Antitumor activity of phenylahistin in vitro and in vivo.

Phenylahistin is a new cell cycle inhibitor produced by Aspergillus ustus. Since phenylahistin was produced as a scalemic mixture of (-)-phenylahistin and its enantiomer, we separated each enantiomer and evaluated their antitumor activity in vitro. (-)-Phenylahistin exhibited antitumor activity against 8 tumor cell lines with IC50 values ranging from 1.8 x 10(-7) to 3.7 x 10(-6), while (+)-phenylahistin exhibited 33-100-fold less potent activity than (-)-phenylahistin did. (-)-Phenylahistin also showed antitumor activity against P388 leukemia and Lewis lung carcinoma cells in vivo.     

Antitumor properties of vindesine-monoclonal antibody conjugates

Summary The anticancer alkaloid vindesine (VDS) was conjugated to four mouse monoclonal antibodies recognizing human tumor-associated antigens. The antibodies were 96.5 (antimelanoma, IgG2a); 791T/36 (antiosteogenic sarcoma, IgG2b); 11.285.14, and 14.95.55 (anticarcinoembryonic antigen, IgG1 and IgG2a respectively). Conjugates VDS-96.5 and VDS-791T/36 were tested in vitro and shown to be specifically cytotoxic for target cells expressing the appropriate antigen. The in vivo effects of the antibodies and conjugates were tested against human tumor xenografts in athymic or immunodeprived mice using multiple treatments. Conjugate VDS-96.5 retarded the initial growth of a melanoma xenograft, whereas free antibody was without effect. Similarly, VDS-791T/36 but not free antibody retarded the growth of osteogenic sarcoma 791T. The most marked antitumor effects observed were those obtained with VDS conjugates of the anti-CEA antibodies against a colorectal tumor xenograft. Antibody 14.95.55 suppressed tumor growth both alone and as a VDS conjugate, whereas 11.285.14 produced only a slight effect alone but an almost complete and lasting suppression of tumor growth as a VDS conjugate. Free VDS had little effect at nontoxic levels. Acute studies showed that VDS-11.285.14 conjugate was considerably less toxic than free VDS in Balb/c mice.     

Antitumor properties of some titanocene chalcogenates

Five chalcogen-coordinated bis(η⁵-cyclopentadienyl)titanium(IV) chalcogenolates were tested against fluid Ehrlich ascites tumor for antitumor properties: the titanocene phenolates (C₅H₅)₂TiCl(2,4,6-OC₆H₂Cl₃) (I) and (C₅H₅)₂Ti(OC₆F₅)₂ (II); the titanocene thiophenolate (C₅H₅)₂Ti(SC₆F₅)₂ (III); the titanocene dithiolene chelate (C₅H₅)₂Ti[cis-1,2-S₂C₂ (CN)₂] (IV); and the titanocene selenophenolate (C₅H₅)₂TiCl(SeC₆H₅) (V). The best antitumor activity and an optimum cure rate of 100% were observed in the case of the pentafluorophenyl derivatives II and III, followed by IV and V which induced cure rates of 90 and 80% respectively. These results confirm that bis(η⁵-cyclopentadienyl)titanium(IV) diacido complexes can be widely varied at the position of the acido ligands without loss of antitumor potency. The titanocene derivatives described in the present study are the first neutral mercapto and seleno titanocene derivatives for which strong antiproliferative properties have been shown.     

Cysteinyl leukotrienes mediate histamine hypersensitivity ex vivo by increasing histamine receptor numbers

BACKGROUND: Hyperresponsiveness to histamine is a key feature of a variety of pathological conditions, including bronchial asthma, food allergy, colitis ulcerosa, and topical allergic disorders. Cells isolated from hyperresponsive individuals do not display exaggerated histamine responses ex vivo and thus the molecular mechanisms underlying histamine responsiveness remain obscure. Importantly, several in vivo observations implicate cysteinyl leukotrienes as possible mediators of increased histamine responses. We decided to investigate whether cysteinyl leukotrienes enhance the cellular reaction to histamine in cell types involved in pathological and immunological histamine hyperresponsiveness, as this might provide an in vitro system for studying histamine responsiveness and could shed light on the underlying molecular mechanisms. MATERIALS AND METHODS: Histamine responsiveness was determined by measuring histamine-induced prostaglandin E(2) production. Scatchard analysis was performed to determine the number of histamine H(1) receptors. Mouse macrophages, primary isolated human peripheral blood monocytes, and human umbilical smooth muscle cells were investigated before and after cysteinyl leukotriene stimulation. Results: In all three cell types tested, cysteinyl leukotrienes instantaneously enhanced histamine-induced prostaglandin E(2) production. This increase in prostaglandin E(2) production coincided with the immediate and transient appearance of additional H(1) receptors on the plasma membrane. CONCLUSIONS: Cysteinyl leukotrienes prime histamine responses by recruiting additional histamine receptors in immunologically relevant cell types in vitro.     

Localization of tritium from histamine in gastric mucosa in vivo

Summary Radioactivity from ³H-histamine administered to a young dog in vivo is taken up by gastric endocrine-like cells whose fine structure is similar to that of the Amine Precursor Uptake and Decarboxylating Cells. Endocrine-like cells in mouse stomach also take up radioactivity from histamine in vivo. A correlated light and electron microscope survey of canine stomach indicates that it is possible to differentiate varieties of gastric endocrinelike cells to some extent on the basis of their affinity for silver in osmium fixed, plastic embedded sections stained by a Bodian technique.Supported by UPHS Grant AM-03247 and Veterans Administration Program No. 594/ 01/9285. 1/69-01.A preliminary report of this work appeared in Surg. Forum 18: 1967.The technical assistance of Grace Yang and Jan Pittman is gratefully acknowledged.     

Antitumor activity of amides of dihydrobetulonic acid in vitro and in vivo

Amides containing homopiperidine and piperazine cycles were synthesized from dihydrobetulonic acid obtained by the oxidation of dihydrobetulin. All substances were shown to have a high antitumor activity (CCID₅₀ = 3.5–36.2 μM) in vitro in lymphoid (CEM-13, U-937) and monocytic (MT-4) human cell lines. Amides containing the methyl- and ethylpiperazine residues do not influence the viability of Lung Lewis Carcinoma cells in culture and do not have a significant effect on its transplants in C57BL/6 mice. However, these amides efficiently inhibit the development of metastases in lungs of these mice. The antimetastatic activity of the studied amides increases with changing the methyl by ethyl aliphatic residue in the piperazine cycle.     

Antitumor activity of alpha-fetoprotein conjugate with doxorubicin in vitro and in vivo

alpha-Fetoprotein (AFP) was conjugated with doxorubicin (DR) using glutaraldehyde as a cross-linking agent. The protein/DR molar ratio in the conjugate is 1 : 2. Cytotoxic activities (CTA) of the AFP-DR conjugate and of the free DR were compared using human mammary gland carcinoma cells, both DR-sensitive (MCF-7Wt) and DR-resistant (MCF-7AdrR). The CTA of the AFP-DR conjugate was fivefold higher than the CTA of the free DR for sensitive cells of the MCF-7Wt line and sevenfold higher for resistant cells of the MCF-7AdrR line. The CTA of the AFP-DR conjugate was also studied in vitro using the proliferating endothelium taken for a model of endothelial cell lining of blood vessels that supply the tumor. The AFP-DR conjugate was shown to have a high CTA for the endothelial cells (IC50 = 2.5 nM); thus, the conjugate is suggested to manifest an anti-angiogenic effect in vivo. The antitumor activity of the AFP-DR conjugate was studied using mice with inoculated melanoma B16 tumors. The treatment of animals significantly inhibited the tumor growth (>97%) and increased by 60% the mean life span of the animals compared to the control. The high antitumor efficiency of the AFP-DR conjugate and the possibility to significantly decrease the tumor cell resistance to DR make this conjugate a promising chemotherapeutic agent.     

Antitumor effects of IL-6 on murine liver tumor cells in vivo

IL-6 is a pleiotropic cytokine that is capable of modulating the diverse functions of hepatocytes such as acute phase responses and inflammation in the liver. To learn its antitumor effects in vivo, the cDNA of IL-6 was transfected into murine liver cells, TIB cells. IL-6-transfected TIB cells (TIB73-IL-6 or TIB75-IL-6) produced much higher levels of IL-6 compared with vector-transfected TIB cells (TIB73-vec or TIB75-vec). To investigate the effects of IL-6 on TIB tumor growth in vivo, IL-6-transfected TIB cells or vector-transfected TIB cells were injected subcutaneously into syngeneic mice. Vector-transfected TIB cells grew rapidly 3 weeks after injection, but IL-6-transfected TIB cells did not grow at all for up to 6 weeks. Pathologically, IL-6-transfected TIB cells demonstrated a severe necrosis and apoptotic pattern. Taken together, these results indicate that IL-6 functions as a growth inhibiting factor in vivo, and another biological role of IL-6 in the liver is suggested.     

新合成的7-氮杂异靛蓝的体内外抗肿瘤作用

对新合成的7-氮杂靛玉红类衍生物N1-(正–丁基)-7-氮杂异靛蓝[N1-(n-butyl)-7-azaisoindigo,7-AI-b]的体内外抗肿瘤作用的研究,为研发具有自主知识产权的靛玉红类抗肿瘤新药打下基础。以不同浓度的7-AI-b作用于肿瘤细胞,MTT法检测细胞活性;建立Heps肝癌荷瘤小鼠模型,评价7-AI-b的体内抗肿瘤作用;计算肝脏指数(liver index,LI)、胸腺指数(thymusindex,TI)、脾脏指数(spleen index,SI),评价化合物的毒副作用;紫外法检测小鼠血清丙二醛(malondialdehyde,MDA)、谷胱甘肽(glutathione,GSH)的含量;HE染色观察肿瘤组织的变化;试剂盒检测细胞周期激酶(cyclin-dependent kinases,CDKs)的活性。结果发现,7-AI-b抑制肿瘤细胞增殖的IC50值为28~40μmol/L,并以时间和剂量依赖性方式抑制A549细胞的增殖。7-AI-b对Heps肝癌具有抑制作用且抑瘤率达到61.85%,与5-Fu的相近;而7-AI-b对于小鼠的毒副作用明显小于后者,表现为体重正常增长,TI、SI和LI均无明显降低;等剂量的7-AI-b效果也明显优于靛玉红;并且7-AI-b能增强荷瘤小鼠的抗氧化能力,使得MDA水平降低,GSH水平升高。另外,7-AI-b对于正常肝细胞株WRL-68和肝癌细胞HepG-2的毒性作用有明显差别,即具有一定的肿瘤细胞选择性。然而,7-AI-b对CDK2/cyclinA的抑制作用较弱。由此,7-AI-b可有效地抑制肿瘤的生长,且毒副作用较小,其机制可能与抑制细胞周期激酶CDKs有关,所以7-AI-b可以作为新型抗肿瘤药物进行研究。     

Release of histamine and adrenaline in vivo following intravenous administration of neurotensin

Plasma histamine levels of rats anesthetized with pentobarbital sodium were significantly increased by intravenous administration of neurotensin (NT, 1 nmole/kg) with the maximum effect at 3 min, and a return to the initial levels in 20 min. Treatment of animals with compound 48/80 or disodium cromoglycate completely inhibited the elevation of histamine level by NT, however, treatment with reserpine or diphenhydramine and adrenalectomy did not affect the elevation. Plasma adrenaline levels increased transiently 1 min after NT injection, and adrenalectomy and treatment with compound 48/80 or diphenhydramine markedly reduced the elevation of adrenaline levels after NT injection. Plasma levels of noradrenaline were unchanged upon NT injection. These results provide direct evidence of the release of endogenous histamine and adrenaline following NT administration, and suggest the contribution of these amines to the NT-induced triphasic blood pressure responses (the first depressor, second pressor and third depressor responses) reported previously.     

Antitumor properties of nonstarch polysaccharides: Fucoidans and chitosans

This review deals with the pharmacology of nonstarch polysaccharides, namely fucoidans and chitosans, isolated from marine organisms. The work summarizes information from the international literature on the antitumor activities of native polysaccharides and their derivatives. The structures and physicochemical properties of these polysaccharides are described and the molecular mechanisms of their antitumor and antimetastatic effects are discussed.     

Antitumor properties of chemically detoxified killed Brucella abortus organisms

Summary Killed Brucella abortus organisms of the vaccinal strain B19 were detoxified by incubation in NaOH. A 24-h incubation in 0.01 M NaOH increased the LD₅₀ of smooth (S) and rough (R) organisms 2–3 times in normal mice and 50–100 times in adrenalectomized mice. This NaOH treatment did not alter the antitumor activity of Brucella abortus as shown in EL4 lymphoma- and Lewis carcinoma-grafted mice. After incubation in NaOH, S bacteria injected IV retained their ability to provoke spleen hypertrophy and antibody synthesis, and S and R organisms injected into he footpad had comparable ability to induce granulomas. NaOH treatment tended to diminish the mitogenic activity of R bacteria for spleen cell cultures.