体外细胞毒性作用;吉姆萨染色法观察CTX对A549细胞形态学的影响;线粒体膜电位(JC-1)法检测CTX诱导A549细胞后细胞JC-1的变化;流式细胞仪检测CTX对A549细胞凋亡的影响;Western blot法测定细胞色素C、凋亡蛋白酶前体(Procaspase)-3、Procaspase-9的表达;通过S180小鼠肉瘤模型检测CTX体内抗肿瘤活性。结果:CTX作用于A549细胞的半数抑制浓度(IC50)为0.770μg/ml;0.5、1.0、2.0μg/ml CTX可引起A549细胞明显缩小,在高倍镜下可观察到胞核皱缩,形成染色质边集等形态学改变;流式细胞仪检测到CTX使A549细胞出现凋亡,并且具有量效关系;5μg/ml CTX作用于A549细胞0.5 h可使细胞JC-1降低;胞浆中检测到细胞色素C时,Procaspase-9的含量没有明显变化,随后逐渐减少,CTX诱导细胞凋亡具有时效关系;体内抑瘤实验显示在剂量为0.5、1.0、2.0 mg/kg时CTX对A549细胞有明显的抑制作用。结论:CTX对A549细胞有细胞毒性,可以使线粒体内细胞色素C释放,并激活Procaspase-9和Procaspase-3诱导A549细胞的凋亡。     

Anti-inflammatory effects of a bioavailable compound, Artepillin C, in Brazilian propolis

Artepillin C is the major compound in the Brazilian green propolis from Baccharis dracunculifolia. Our aim in this study was to investigate the anti-inflammatory effects, absorption, and bioavailability of Artepillin C in mice. The animals used were male Swiss mice subjected to: paw oedema by carrageenan (300 microg/paw), carrageenan-induced peritonitis, and prostaglandin E(2) determination. We also measured in vitro nitric oxide production by RAW 264.7 cells and NF-kappaB activity in HEK 293 cells. Finally, we measured the absorption and bioavailability of Artepillin C in plasma from mice by means of GC-MS after a single oral dose (10 mg/kg). In vivo, Artepillin C produced a maximal inhibition of 38% after 360 min on paw oedema. Artepillin C also decreased the number of neutrophils during peritonitis (IC(50): 0.9 (0.5-1.4) mg/kg). Treatment with Artepillin C decreased prostaglandin E(2) by 29+/-3% and 58+/-5% at 1 and 10 mg/kg, respectively, with a mean ID(50) of 8.5 (8.0-8.7) mg/kg). Similarly, in in vitro models, Artepillin C (3, 10, or 100 microM) decreased nitric oxide production by RAW 264.7 cells with a mean IC(50) of 8.5 (7.8-9.2) microM. In HEK 293 cells, Artepillin C reduced NF-kappaB activity with a mean IC(50) of 26 (22-30) mug/ml), suggesting anti-inflammatory activity, particularly during acute inflammation. Lastly, Artepillin C was absorbed after an oral dose (10 mg/kg) with maximal peaks found at 1 h (22 microg/ml). Collectively, Artepillin C showed anti-inflammatory effects mediated, at least in part, by prostaglandin E(2) and nitric oxide inhibition through NF-kappaB modulation, and exhibited bioavailability by oral administration.     

The α-naphthoxyacetic acid-elicited retching involves dopaminergic inhibition in mice

Alpha-naphthoxyacetic acid (α-NOAA), one of the jumping-inducers, elicited a dose-dependent retching behavior at doses ranging from 250 to 550 mg/kg in mice and vomiting at a dose of 550 mg/kg in pigeons. Protoveratrine-A (PV-A, 0.1 mg/kg), a veratrum alkaloid, also induced retching in mice and vomiting in pigeons, while apomorphine (2 mg/kg) produced neither retching in mice nor vomiting in pigeons though it induced feeding in pigeons. The retching elicited by α-NOAA or PV-A was not significantly affected by scopolamine, aminooxyacetic acid and γ-butyrolactone, but was markedly inhibited by apomorphine (2 mg/kg), this inhibitory effect being antagonized without significance by haloperidol which did not itself augment the retching. These results imply that the retching elicited by α-NOAA or PV-A seems to involve at least in part an inhibition of dopaminergic neuron activity.     

螺旋藻多糖对小鼠和犬造血系统的化学和放射防护作用

目的：研究螺旋藻多糖（PSp)对环磷酰胺和^60Co-γ射线所致小白鼠和犬造血系统抑制的影响。方法：腹腔注射环磷酰胺以及用^60Co-γ射线照射分别诱发小鼠和犬的骨髓损伤。全血细胞计数和骨髓有核细胞计数,用紫外分光光度计检测骨髓DNA的含量。结果：环磷酰胺和^60Co-γ射线分别造成小鼠和犬骨髓造血系统抑制性损伤。PSp 30,60mg/kg能升高小鼠全血白细胞数和骨髓有核细胞数以及DNA含量;PSp 12mg/kg能使犬骨髓有核细胞数,以及外周血红细胞、白细胞及血红蛋白水平得以回升（P＜0．01）,其疗效优于盐酸小壁胺。结论：PSp对造血系统有化学保护和放射保护作用。     

Suppression of thioredoxin system contributes to silica-induced oxidative stress and pulmonary fibrogenesis in rats

Silicosis is one of the most prevalent occupational lung diseases worldwide. This study aimed to investigate the possible mechanism that silica affected thioredoxin (Trx) system during the development of silicosis in vivo. Male Wistar rats were randomly divided into saline group and silica group in which rats were intratracheally instilled with a single dose of silica suspension (50 mg in 1 ml saline/rat). After 7, 15 or 30 days instillation, rats were sacrificed. Biochemical parameters and histopathology were assessed. Our results demonstrated that silica could significantly cause the accumulation of reactive oxygen species (ROS) and malondialdehyde (MDA) as well as activate antioxidative protein Nuclear factor erythroid 2-related factor 2 (Nrf2) and its downstream protein Trx in the early exposure to silica. The inhibition of Trx activity and the down-regulated expression of thioredoxin reductase (TrxR), suggesting that the function of Trx system may be suppressive induced by silica. Content of lung hydroxyproline and histopathological results showed significant fibrosis development with time. In conclusion, our study demonstrated that silica could suppress the Trx system to perturb the redox balance, elicit oxidative stress, and eventually induce pulmonary fibrosis.     

Curcumin targeting the thioredoxin system elevates oxidative stress in HeLa cells

The thioredoxin system, composed of thioredoxin reductase (TrxR), thioredoxin (Trx), and NADPH, is ubiquitous in all cells and involved in many redox-dependent signaling pathways. Curcumin, a naturally occurring pigment that gives a specific yellow color in curry food, is consumed in normal diet up to 100 mg per day. This molecule has also been used in traditional medicine for the treatment of a variety of diseases. Curcumin has numerous biological functions, and many of these functions are related to induction of oxidative stress. However, how curcumin elicits oxidative stress in cells is unclear. Our previous work has demonstrated the way by which curcumin interacts with recombinant TrxR1 and alters the antioxidant enzyme into a reactive oxygen species (ROS) generator in vitro. Herein we reported that curcumin can target the cytosolic/nuclear thioredoxin system to eventually elevate oxidative stress in HeLa cells. Curcumin-modified TrxR1 dose-dependently and quantitatively transfers electrons from NADPH to oxygen with the production of ROS. Also, curcumin can drastically down-regulate Trx1 protein level as well as its enzyme activity in HeLa cells, which in turn remarkably decreases intracellular free thiols, shifting the intracellular redox balance to a more oxidative state, and subsequently induces DNA oxidative damage. Furthermore, curcumin-pretreated HeLa cells are more sensitive to oxidative stress. Knockdown of TrxR1 sensitizes HeLa cells to curcumin cytotoxicity, highlighting the physiological significance of targeting TrxR1 by curcumin. Taken together, our data disclose a previously unrecognized prooxidant mechanism of curcumin in cells, and provide a deep insight in understanding how curcumin works in vivo.     

Sister chromatid exchanges produced by imipramine and desipramine in mouse bone marrow cells treated in vivo

Imipramine and desipramine are two widely used tricyclic antidepressants which have shown conflicting results in regard to their in vitro genotoxic evaluation. The aim of this investigation was to determine the capacity of these compounds to induce in vivo sister-chromatid exchanges (SCEs) in mouse bone marrow cells. For each compound, the animals were organized in five groups constituted by five individuals. They were intraperitoneally (ip) administered with the test substances as follows: a negative control group treated with 0.4 ml of distilled water, a positive control group administered with cyclophosphamide (70 mg/kg), three groups treated with imipramine (7, 20 and 60 mg/kg), and three other groups treated with desipramine (2, 20 and 60 mg/kg). The general procedure included the subcutaneous implantation to each mouse of a 5-bromodesoxyuridine tablet (45 mg), and 1 h later, the administration of the chemicals involved. Twenty-one hours after the tablet implantation, the mice received colchicine, and 3 h later their femoral bone marrow was obtained in KCL, fixed, and stained with the Hoechst-Giemsa method. The results showed that both compounds were SCE inducers, starting from the second tested dose. The response of these compounds was dose-dependent, and showed that the highest tested dose increased about four times the SCE control level. The cellular proliferation kinetics was not affected by the chemicals, and the mitotic indexes were slightly diminished with the highest dose. These results indicate an in vivo genotoxic potential for both chemicals, and suggest that it is pertinent to follow their evaluation in other models.     

Rituximab,Cyclophosphamide, Dexamethasone (RCD) regimen induces cure in WSU-WM xenograft model and a partial remission in previously treated Waldenstrom's macroglobulinemia patient

Waldenstrom's macroglobulinemia (WM) is an uncommon lymphoproliferative disease which remains incurable with current treatment protocols. We have previously established a permanent WM cell line, WSU-WM, which grows as a xenograft in severe combined immune deficient (SCID) mice. In this study, we investigated the antitumor effects of Rituximab (RTX), Cyclophosphamide (CTX), Dexamethasone (DEX) [RCD]-Regimen in vivo WSU-WM SCID xenograft and in a patient with WM. For the pre-clinical efficacy study, WSU-WM-bearing SCID mice were randomly assigned to receive RTX (150 mg/kg/inj, i.v., QDX5), CTX (90 mg/kg/inj, s.c. QDX5) as single agents or diluent. The combination group received RTX at 150 mg/kg/inj, QDX5; CTX at 150 mg/kg/inj, QODX3 and DEX at 1.0 mg/kg/inj, i.v., QDX5. Tumor growth inhibition (T/C), tumor growth delay (T - C), and log10 kill (net) for RTX and CTX were 24.5%, 37 days, 5.52 and 88%, 0.0 days, 0.0log10 kill, respectively. No cures were observed with either agent; however, all mice (6/6, with bilateral tumors) were cured when treated with RCD-regimen. A 57-year-old patient with relapsed WM was treated with the RCD-regimen and showed an excellent partial remission for seven months. The patient tolerated the treatment very well, the hemoglobin improved dramatically, platelets remained stable, the IgM level normalized and there was only minimal involvement of bone marrow. Based on these results, the RCD regimen is effective against WM and its activity should be further evaluated in clinical trials.     

Relationship between the effects of dexamphetamine on locomotion and on striatal [3H]GBR 12783 binding in vivo

In mice, low doses (1-2-4 mg/kg s.c.) of dexamphetamine stimulated locomotor activity in a dose-dependent manner. Over the same range of doses the drug dose dependently inhibited the in vivo striatal binding of the dopamine uptake inhibitor, [3H]GBR 12783. At 3 mg/kg dexamphetamine, the stimulant effect and the inhibition of the striatal binding of [3H]GBR 12783 displayed a similar time course. Pretreatments that either increased (L-DOPA 200 mg/kg, benserazide 50 mg/kg i.p.) or decreased (reserpine 5 mg/kg s.c., alpha-methyl-p-tyrosine 200 mg/kg) striatal dopamine levels did not modify the inhibition by dexamphetamine of [3H]GBR 12783 binding in vivo. This suggests that the inhibition is due to a direct effect of dexamphetamine, not mediated by endogenous dopamine, and further that a unique site is responsible for the neuronal uptake of dexamphetamine and for the binding of pure dopamine uptake inhibitors.