Antitumor effects of 5-fluorouracil-bound organic silicon compound

5-fluoro-3,4-dihydro-2,4-dioxo-N-[2-2- (dimethylphenylsilyl)ethylthioethyl]-1(2H)-pyrimidinocarb oxamide (SDK-12B-5), a novel antitumor agent, is covalently linked with 5-fluorouracil (5-FU) and 2-[(2-dimethylphenylsilyl)ethylthio] ethylamine(SDK-103) which possesses itself antitumor activity against murine solid tumors. It has a broad antitumor spectrum in experimental tumor systems including murine leukemias. Furthermore, SDK-12B-5 administered p.o. with various treatment schedules inhibited significantly the tumor growth of human breast cancer (MX-1), colon cancer (Co-4) and lung cancer (LX-1 and OAT) cells in BALB/c nu/nu mice and the chemotherapeutic index was about 10 for 4 different human cancer xenografts. In the Lewis lung carcinoma (LLC) metastasis model, SDK-12B-5 in combination with amputation of tumors inhibited significantly both the lymph node metastases and lung metastases of LLC and prolonged the life span (%ILS:91%) of BDF1 mice. We also found that the cell killing effect of SDK-12B-5 was affected by both concentration and exposure time in cultured human lung cancer (OAT) cells using soft-agar colony assay. A significant augmentation of delayed type hypersensitivity (DTH) response induced by SDK-12B-5 in comparison with the mixture of SDK-103 and 5-FU was seen when it was administered p.o. simultaneously with the immunization of sheep red blood cell (SRBC) in retired CD1 mice. From the studies on tissue distribution and pharmaco-kinetics of SDK-12B-5 by HPLC and ICP analysis. the persistence of SDK-12B-5 levels in serum and tumors was correlated with the findings that a maximum chemotherapeutic effect was obtained when SDK-12B-5 was administered p.o. repeatedly with every other day to avoid the cumulative toxicity.     

叶绿酸抗肿瘤作用及其机制的研究

叶绿酸是通过水解叶绿素去除疏水性叶绿植醇侧链而获得的一种水溶性的衍生物.它经大量试验显示具有很强的抗诱变性和较好的抗肿瘤作用.其机制涉及叶绿酸抑制致癌物DNA加合物的形成,调节生物转化系统代谢酶水平及活性,抗氧化活性和清除自由基活性,调控细胞周期等方面.它在肿瘤防治中显示了良好的应用前景.综述叶绿酸抗肿瘤作用及其机制,肿瘤防治中的应用,并提出目前开展的研究和将来需探索的方向.     

Carcinogenic effects of ptaquiloside in bracken fern and related compounds

Consumption of the bracken fern Pteridium aquilinum by cattle has been shown to induce bladder and intestinal carcinomas in cattle and to cause a number of diseases in other farm animals. An unstable glucoside named ptaquiloside, containing a reactive cyclopropane ring, has been isolated from the fern and its potent carcinogenicity proven. Nineteen of 31 ferns tested by chemotaxonomic methods in Japan have been found to contain potentially carcinogenic ptaquilosides as have Cheilanthes sieberi and Pteridium esculentum. Hydrolysis of ptaquilosides leads to pterosins; under milder conditions a dienone which is believed to be the primary carcinogen is obtained. Hypacrone, a sesquiterpine containing a reactive cyclopropane ring, has been isolated from Hypolepis punctata and its structure proved by synthesis. Illudins, structurally similar to ptaquiloside, have been isolated from the basidiomycete Omphalotus illudens. These give anti-tumour activity and similar reactivity with nucleophiles to ptaquiloside. Compound CC-1065, a highly toxic antibiotic also containing a cyclopropane ring, has been isolated from Streptomyces zelensis. The mechanism of its reactivity with DNA has been compared to that of ptaquiloside and the small structural differences between carcinogenic and anti-tumour activity discussed. Both CC-1065 and adozelesin, a synthetic analogue with anti-tumour activity, have been shown to alkylate the N-3 atom of adenine in a certain sequence of DNA. The reactivity of cysteine with ptaquilosides and illudins is discussed, as is the role of cysteine alkylating agents in apoptosis.     

Cancer chemopreventive effects of constituents of Caesalpinia ferrea and related compounds

The anti-tumor promoting effects of fruits of Caesalpinia ferrea MART. (Leguminosae) were tested by the in vitro Epstein-Barr virus early antigen (EBV-EA) activation assay, and its active constituents were identified as gallic acid (1) and methyl gallate (2). A total of 49 related compounds of 1 and 2 were analysed for the effects by this assay, and the structure activity relationships have been proposed. Three acetophenone derivatives, 2,6-dihydroxyacetophenone (48), 2,3,4-trihydroxyacetophenone (50) and 2,4,6-trihydroxy- acetophenone (51) were found to show potent inhibitory activity.     

Marine pharmacology in 2000: antitumor and cytotoxic compounds

During 2000, marine antitumor pharmacology research aimed at the discovery of novel antitumor agents was published in 85 peer-reviewed articles. The purpose of this article is to present a structured review of the antitumor and cytotoxic properties of 143 marine natural products, many of them novel compounds that belong to diverse structural classes, including polyketides, terpenes, steroids and peptides. The organisms yielding these bioactive compounds comprised a taxonomically diverse group of marine invertebrate animals, algae, fungi and bacteria. Antitumor pharmacological studies were conducted with 19 marine natural products in a number of experimental and clinical models that defined or further characterized their mechanisms of action. Potentially promising in vitro cytotoxicity data generated with murine and human tumor cell lines were reported for 124 novel marine chemicals with as yet undetermined mechanisms of action. Noteworthy is the fact that marine anticancer research clearly remains a multinational effort, involving researchers from Austria, Australia, Brazil, Canada, England, France, Germany, Greece, Indonesia, Italy, Japan, New Zealand, Russia, Spain, South Korea, Switzerland, Taiwan, the Netherlands and the United States. Finally, this 2000 overview of the marine pharmacology literature highlights the fact that the discovery of novel marine antitumor agents continued at the same high level of research activity as during 1998 and 1999.     

Cardiotoxic effects of antitumor agents

Summary Cardiotoxic effects related to treatment with some antitumor agents (chiefly anthracycline antibiotics, cyclophosphamide, corticosteroids, 5-fluorouracil, and radiation therapy), their association, and contemporaneous administration of other (potentially) cardiotoxic drugs are reviewed.Experimental models, clinical findings, and diagnostic methods are briefly described.Pathogenetic factors and interactions of antitumor drugs with biomembranes, DNA, and immune reactions are discussed.Montedison-Pharmaceutical Division     

The antitumor effects of interferon

Interferons show antitumor activity in patients with various malignancies. The mechanism(s) of the antitumor effects are not altogether clear. In one experimental animal model discussed herein, mice were injected with Friend erythroleukemia cells and treated with mouse interferon alpha/beta. The results suggest that interferon does not act directly on the tumor cells but acts via host mechanisms that are still ill defined.     

Inhibition of carcinogenic effects of polycyclic hydrocarbons by benzyl isothiocyanate and related compounds.

Benzyl isothiocyanate and phenethyl isothiocyanate, two compounds found in cruciferous plants, and phenyl isothiocyanate, a synthetic compound, all inhibit 7,12-dimethylbenz[a]anthracene (CMBA)-induced mammary tumor formation in female Sprague-Dawley rats when administered 4 hours prior to the DMBA. Comparable studies in which benzyl isothiocyanate was administered 24 hours before or 4 hours after DMBA showed almost complete loss of inhibition. Additions of benzyl isothiocyanate or phenethyl isothiocyanate to a diet containing CMBA inhibited formation of neoplasms of the forestomach and pulmonary adenomas in female ICR/Ha mice. Addition of benzyl isothiocyanate to a diet containing benzo[a]pyrene also inhibited carcinogenesis of the mouse forestomach due to this carcinogen. The finding of two additional anutrient dietary compounds which inhibit chemical carcinogenesis focuses on the possibility that dietary constituents of this nature may diminish the impact of exposures to chemical carcinogens.     

Selective effects of Lipiodolized antitumor agents

Lipiodol Ultra-Fluid (Lipiodol) remains selectively in the tumor for an extended time when applied through arteries feeding the tumor. Although lipophilic antitumor drugs are selective when combined with Lipiodol, wide application of common hydrophilic agents is limited, as these compounds are insoluble in oil. We propose "Lipiodolization" of water-soluble agents using as an intermediate Urografin, a water-soluble contrast medium. Thirteen patients with primary hepatocellular carcinoma were treated with this Lipiodol-Urografin system containing antitumor agents. Marked decrease in serum alpha-fetoprotein (AFP) levels, decrease in tumor size in the hepatic imaging, and histologic studies of the resected specimen revealed this mode of therapy to be effective in 10 of 13 patients (77%) with hepatocellular carcinoma. Lipiodolization of antitumor agents is a new approach to selective cancer chemotherapy.     

Exposure of mouse skin to organic peroxides: subchronic effects related to carcinogenic potential

Screening of newly synthesized organic peroxides for tumor initiating/promoting activity would be greatly facilitated if predictive methodologies could be developed using topical exposures shorter than those required for definitive tumor assessment in mouse skin models. Nine organic peroxides [benzoyl peroxide (BZP), di-t-butyl peroxide (DTBP), t-butyl peroxybenzoate (TBPB), p-t-butyl isopropylbenzene hydroperoxide (TBIBHP), cumene hydroperoxide (CHP), dicetyl peroxydicarbonate (DPD), dicumyl peroxide (DCP), methyl ethyl ketone peroxide (MEKP) and O,O-t-butyl-O-(2-ethylhexyl) monoperoxycarbonate (TBEC)] were evaluated for their ability to increase biomarkers of tumor promotion in mouse skin, i.e. sustained epidermal hyperplasia, dermal inflammation and oxidative DNA damage. Evaluations were performed using SENCAR mice exposed topically for 4 weeks. The organic peroxides varied in their effects on these biomarkers. BZP, TBPB and TBIBHP exhibited significant increases in all three biomarkers associated with tumor promoting activity, CHP produced increases only in sustained epidermal hyperplasia and dermal inflammation, MEKP and DCP produced increases only in sustained epidermal hyperplasia and TBEC produced an increase only in dermal inflammation. DTBP and DPD had no effect on the three parameters studied. TBPB and TBIBHP were selected for further examination of their ability to produce mutations in codons 12, 13 and 61 of the c-Ha-ras protooncogene, i.e. those mutations known to be involved in the initiation of mouse skin tumors, because they were the only peroxides to exhibit significant positive results in all assays except the Ha-ras mutation following 4 weeks of exposure. Evaluations were performed using SENCAR mice dosed topically for 8 or 12 weeks in a complete carcinogenesis protocol or 16 weeks in an initiation/promotion protocol using 7,12-dimethylbenz[a]anthracene, urethane, benzo[a]pyrene and N-methyl-N'-nitro-N-nitrosoguanidine as positive controls. Neither TBPB nor TBIBHP produced detectable mutations in the c-Ha-ras protooncogene, indicating that they are not likely to possess tumor initiating or complete carcinogenic activity.     

Suramin: prototype of a new generation of antitumor compounds

Suramin is a polysulfonated compound originally developed nearly 75 years ago for use as a trypanocidal agent. Recent studies indicate that suramin can also disrupt mammalian cell function, notably by blocking growth factor--receptor interactions and by inhibiting the activity of enzymes that are critical for cell growth and proliferation. These observations, together with the finding that clinically achievable concentrations of the drug are toxic to many human tumor cell lines, have prompted clinical investigations of suramin's efficacy as an antitumor agent. This review considers the possible mechanisms that may underlie suramin's cytotoxic effects and discusses ongoing clinical trials in cancer patients.     

丙戊酸抗肿瘤作用研究进展

丙戊酸(VPA)是目前临床上广泛应用的广谱抗癫痫药,近年来发现它同时还是组蛋白去乙酰化酶抑制剂(HDACI).大量实验研究表明,丙戊酸可以通过诱导细胞周期停滞、凋亡和分化以抑制肿瘤细胞生长增殖,同时还具有抑制肿瘤血管生成和转移作用.丙戊酸的长半衰期和较好的生物利用性以及较低的有效药物浓度,使其作为一种新型抗癌药物有着更好的开发利用前景.     

丙戊酸抗肿瘤作用研究进展

丙戊酸（VPA）是目前临床上广泛应用的广谱抗癫痫药,近年来发现它同时还是组蛋白去乙酰化酶抑制剂（HDACI）.大量实验研究表明,丙戊酸可以通过诱导细胞周期停滞、凋亡和分化以抑制肿瘤细胞生长增殖,同时还具有抑制肿瘤血管生成和转移作用.丙戊酸的长半衰期和较好的生物利用性以及较低的有效药物浓度,使其作为一种新型抗癌药物有着更好的开发利用前景.     

呼气挥发性有机物检测在癌症诊断中的应用

 挥发性有机化合物(VOC)是一类在常温下以蒸汽形式存在的有机物。人体内多种代谢及氧化应激反应可产生内源性VOC,它们通过血流最终到达肺部并排出体外。各种研究表明,人体处在癌症、炎症等病理状态下,呼气中VOC成分会产生显著变化。应用敏感度极高的仪器对其检测,不仅有可能在早期发现疾病,还能做到检查的无创和便捷,减少患者痛苦。因此,呼气VOC检测在肺癌等肿瘤性疾病的早期诊断中具有广阔的应用前景。     

Evaluation of antitumor drug side effects in small animals

Summary This is an initial report on the development of screening tests for side effects of antitumor drugs, with small amounts of compound and short time intervals. These tests are based on acute dosing of mice and various blood or serum measurements: (a) total white blood cell count for leukopenia; (b) BUN for kidney toxicity; (c) SGPT for liver toxicity; and (d) creatine phosphokinase MB isozyme (CPK-MB) for cardiotoxicity. A correlation with the toxicity observed in other species is developed by establishing the effect of a prototype compound for each toxicity and tests of one or more compounds expected to lack such toxicity. On the basis of the limited number of compounds studied all four tests, although varying in sensitivity, seem to correlate with the results of tests in other species and with known effects in man. Final validation of these acute tests, especially the CPK-MB, will require both further study of histopathologic effects and correlation with results from clinical trials of an extended list of agents.     

Protective effects of propolis and related polyphenolic/flavonoid compounds against toxicity induced by irinotecan

Despite the excellent chemotherapeutic effect of irinotecan, its cytotoxicity and genotoxicity in normal cells remains a major problem in chemotherapy. This study was carried out to find whether propolis preparations and related flavonoids (quercetin, naringin) might enhance irinotecan-induced cytotoxicity to tumor cells in mice bearing Ehrlich ascites tumors (EAT) while protecting normal blood, liver, and kidney cells. The preparation of propolis and their flavonoids were given to mice intraperitoneally at a dose of 100 mg kg⁻¹ body weight for three consecutive days before the ip injection of EAT cells (2 × 10⁶). Irinotecan was administered ip at dose of 50 mg kg⁻¹ on days 3, 4, and 5 after tumor cell inoculation. The combination treatment resulted in substantial inhibition of the growth of EAT cells as well as treatment with quercetin or irinotecan alone, whereas other treatment by itself showed little effect. However, when mice were pre-treated with test components prior to irinotecan, the frequencies of irinotecan-induced micronuclei (MN) was decreased but in mice bearing tumor QU and EEP increased number of micronucleated cells. Propolis preparation and related flavonoids were found to exhibit an important immunomodulatory effect and could decrease irinotecan-induced toxic and genotoxic effects to normal cells without effecting irinotecan cytotoxicity in EAT cells.     

消乳岩丸抗肿瘤作用的体外试验研究

用MTT法测定消乳岩丸对 5株人肿瘤细胞系的抑瘤作用。结果消乳岩丸对 5株人肿瘤细胞系均有不同程度的抑瘤作用 ,有明显量效关系。高剂量组有较高抑制作用 ,GLC、MCF 7、KB、宫 -743和MGC 80 3的抑制率分别为69 17%、81 77%、62 72 %、77 92 %和 81 43 %。初步研究结果提示 ,中药消乳岩丸体外对人肿瘤细胞有较高的抑瘤作用。