Avermectins inhibit multidrug resistance of tumor cells

The modification of the sensitivity of Hep-2 and P388 tumor cells to taxol and vincristine, substrates of multidrug resistance proteins, by naturally occurring avermectins and the effect of avermectins on the accumulation of calcein in cells and the efflux of rhodamine 123 were studied. While avermectins did not affect the sensitivity of tumor cells to hydrogen peroxide and cisplatin, they significantly enhanced the sensitivity of cells of both wild-type and resistant strains to taxol and vincristine. The coefficients of modification for resistant strains were substantially higher. Avermectins suppressed the efflux of rhodamine 123 from cells and increased the accumulation of calcein in cells. The relative inhibitory activity of avermectins depended on the cell type and on the substrate of multidrug resistance proteins whose transport they suppressed (vincristine, taxol, rhodamine 123, calcein acetoxymethyl ester). The least active was avermectin B1 or ivermectin; the most active avermectins varied depending on the substrate and the cell type. In the case of vincristine transport, the most active avermectin was almost by one order of magnitude more effective than the traditional inhibitor of multidrug resistance cyclosporin A. This property of avermectins can be used in tumor therapy by combining application of avermectins with antitumor preparations, the substrates of multidrug resistance proteins.     

Azinomycins A and B, new antitumor antibiotics. III. Antitumor activity

Azinomycins A and B, isolated from the culture broth of Streptomyces griseofuscus S 42227, were examined for antitumor activities against P388 leukemia, P815 mastocytoma, B-16 melanoma, Ehrlich carcinoma, Lewis lung carcinoma and Meth A fibrosarcoma. Azinomycin B was markedly effective against the intraperitoneally inoculated tumors such as P388 leukemia, B-16 melanoma and Ehrlich carcinoma. The intraperitoneal administration of azinomycin B showed 57% survivors for 45 days and 193% ILS against P388 leukemia. For Ehrlich carcinoma, azinomycin B gave 161% ILS and 63% survivors for 45 days, but solid tumors such as Lewis lung carcinoma and Meth A fibrosarcoma were not susceptible to repeated injection of this substance. Azinomycin A was somewhat less effective than azinomycin B for the tumor systems tested.     

一些植物成分对实验肿瘤的作用

观察了18个植物成分对S180、Lewis肺癌、B16黑色素瘤、Ehrlich腹水癌、白血病P388、L1210和L615等小鼠肿瘤的疗效。以白血病P388和L1210最为敏感,L615最不敏感。此外,试验了高三尖杉酯碱、美登素、羟基喜树碱和长春新碱对Friend白血病的疗效,仅高三尖杉醋碱有明显疗效。部分样品还观察了对~3H标记的前体参入肿瘤细胞核酸和蛋白质的影响。     

Antitumor effects of royal jelly (RJ)

Antitumor effects of Royal Jelly (RJ) were investigated employing the transplantable tumors of mouse advance leukemia L1210 and P388 strains and Ehrlich, Sarcoma-180 ascites and solid tumor strains. RJ was administered orally in a prophylactic-therapeutic (30 days before and 30 days after the transplantations of tumor cells) or a therapeutic (30 days after the transplantations of tumor cells) manner. Tumor cells were transplanted i.p. (ascites tumor) or s.c. (solid tumor). The daily dose of RJ was 0 (control), 10, 100, or 1000 mg/kg. In the case of the therapeutic experiments employing advance leukemia L1210 and P388 strains, which gave quite a short survival period of 8 approximately 9 days, RJ did not show any antitumor effect. In the case of the therapeutic RJ application employing the Sarcoma-180 ascites tumor, which gave a moderate survival period of 16 days, the increased life span was 9.3 approximately 19.3%; and with the Ehrlich ascites tumor (survival period of 22.1 days), the increased life span was 20.4% (RJ 10 mg/kg . day) and 17.6% (RJ 1,000 mg/kg . day), but no antitumor effect was observed at the dose of 100 mg/kg . day. In the case of the therapeutic experiment employing Ehrlich solid tumor, tumor growth inhibition was 25.3 approximately 54.8%, where as the use of the prophylactic-therapeutic regimen gave a tumor growth inhibition of 38.3 approximately 45.7%. In the case of the therapeutic RJ application employing Sarcoma-180 solid tumor, tumor growth inhibition was 45.1 approximately 59.7%, where as the prophylactic-therapeutic regimen gave a tumor growth inhibition of 49.1 approximately 56.1%.(ABSTRACT TRUNCATED AT 250 WORDS)     

Synthesis and Cytotoxic Action of 3,5-Isoxazolidinediones and 2-Isoxazolin-5-ones in Murine and Human Tumors

The 3,5-isoxazolidinediones and 2-isoxazolin-5-ones demonstrated potent cytotoxicity against the growth of human Tmolt₃ T cell leukemia, murine P388 and L1210 leukemias, as well as human HeLa-S³ uterine carcinoma and glioma tumor cell growth. The specificity of the 3,5-isoxazolidinedione and 2-isoxazoline-5-one derivatives as cytotoxic agents varied with the histological type of tumor cell. Selected compounds were active against solid HeLa uterine, KB nasopharynx, skin A431, SW-480 adenocarcinoma, osteosarcoma and glioma growth. Selected compounds demonstrated in vivo antineoplastic activity against Ehrlich ascites carcinoma growth. In L-1210 leukemia cells, the agents blocked DNA and protein synthesis at 25,50 and 100 μM over 60 min. The agents were effective in reducing rate limiting enzymes in the de novo purine and pyrimidine pathways. In addition they suppressed dihydrofolate reductase and ribonucleoside reductase activities with moderate inhibition of DNA and RNA polymerase activities. DNA itself was not a target of the agents.     

9-Hydroxybenfluron: effect on energy-yielding processes in Ehrlich ascites and P388 murine leukemia cells.

The main purpose of the present investigation was to study the effect of 9-hydroxybenfluron (HBF) on aerobic glucose consumption, lactic acid formation, content of total (T-SH) and non-protein thiol groups (NP-SH), endogenous respiration and levels of ATP in both Ehrlich ascites and P388 murine leukemia cells. The lowest concentrations of HBF significantly stimulated both glucose consumption and lactate formation in Ehrlich ascites cells. HBF decreased the level of both T-SH and NP-SH in Ehrlich cells. However, the decrease in the level of NP-SH was significantly higher. Both respiration and ATP levels were inhibited more markedly in Ehrlich than in P388 cells. In P388 cells a significant decrease in ATP level (67%) was noted only at the highest concentration of HBF (100 mumol/l).     

长春花生物碱部分之一 AC-875的抗肿瘤作用及毒性

木文对长春花(Catharanthus roseus Linn.G.Don)中分离提出的生物碱AC-875进行了毒性及抗癌作用的实验研究.试验结果表明AC-875在20-42毫克/公斤时,对小鼠Ehrlich腹水癌及腹水型肝癌均有明显的抑制作用.当剂量为10毫克/公斤时,对大鼠腹水型吉田肉瘤也有较好的疗效.在实体瘤的治疗中,注射35毫克/公斤,对小鼠S-180仅有轻度抑制作用,且不太稳定.对小鼠网织细胞瘤、Ehrlich腹水癌实体瘤、大鼠Jensen肉瘤及Walker癌等则无抑制作用.给小鼠腹腔注射AC-875的急性LD₅₀为170毫克/公斤,亚急性LD₅₀为61毫克/公斤.给大白鼠腹腔注射AC-875的意性及亚急性LD₅₀分别为122毫克/公斤及18毫克/公斤.给家兔静脉注射8毫克/公斤AC-875时,心电图无明显变化.静脉注射AC-875 1毫克/公斤、2.5毫克/公斤或皮下注射5毫克/公斤,对狗的肝、肾功能、尿常规、红血细胞、血红蛋白及体重均无明显影响,但2.5和5毫克/公斤组,狗的白细胞有下降现象.     

Pharmacological and toxicological studies on new Rh(I) organometallic complexes.

New rhodium(I) complexes, belonging to the general structure [Rh(CO)2 (L)], where dithiocarbamate and xanthate derivatives, were synthesized and assayed as cytostatic and antitumour agents in vitro against KB cells and in vivo against P388 leukaemia, Ehrlich ascites carcinoma, Sarcoma 180 ascites and ADJ/PC6A solid tumour. Assays against five trypanosoma strains were also performed. Among the new compounds the [Rh(CO)2 (DPA-dtc)] appeared to be active in all biological systems without showing evident nephrotoxicity.     

Synthesis and antitumor evaluation of selected 5,6-disubstituted 1(2)H-indazole-4,7-diones

A series of novel aziridinyl-substituted 1(2)H-indazole-4,7-diones and related 1(2)H-indazole-4,7-diones was synthesized and tested against Ehrlich ascites carcinoma growth in male CF1 mice. Ten of the test compounds, including two aziridinyl-substituted 1(2)H-indazole-4,7-diones, were found to be significantly active (inhibition of tumor growth greater than 80%) in the Ehrlich ascites carcinoma screen. Several structure-activity relationships were indicated for antitumor activity in this screen. An aziridinyl-substituted derivative, 5-aziridinyl-6-chloro-1H-indazole-4,7-dione (8a), also exhibited significant activity against the growth of P-388 lymphocytic leukemia cells in male BDF1 mice (% T/C = 145; % T/C greater than 125 is considered significant).     

Beta-[1-Phenyl-5-bis(beta-chloroethyl)-amino-benzimidazolyl-(2)]-DL-alanine (ZIMET 3164): an immunosuppressant without marked anti-cancer effect

ZIMET 3164 inhibited the growth of sarcoma 180 P, sarcoma 180 G, and Walker 256 carcinosarcoma, but was unable to prolong the survival time of mice bearing Ehrlich ascites carcinoma or the leukaemias L 1210 and LAJ I to a worthwhile extent. The primary and secondarantly suppressed in mice. The drug exerted maximum effect when given on days--2 to +2 relative to antigenic stimulus. Administration exclusively prior to immunization induced only moderate immunosuppression while injection afterwards failed to affect the primary response at all, suggesting that the drug interfers with the afferent limb of immune response. In general, ZIMET 3164 proved to be half as effective as cyclophosphamide, but more effective than chlorambucil.     

9-Hydroxybenfluron: cytostatic effects and inhibition of macromolecular biosynthesis in Ehrlich ascites and P388 murine leukemia cells.

Primary screening in vitro and study on the mode of action of 9-hydroxybenfluron (HBF) in both murine P388 leukemia and Ehrlich ascites carcinoma cells have been performed. Metabolite HBF is approximately twice as effective as a reference drug (benfluron). To elucidate the biochemical mode of action, the effect of HBF on the biosynthesis of macromolecules indicated by the incorporation rate of [14C]adenine (in DNA and RNA), [14C]thymidine (in DNA), [14C]uridine (in RNA) and [14C]valine (in protein) was studied in concentration and time dependence. HBF inhibited incorporation of all four precursors into the trichloroacetic acid-insoluble fraction of Ehrlich ascites cells. The fact that incorporation of these four precursors is inhibited suggests that the effect of HBF lies at an underlying level of energy generation or transfer rather than at specific reactions in the biosynthesis of DNA and proteins.     

蟾蜍毒素对小鼠移植艾氏腹水癌肿瘤细胞的抑制及毒副作用的实验研究

目的探讨醇溶性蟾蜍毒素在小鼠体内对艾氏腹水癌肿瘤细胞的抑制作用及其毒副作用。方法本研究用乙醇溶解蟾蜍分泌物原浆,采用减压蒸馏等方法进一步部分分离纯化,获得醇溶性的蟾蜍毒素混合物(EET),将其作用于艾氏腹水癌荷瘤小鼠模型,计算小鼠的生命延长率,同时通过血生化和病理等检测观察其对各脏器的毒副作用。结果5 mg/kg和0.5 mg/kg的EET对艾氏腹水癌荷瘤小鼠的生命延长率分别是42.6%(P<0.05)和33.7%(P<0.05);同时,0.5 mg/kg的EET可明显升高白细胞达(11.8±3.9)×109/L(P<0.05)。但EET在5 mg/kg时可引起总胆红素升高达(42.5±9.8)μmol/L(P<0.05)。结论0.5~5 mg/kg的EET可以明显抑制荷瘤小鼠体内艾氏腹水癌肿瘤细胞的生长,但EET的剂量达到5 mg/kg时可以损伤肝脏。     

N-甲基-8,9-次甲二氧基-2-羧基氯化菲啶季铵盐的合成

Ｎ甲基８，９次甲二氧基２羧基氯化菲啶季铵盐的合成杨洪勤蔡俊超（中国科学院上海药物研究所，上海２０００３１）翁尊尧等曾对氧化石蒜碱（ＡＴ１８４０，Ｉ）的抗肿瘤活性与结构关系进行了研究［１～３］，指出Ｉ分子中Ｎ－Ｏ－Ｏ三者的距离，酚羟基...     

Arugomycin, a new anthracycline antibiotic. III. Biological activities of arugomycin and its analogues obtained by chemical degradation and modification

Biological activities of arugomycin and its analogues obtained by chemical degradation and modification were evaluated. Differences in the sugar moieties affected their biological activities including induction of differentiation of mouse Friend erythroleukemia cells and mouse myeloid leukemia cells, antitumor activities against sarcoma S-180, Ehrlich ascites carcinoma and P388 leukemia, and cytotoxicity against murine leukemia cells. Some relationships were found between the sugar moieties and biological activities.     

Antitumor agents LXIII: the effects of microlenin on nucleic acid and protein syntheses of Ehrlich ascites cells

Microlenin, a novel dimeric sesquiterpene lactone isolated from Texas Helenium microcephalum, was shown to inhibit Ehrlich ascites carcinoma growth. Metabolic studies demonstrated that DNA synthesis and protein synthesis were significantly inhibited by two doses of microlenin at 5 mg/kg/day. DNA synthesis appeared to be blocked at several sites including DNA polymerase, purine synthesis, and dihydrofolate reductase. Thymidine nucleotide pools were significantly reduced by microlenin. Protein synthesis inhibition by microlenin appeared to occur during the initiation step of polypeptide synthesis. The metabolic effects of microlenin were similar to other sesquiterpene lactones in the Ehrlich ascites carcinoma cells. However, a lower dose of microlenin was required to bring about these metabolic effects when compared with other sesquiterpene lactones. Thus, microlenin may be a more likely therapeutic agent than helenalin which has demonstrated cellular toxicity.     

Isolation and characterization of terpentecin, a new antitumor antibiotic

A new antitumor antibiotic, terpentecin was isolated from the culture broth of strain MF730-N6. Strain MF730-N6, isolated from soil, was found to belong to the genus Kitasatosporia. The antibiotic was extracted with chloroform, purified by column chromatography using silica gel and Diaion HP-20 successively, and finally purified by high performance reverse-phase thin layer chromatography. The molecular formula of terpentecin was determined to be C20H28O6 (molecular weight, 364). The antibiotic inhibited the growth of Gram-positive and Gram-negative bacteria, and prolonged the survival period of mice bearing leukemia L-1210, P388 and Ehrlich ascites carcinoma.     

Antineoplastic agents. 1. N-Protected vinyl, 1,2-dihaloethyl, and cyanomethyl esters of phenylalanine

A series of N-protected vinyl, 1,2-dihaloethyl, and cyanomethyl esters of phenylalanine was synthesized and these compounds were evaluated for antitumor activity against the growth of Ehrlich ascites carcinoma in CF1 male mice (33 mg/kg/day), Walker 256 carcinosarcoma in Sprague-Dawley male rats (2.5 mg/kg/day), and P388 lymphocytic leukemia in DBA/2 mice (20 mg/kg/day). Structure-activity relationships were evaluated and acute toxicity studies (LD50 determinations) in male CF1 mice were also carried out on selected compounds. Carbobenzoxy-L0phenylalanine vinyl ester (5), N-carbobenzoxy-L-phenylalanine 1,2-dibromoethyl ester (12), and N-carbobenzoxy-L-phenylalanine cyanomethyl ester (8) were found to be very potent inhibitors of Ehrlich ascites tumor growth at nontoxic doses cited above. Compounds 5 and 12 also tripled survival time in the Walker 256 system. LD50 values for compounds 5, 12, and 8 were greater than 2000 mg/kg (greater than 6.15 mmol/kg), 74 mg/kg (0.15 mmol/kg), and 150 mg/kg (0.44 mmol/kg), respectively.     

The difference of drug sensitivity of tumor cells on N-ethyloxycarbonylaminomethyl-L-isoleucine (A-145 (author's transl)]

N-Ethyloxycarbonylaminomehyl-L-isoleucine (A-145), a novel antitumor amino acid derivative, is an anti-tumor agent effect in cases of Ehrlich ascites rather than against Sarcoma-180. The chemotherapeutic index of A-145 was 14.9 for Ehrlich ascites carcinoma and 4.2 for ascites Sarcoma-180. Experimental studies on ddy mice regarding the difference in susceptibility of these two tumor cell lines to A-145 gave the following results. In in vivo experiments, the uptake of 14C-A-145 by Ehrlich ascites carcinoma was greater than by Sarcoma-180, i. e. the uptake ratio of Ehrlich ascites carcinoma/Sarcoma-180 was 1.52 at 30 min and 2.7 at 24 hr after injection. In in vivo experiments, there was no remarkable difference between Ehrlich ascites carcinoma and Sarcoma 180 in the subcellular distribution of 14C-A-145, and the majority of the radioactivity taken up was distributed in nuclei and cytosol fractions. In in vitro experiments, the uptake of 14C-A-145 by both cell lines was found to be temperature sensitive, glucose dependent, and decreased on addition of KCN, 2, 4-dinitrophenol or iodoacetic acid. In in vitro experiments, competitive inhibition by L-isoleucine on 14C-A-145 uptake into tumor cells was observed in both cell lines, however, in vitro experiments, the inhibitory effect of A-145 on cell growth in cultured Sarcoma-180 was not reversed by L-isoleucine.     

On structure-activity relationships of N'methyl-N'-beta-chloroethyl-benzaldehyde hydrazones (author's transl)

The inhibition of uridine and thymidine in Ehrlich ascites cells is a basic property of the methylhydrazone structure and is reinforced by introducing a beta-chloroethyl group. This was shown by variation of the substituents at the N'-nitrogen atom of N'-methyl-N'-beta-chloroethyl-benzaldehyde hydrazone. Probably this action is due to an ethylenimmonium intermediate. This is derived from the observation that substituents which increase the nucleophilic property of the N'-nitrogen atom show a greater inhibitory effect in vitro. The therapeutic effect, however, is not enhanced when tested on the solid Ehrlich ascites tumor of mice. A better therapeutic effect resulted from introduction of chlorine atoms in positions 3 and 4 of the ring which inhbiits as well a probable metabolic hydroxylation of the ring.     

Pharmacological study on kefir--a fermented milk product in Caucasus. I. On antitumor activity (1)]

The antitumor activity of kefir (YK-1), a fermented milk product in Caucasus, was investigated. YK-1 at oral doses of 100 or 500 mg/kg inhibited the proliferation of solid tumor of Ehrlich ascites carcinoma transplanted subcutaneously in mice. YK-1 did not show an inhibitory effect on the ear swelling induced contact dermatitis caused by picryl chloride (PC-CD). However, YK-1 inhibited the immunosuppression in Ehrlich carcinoma-bearing mice and with the frozen and dried ascites of the tumor-bearing mice containing immunosuppressive substances (EC-sup) in PC-CD-induced mice. And also, YK-1 activated the immunosuppressive activity of spleen cells of mouse treated with EC-sup. These results suggest that YK-1 may have antitumor activity against Ehrlich carcinoma and activate the immunosuppression with it.