In vivo toxicity and antitumor activity of mangosteen extract

Mangosteen (Garcinia mangostana) has been widely used in the traditional medicine of Thailand to treat various ailments, especially diseases of the digestive system and infections. Many reports show antiproliferation of crude extracts and active constituents from mangosteen against many cancer cell lines. Therefore, the current study is proposed to demonstrate in vivo evidence on the antitumor activity of mangosteen. Crude methanolic extract (CME) from mangosteen pericarp including 25.19 % α-mangostin as an active xanthone was used in this study. The inhibition on tumor cell proliferation of CME was preliminarily evaluated against the murine colon cancer cell line NL-17 with an IC₅₀ value of 17 and 84 μg/ml based on WST-1 and LDH assays, respectively. The safety dose for animal application was assessed by in vivo toxicity studies using female BALB/c mice. Acute toxicity showed an LD₅₀ value and approximate lethal dose at 1,000 mg/kg, whereas the suitable dose for short-term study should be ≤200 mg/kg. The effective dose for antitumor activity of CME was found to be between 100 and 200 mg/kg, with a tumor size reduction of 50–70 %. Histological staining clearly illustrated a decrease of tumor cell density in the footpad in a dose-dependent manner. The median survival time and life span significantly increased in tumor-bearing mice with CME treatment. This study suggests that CME possesses a powerful antitumor activity. Therefore, it is worth undertaking further investigation to identify active compounds and obtain a deeper understanding of their mechanism, in order to acquire novel effective anticancer drugs.     

抗菌肽的抗肿瘤作用研究新进展

抗菌肽是一类广泛存在于生物体内的天然小分子多肽,它是机体免疫系统的天然组分,具有抗菌、抗炎及抗病毒等作用.许多抗菌肽具有抗肿瘤活性,而且在细胞选择性和耐药性方面也拥有独特的优势.本文综述抗菌肽的抗肿瘤机制及应用.     

alpha-fluoro-beta-alanine: effects on the antitumor activity and toxicity of 5-fluorouracil

We have shown previously that (R)-5-fluoro-5,6-dihydrouracil (FUraH(2)) attenuates the antitumor activity of 5-fluorouracil (FUra) in rats bearing advanced colorectal carcinoma. Presently, we found that alpha-fluoro-beta-alanine (FBAL), the predominant catabolite of FUra that is formed rapidly via FUraH(2), also decreased the antitumor activity and potentiated the toxicity of FUra. In rats treated with Eniluracil (5-ethynyluracil, GW776), excess FBAL, in a 9:1 ratio to FUra, produced similar effects when administered 1 hr before, simultaneously with, or 2 hr after FUra. FBAL also decreased the antitumor activity of FUra in Eniluracil-treated mice bearing MOPC-315 myeloma at a 9:1 ratio with FUra, but not at a 2:1 ratio. FBAL did not affect the antitumor activity of FUra in mice bearing Colon 38 tumors. We also evaluated the effect of thymidylate synthase (TS) and thymidine kinase (TK) from tumor extracts after FUra +/- Eniluracil +/- FBAL treatment. The activity of TK was similar among the three groups at both 18 and 120 hr. There was also no difference in TS inhibition ( approximately 35%) at 18 hr. However, significantly more TS inhibition was observed in the Eniluracil/FUra group than in the FUra-alone group at 120 hr. FBAL did not alter the effect of Eniluracil/FUra in TS inhibition. Neither FUraH(2) nor FBAL affected the IC(50) of FUra in culture. Thus, the effect of FBAL did not result from direct competition with FUra uptake or immediate anabolism. Either another downstream catabolite that is not formed in cell culture is the active agent, or the effect requires the complexity of a living organism or an established tumor.     

Studies on the antitumor activity ofDuchesnea indicae Herba

As a part of finding the biologically active components fromDuchesnea indica (Andr.)Focke (Rosaceae), antitumor activities of its water soluble fractions have been studied. The fractions were examined for antitumor activity against sarcoma 180 implanted in mice. The antitumor inhibition ratios of the water soluble fractions fromDuchesnea indica were 17.9, 37.1, 62.7, 60.1, 62.4%, respectively.     

The effect of L-3, 4-dehydroproline on the antitumor activity and toxicity of bleomycin

Pulmonary fibrosis is a serious side effect that limits the therapeutic utility of bleomycin (BLM). Recently, it has been demonstrated that L-3, 4-dehydroproline (DHP), a proline analog, significantly reduced the extent of pulmonary fibrosis in rats administered BLM intratracheally. The present studies were performed to determine the effect of DHP on the oncolytic and toxicologic effects of BLM. DHP (25 mg/kg/day) administered sc concomitantly with BLM (4 mg/kg/day) for 9 consecutive days following a sc inoculation of B16 melanoma cells in BDF1 had no effect on tumor growth inhibition by BLM when tumor growth rate was assessed by tumor volume and by tumor weight. To determine the effect of DHP on the toxicity of BLM, DHP (25 mg/kg/day) and BLM (10 mg/kg/day) were administered to Sprague-Dawley rats for 5 consecutive days followed by 2 days of rest and 5 additional days of drug administration. BLM administration produced decreased body weight gain, acute leukocytopenia, delayed elevation in blood nitrogen levels, chronic lung and kidney disease, and alopecia. Animals administered BLM plus DHP had a similar toxicologic profile. One striking difference was that no animal administered BLM plus DHP developed alopecia, whereas five of eight rats administered BLM alone displayed this untoward effect. These results suggest that DHP neither diminishes the oncolytic activity nor exacerbates the nonpulmonary toxicity of BLM, DHP would appear, therefore, to be a potential candidate as an antifibrotic adjunct to BLM therapy.     

烯二炔类大分子抗肿瘤抗生素C1027抗菌与抗肿瘤活性差异的研究

Ｃ１０２７具有极强杀伤肿瘤细胞活性,作用靶点在ＤＮＡ,但Ｃ１０２７ 的抗菌活性不强,如能了解差别出现的原因,就可进一步掌握Ｃ１０２７的抗菌作用机制,并为将来在临床上确定其应用范围打下良好基础。对Ｃ１０２７ 的抗肿瘤活性与抗菌活性的差异的初步研究结论如下：大分子Ｃ１０２７ 与小分子博莱霉素Ａ５ 相比,对肿瘤细胞抑制作用明显高于后者;对细菌的抑制作用却明显低于博莱霉素Ａ５;对支原体的抑制作用略大于博莱霉素Ａ５ 。Ｃ１０２７（１００～０．０１ｍ ｇ／Ｌ）对大肠埃希氏菌Ｂ原生质体ＤＮＡ合成几乎无抑制作用,同对大肠埃希氏菌Ｂ菌体的ＤＮＡ合成抑制作用相比,差别不大。细胞壁并非阻碍Ｃ１０２７损伤大肠埃希氏菌ＢＤＮＡ的主要因素。     

甘露醇和苯甲酸钠对阿霉素毒性和抗肿瘤活性的影响

甘露醇和苯甲酸钠对阿霉素毒性和抗肿瘤活性的影响曹兆丰，张尚明，王秋菊，罗玲，户万秘，崔学增（华北煤炭医学院免疫病理及细胞毒理研究室，唐山０６３０００）阿霉素（ｄｏｘｏｒｕｂｉｃｉｎ，Ｄｏｘ）作为多种恶性肿瘤的主要化疗药物已得到广泛应用，但由于其对心脏...     

Effect of deoxyuridine coadministration on toxicity and antitumor activity of fluorouracil and floxuridine.

The addition of deoxyuridine (UDR) to fluorouracil (FU) or floxuridine (5-fluoro-2' deoxyuridine) (FUDR) produced a substantial increase in their toxicity in BDF1 mice. Antitumor assays using sarcoma 180 tumor-bearing mice showed a concomitant increase in tumor growth inhibition for the nucleoside-drug combination over identical doses of the single drug. However, no significant increase in antitumor activity with the combination treatment was demonstrated when equitoxic doses were given. Additional support for the therapeutic equality of the single and combination drug regimens was the similarity of the therapeutic indexes for each treatment regimen involving either fluorouracil or floxuridine. The results suggested that any therapeutic benefit achieved with the combination therapy could be duplicated with either fluorouracil or floxuridine at a higher dose.     

Aminopterin—Monoclonal antibody conjugates: antitumor activity and toxicity

Drug-antibody conjugates are undergoing close scrutiny as new antitumor agents because they confer increased drug specificity, producing higher accumulation in the tumor and less systemic toxicity than free drug. Consequently this has led to the use of drugs more toxic than those that can normally be used. How-ever, contrary to these conclusions immunoconjugates containing aminopterin (AMN), while having potent antitumor activity, are more toxic than free drug. AMN, a more toxic analog of the folic acid antagonist methotrexate (MTX), was coupled to the anti-Ly-2.1 antibody and the in vivo activity of the conjugate was tested against the Ly-2.1⁺ murine thymoma ITT(1)75NS E3 (E3). The aminopterin conjugates had molar ratios of 4-6 residues of AMN per MoAb molecule and retained 50% of the original antibody activity. A single dose of 75 μg AMN-anti-Ly-2.1 inhibited tumor growth by 30% and injection of 105 μg AMN-MoAb conjugate, in three doses, caused 63% tumor growth inhibition. Considerably higher doses of free AMN are required to produce similar tumor inhibition. Injection of 90 μg AMN-anti-Ly-2.1 or 900 μg free AMN produced signs of toxicity or death in the mice. Hematological examination revealed severe depletions in white blood cell (control, 7.71 × 10³/μl; AMN, 3.39 × 10³/μl; and AMN-anti-Ly-2.1, 1.29 × 10³/μl and platelet (control, 501.6 × 10³/μl; AMN, 234.7 × 10³/μl; and AMN-anti-Ly-2.1, 157.1 × 10³/μl) numbers for free and conjugated forms of AMN. Histological and hematological examinations indicate that there are similar sites of toxicity after AMN and AMN-MoAb conjugate treatment. The studies showed that the AMN-anti-Ly-2.1 conjugate is a potent antitumor agent and is capable of reducing the growth of subcutaneous tumors.     

CC-1065 analogues bearing different DNA-binding subunits: synthesis,antitumor activity,and preliminary toxicity study

CC-1065 analogues bearing different DNA-binding subunits were synthesized. A terminal C5-NO2 and -F moiety at the DNA-binding subunit increased the drug's potency and antitumor efficacy. A C5-OCH3 reduced the potency and antitumor efficacy. Compound (+/-)-7, bearing a trans double bond, had increased antitumor efficacy. A preliminary toxicity study indicated that terminal C5-OCH3 and -acetamido moieties at the DNA-binding subunit caused delayed death in mice.     

不同粒径炉甘石体外抑菌作用的研究

目的:比较200、300、400、500、1000目粒径炉甘石体外抑菌活性的差异.方法:采用激光粒度分析仪对炉甘石进行粒径分布分析;采用表面及孔径分析仪测定炉甘石的相关物理性质;用微量稀释法比较不同粒径炉甘石对供试菌的体外抑菌活性和最低抑菌浓度.结果:不同粒径炉甘石均有抑菌效果,其中1000目粒径炉甘石抑菌效果相对较好.结论:粒径越小、越均匀、粒径分布范围越窄,抑菌活性越强.     

新型查尔酮类化合物的合成及其抗肿瘤活性

目的 设计并合成新型查尔酮类化合物, 初步评价其体外抗肿瘤活性。方法 以2,4-二羟基苯乙酮为原料,经酚羟基烷基化、氯甲基化、氮烷基化、 羟醛缩合 4 步反应合成目标化合物。以A-549(人肺腺癌细胞株)、SGC-7901(人胃癌细胞株)、SW-1990(人胰腺癌细胞株)、MCF-7(人乳腺癌细胞株) 4 种肿瘤细胞为测试细胞株, 采用 MTT 法测定目标化合物的抗肿瘤活性。结果与结论 合成了 16 个新型查尔酮类化合物, 其结构经 ¹H-NMR 谱确证。体外抗肿瘤活性数据表明: 合成的目标化合物具有较好的抗肿瘤活性, 可进行更深入的研究。     

Novel polyazaheterocyclic systems: Synthesis,antitumor, and antimicrobial activities

A series of new polyazaheterocyclic ring systems was synthesized via the reaction of enaminone 5 with active methylene compounds, hydrazine hydrate, hydroxylamine, and heterocyclic amines. The structures of the newly synthesized compounds were substantiated on the basis of spectral data and elemental analyses. The antitumor activity of the enaminone 5 against the human breast cell line MCF-7, the liver carcinoma cell line HEPG2-1, and HELA cells was determined. In addition, the antimicrobial activity of some selected products was evaluated.