日本粗榧中抗肿瘤生物碱的分离工艺

从常绿乔木日本粗榧(Cephalotaxusharringtonis)中分得几种生物碱,对小鼠淋巴白血病 L1210和 P388具有明显的疗效。这些活性生物碱为三尖杉碱(Ⅰ)的酯类化合物,包括长梗粗榧碱(Ⅱ)、异长梗粗榧碱(Ⅲ)、高长梗粗榧碱(Ⅳ)和脱氧长梗粗榧碱(Ⅴ)。生物碱Ⅱ和Ⅳ己完成了临床前的药理评     

抗生素R-588A的抗肿瘤作用

抗生素R-588A是由紫红链孢囊菌产生的蒽环类物质,经研究鉴别为洋红霉素。用7种小鼠移植性肿瘤研究抗生素R-588A的抗肿瘤活性,结果表明,该抗生素对淋巴肉瘤Lio-1 和白血病L7212有显著抑制作用,对肉瘤180、Lewis肺癌、白血病L1210和P388有中度抑制作用。对白血病L615无抑制作用。     

三尖杉酯类生物碱对L615及P388白血病细胞cAMP含量的影响

实验证明,三尖杉酯类生物碱对某些动物移植性白血病和实体瘤有不同程度的疗效。在治疗剂量下,三尖杉酯碱能抑制肿瘤细胞有丝分裂,降低肝、脾和肿瘤组织的核酸含量,明显抑制DNA合成。三尖杉酯碱对白血病L1210杀伤动力学研究表明,它是一个细胞周期非特异性抗肿瘤药,但对S期细胞有强烈杀伤作用,对G_0期细胞也有一定影响。临床     

去氧三尖杉酯碱的合成

去氧三尖杉酯碱(Deoxyharringtonine,Ic)对小鼠白血病 P 388有显著的抑制作用,本文报道由三尖杉碱(Ia)合成 Ic。     

美登木素细胞毒作用的初步研究

美登木素是从 Maytenus serrata 及 buch-ananii 等东非灌木中分离得的 ansa 大环化合物,可延长 P388淋巴白血病、B16黑色素瘤及 Lewis 肺癌小鼠的生命。本文报导了美登木素在体外及体内对小鼠白血病的一些作用方式。结果表明,毫微克分子浓度的美登木素即可抑制培养细胞 L1210、L5178Y 及 P388的生长。其中以 P388最为敏感,处理48小时后的 ED_(50)为6×10~(-10)克分子,L1210与 L5178Y 的 ED_(50)分别     

阿克拉霉素A:新型蒽环类抗菌素治疗血癌的临床进展

作用机理及临床前研究阿克拉霉素(ACM)是第二代蒽环类抗生素。体外实验显示,ACM 与阿霉素有明显差别,前者更具有亲脂性,易进入细胞内并维持高浓度,且能迅速转运进入细胞核。阿霉素是强的DNA 合成抑制剂;ACM 是RNA 多聚酶抑制剂,较少诱变性。ACM 对L 1210、Friend 红白血病、P 388等实验性白血病以及6 C 3 HED 淋巴肉瘤均有效,ACM 对L 1210白血病,Lewis 肺癌和B 16黑色素瘤的疗效低于阿霉素;但对阿霉素和柔红霉素无效的Friend 红白血病细胞株却有效;对耐药的L 1210和P 388细胞株无治疗作用。     

30例慢性粒细胞白血病的临床治疗分析

目的观察高三尖杉酯碱联合羟基脲治疗慢性粒细胞白血病（CML）的临床效果。方法将30例患者随即分为观察组与对照组,观察组应用高三尖杉酯碱（HHT）联合羟基脲对照组单纯应用羟基脲,两组进行临床疗效的对比研究。结果观察组的总有效率为62．85％,对照组为31．34％,两组的临床疗效差异具有统计学意义（P〈0．05）。结论高三尖杉酯碱联合羟基脲治疗慢性粒细胞白血病临床效果好,毒副作用轻微,是为一种可广泛应用的治疗方案。     

噻唑烷酸类化合物的合成及其抗肿瘤作用的研究

改变噻唑烷酸结构,合成了它的8个2-位取代的衍生物,其中化合物5对小鼠艾氏腹水癌、白血病 L 1210、白血病 P 388显示较高的活性。     

小鼠造血干细胞和P388白血病干细胞对5种抗癌药的敏感性比较

用脾集落形成法比较了5种抗癌药对小鼠造血干细胞(NCFU-S)和P₃₈₈白血病干细胞(LCFU-S)的作用。三尖杉酯碱、半合成三尖杉酯碱、高三尖杉酯碱和环磷酰胺对两类干细胞作用的剂量—反应曲线呈指数形,效能比依次为5.15,6.01,7.96和9.98。阿糖胞苷对NCFU-S无明显作用,但对LCFU-S杀伤作用强,大剂量时剂量—反应曲线趋于水平。当三尖杉酯碱、高三尖杉酯碱和半合成三尖杉酯碱的剂量分别低于0.30,0.28和0.75mg/kg时,对LCFU-S无明显作用,剂量—反应曲线上出现“肩形”,提示LCFU-S在小剂量三尖杉酯类生物碱作用下,有一受亚致死性损伤后修复过程。     

小鼠造血干细胞和P_(388)白血病干细胞对5种抗癌药的敏感性比较

用脾集落形成法比较了5种抗癌药对小鼠造血干细胞(NCFU-S)和P_(388)白血病干细胞(LCFU-S)的作用。三尖杉酯碱、半合成三尖杉酯碱、高三尖杉酯碱和环磷酰胺对两类干细胞作用的剂量—反应曲线呈指数形,效能比依次为5.15,6.01,7.96和9.98。阿糖胞苷对NCFU-S无明显作用,但对LCFU-S杀伤作用强,大剂量时剂量—反应曲线趋于水平。当三尖杉酯碱、高三尖杉酯碱和半合成三尖杉酯碱的剂量分别低于0.30,0.28和0.75mg/kg时,对LCFU-S无明显作用,剂量—反应曲线上出现“肩形”,提示LCFU-S在小剂量三尖杉酯类生物碱作用下,有一受亚致死性损伤后修复过程。     

Modulation of thiol pools by vitamin K3 and its effect on survival of sensitive and resistant murine tumor cells.

Cytotoxic effects of vitamin K3 were evaluated utilizing the P388/S, L1210, EAT, S-180 and a multidrug-resistant variant of the P388 leukemia cells (P388/ADR). Antitumorigenic potential of vitamin K3 was assessed by MTT and DNA and RNA biosynthesis inhibition assay. A dose-dependent inhibition of P388/S and P388/ADR cell survival and [3H]thymidine and [3H]uridine incorporation (as a function of DNA and RNA biosynthesis) was observed in tumor cell types exposed to vitamin K3 concentrations ranging from 1 to 100 microM. One hundred mg/kg vitamin K3 caused a 32 and 52% increase in life span of the sensitive and resistant P388 leukemia tumor-bearing mice. Induction of DNA strand breaks at 100 microM vitamin K3 was greater in P388/S than in P388/ADR cells. In vitro treatment with vitamin K3 (100 microM) reduced the intracellular levels of GSH by 40, 47, 6, 15 and 14% in P388/S, P388/ADR, EAT, S-180 and L1210 tumor cells, respectively. In vivo treatment with 100 mg/kg vitamin K3 reduced the GSH content by 18 and 38% and increased the activity of the enzyme GSH-S-transferase and gamma-glutamyl transpeptidase. Effects of free radical scavengers and of compounds that modulate the GSH metabolism on the cytotoxicity of vitamin K3 were also investigated. Results indicate that vitamin K3 interacts with the tumor cell thiol pools while eliciting its antitumor effects and suggest the utility of vitamin K3 in dealing with the growing problem of multidrug resistance.     

三尖杉酯类生物硷对小鼠白血病P388及L615蛋白质生物合成的影响

本文初步观察了四种三尖杉酯硷对³H-DL-亮氨酸、³H-L-门冬酰胺、¹⁴C-DL-苯丙氨酸掺入小鼠白血病P₃₈₈腹水细胞及L₆₁₅。脾组织蛋白质的作用。实验结果表明,在等毒性剂量(1/5 LD₅₀)下,一次腹腔(或静脉)给药,四种酯硷对P₃₈₈腹水细胞及L₆₁₅脾组织蛋白质生物合成抑制明显,作用较快,并具有相似的时间—反应曲线。一般在24小时基本恢复。     

半合成三尖杉酯碱的抗肿瘤作用及毒性研究

Partial synthetic harringtonine was prepared as a mixture of two diastereoisomers ——harringtonine and epiharringtonine. Experimental chemotherapeutic studies'revealed that the partial synthetic harringtonine was as active as the natural harringtonine in rodent tumors (L615, L1210, and P388 leukemia, Lewis lung carcinoma, S180 and Walker256 careinosarcoma). Toxicity studies showed that the LD₅₀ of the synthetic mixture was twice as that of natural harringtonine. The biological activity of one of the diastereoisomers epiharringtonine was shown to be less than 1% of that of the other diastereoisomer——harringtonine. Epiharringtonine given intraperitoneally did not prolong the survival time of P388 leukemia mice. However, the effect of epiharringtonine in combination with harringtonine was higher than that of harringtonine alone.     

Synthesis, chemistry, and antineoplastic activity of alpha-halopyridinium salts: potential pyridone prodrugs of acylated vinylogous carbinolamine tumor inhibitors

A series of 4- and 5-[2,3-dihydro-6,7-bis[[(N-alkylcarbamoyl)oxy]methyl]-1H-pyrrol izin-5- yl]-2-halopyridinium iodides were synthesized. The rates of hydrolysis of the alpha-halopyridinium salts to the corresponding pyridones, and the reactivities of the carbamate moieties were studied as a function of pH, buffer composition, and ionic strength. The 4- and 5-pyrrolizinyl-2-halopyridinium iodides and the corresponding pyridones were evaluated against P388 lymphocytic leukemia in vivo. The alpha-fluoropyridinium compounds were active but the alpha-chloro compounds were not. This activity was correlated with the rates of hydrolysis of the alpha-halopyridinium compounds to the active pyridone. Compounds that were active in the P388 screen were evaluated in L1210 leukemia, M5076 carcinoma, and MX-1 mammary xenograft assays in mice.     

新抗癌有效成分海南粗榧内酯(Hainanolide)结构的研究

自海南粗榧树皮中分离出两种新的化合物即海南粗榧内酯和海南粗榧内酯醇,海南粗榧内酯是一种新抗癌有效成分。动物试验结果表明对L₆₁₅、S₁₈₀、Lewis肺癌P₃₈₈和L₁₂₁₀均显活性。根据X-衍射分析、核磁共振谱、红外光谱、紫外光谱、旋光光谱和质谱等证明海南粗榧内酯是一种新的结构类型的抗癌化合物,其结构式为Ⅰ。海南粗榧内酯醇的结构与海南粗榧内酯的结构很相似,其结构的研究正在进行中。     

1-Amino-substituted 4-methyl-5H-pyrido[4,3-b]indoles (gamma-carbolines) as tricyclic analogues of ellipticines: a new class of antineoplastic agents

A series of 1-amino-substituted 4-methyl-5H-pyrido[4,3-b]indoles that are structurally related to ellipticines by deletion of a ring have been synthesized in order to evaluate their DNA affinity, their in vitro cytotoxicity on L1210 cultured cells, and their in vivo antitumor activity. Among 24 derivatives that have been prepared and studied for the structure-activity relationship in this new class of antineoplastic agents, those that have a NH(CH2)3N(R)2 side chain (R = CH3 or C2H5) at their 1-position, a 4-methyl group, and an 8-OH substituent, either with a 5-NH or with a 5-NCH3 group, show the most potent cytotoxicities on L1210 cultured cells and in vivo antitumor properties in P388 and L1210 leukemia systems. In vivo antineoplastic activity of the most potent products was confirmed in P388 and L1210 leukemia systems. In vivo antineoplastic activity of the most potent products was confirmed on other mouse experimental tumors from the standard NCI screening:B16 melanoma and C38 adenocarcinoma.     

Alterations in [3H]thymidine incorporation into DNA and [3H]uridine incorporation into RNA induced by 5-azacytidine in vivo.

Administration in vivo of 5-azacytidine (5-aza-CR) caused suppression of [³H]thymidine ([³H]TdR) incorporation into DNA of bone marrow and gastrointestinal mucosa of mice and a more prolonged suppression of L1210 ascites tumor. Single doses of 5-aza-CR caused a modest and short-lived suppression of incorporation of [³H]uridine ([³H]UR) into nuclear RNA of L1210 ascites tumor cells. No suppression of [³H]UR incorporation into RNA of bone marrow or gastrointestinal mucosa was observed. L1210 tumor cells resistant to the other active cytidine analogue, cytosine arabinoside, demonstrated less disruption of [³H]TdR incorporation after exposure to 5-aza-CR, suggesting some cross resistance in the effects of these two drugs on DNA synthesis. Survival studies carried out in mice bearing both the sensitive and resistant L1210 tumor cell lines confirmed cross resistance of the anti-tumor effects of the two cytidine analogues. Second doses of 5-aza-CR, with the timing og administration based upon the differing patterns of recovery of [³H]TdR incorporation between normal tissues and tumor cells, led to a prolongation of survival in mice bearing the sensitive L1210 ascites tumor.     

Synthesis and biological properties of some 6H-pyrido[4,3-b]carbazoles

The effect of methyl substitution on the biological properties of the ellipticines was reexamined. 9-Hydroxy-6H-pyrido[4,3-b]carbazole was synthesized and shown to be devoid of antitumor activity in murine P388 lymphocytic leukemia in mice. 5-(Hydroxymethyl)-11-methyl-6H-pyrido[4,3-b]carbazole (46) and its N-methylcarbamate (48) were synthesized and their effect on macromolecular synthesis in HeLa cells and their antitumor properties were compared with those of ellipticine. In contrast to the alkaloid 1 and the hydroxymethyl derivative 46, which produced partially reversible inhibition of [3H]thymidine incorporation, the carbamate ester irreversibly blocked incorporation of the tritiated pyrimidine. The ester was also a more potent antitumor agent in P388 lymphocytic leukemia than 1 or 46.     

Potential antitumor agents. 51. Synthesis and antitumor activity of substituted phenazine-1-carboxamides

In a further investigation of electron-deficient DNA-intercalating ligands as antitumor drugs, a series of substituted N-[2-(dimethylamino)ethyl]phenazine-1-carboxamides have been synthesized and evaluated. Fluorine-directed ring closure of N-phenyl-3-nitroanthranilic acids provided a new, unequivocal synthesis of several of the required phenazine-1-carboxylic acids, and the corresponding carboxamides were prepared and evaluated against L1210 leukemia in vitro and against P388 leukemia and Lewis lung carcinoma in vivo. Substitution on the phenazine ring was broadly tolerated, and the cytotoxicity of the resulting compounds correlated positively with the electron-withdrawing power of the substituent group. The positional effects of substituents were even more evident, with 9-substituted compounds being the most active. One derivative, N-[2-(dimethylamino)ethyl]-9-methoxyphenazine-1-carboxamide, had activity against Lewis lung carcinoma in mice equal to that of the best DNA-intercalating agents yet described, being capable of effecting a high-proportion cure of the advanced disease.