Contradictory antitumor efficacies produced by the combination of DNA attacking drugs and polyamine antimetabolites

The antitumor effects of two polyamine antimetabolites, alpha-difluoromethylornithine (DFMO) and methylglyoxal-bis-guanylhydrazone (MGBG), when combined with cis-diamminedichlroplatinum (CDDP) or mitomycin C (MMC), were studied using human gastric cancer cells xenotransplanted into nude mice. DFMO 1000 mg/kg and MGBG 50 mg/kg were given intraperitoneally for 6 successive days, while CDDP 3 mg/kg or MMC 2 mg/kg was given every second day. Although DFMO and MGBG plus MMC did suppress the tumor growth, the combination with CDDP led to no suppression, and rapid growth occurred after the cessation of therapy. The inhibition of tumoral DNA biosynthesis and a decline in polyamine levels, were also not observed. The polyamine antimetabolites when used with CDDP did not produce the desired antitumor efficacy, even though the platinum concentration in the tumor tissue was high. On the contrary, however, DFMO and MGBG when combined with MMC did suppress tumor growth, inhibited DNA biosynthesis, and tissue polyamine levels were low. These results suggest that though CDDP and MMC belong to a similar category of DNA attacking, bifunctional alkylating agents, the findings of these two drugs are contradictory. Here, the mechanism of action no doubt plays a contributory role.     

Enhanced antitumor efficacy with a combination of hyperthermochemotherapy and thermosensitization with polyamine antimetabolites in nude mice

In an attempt to enhance the antitumor effects of hyperthermochemotherapy, methylglyoxal-bis-guanylhydrazone (MGBG) and alpha-difluoromethylornithine (DFMO) were used in combination with hyperthermochemotherapy of 1-(4-amino-2-methyl-5-pyrimidinyl)-methyl-3-(2-chloroethyl)-3-nitrosoure a (ACNU) against human gastric cancer (ST-2) xenotransplanted into nude mice. After priming with DFMO and MGBG, ACNU was given ip and subsequently, a 23 minute-hyperthermia was carried out by placing the leg with the tumor into a water bath of a temperature of 43.5 +/- 0.1 degrees C. The second hyperthermic treatment was given in the same manner after 48 hours. MGBG and DFMO were administered for 4 successive days from the previous day of the first hyperthermia. In mice treated with DFMO plus MGBG, either tumor growth or tumor tripling time was much the same as in the control, while in mice given MGBG, DFMO plus heat, there was a diminution in tumor growth. Hyperthermia together with MGBG, DFMO plus ACNU brought about remarkable antiproliferative effects on ST-2 tumor growth, compared to three regimens with MGBG, DFMO plus heat, MGBG, DFMO plus ACNU, as well as ACNU plus heat. These data suggest that a combination of MGBG with DFMO leads to a favorable thermosensitization to the antitumor efficacy of ACNU.     

Enhanced antitumor efficacy with a combination of hyperthermochemotherapy and thermosensitization with polyamine antimetabolites in nude mice

In an attempt to enhance the antitumor effects of hyperthermochemotherapy, methylglyoxal-bis-guanylhydrazone (MGBG) and alpha-difluoromethylornithine (DFMO) were used in combination with hyperthermochemotherapy of 1-(4-amino-2-methyl-5-pyrimidinyl)-methyl-3-(2-chloroethyl)-3-nitrosourea (ACNU) against human gastric cancer (ST-2) xenotransplanted into nude mice. After priming with DFMO and MGBG, ACNU was given ip and subsequently, a 23 minute-hyperthermia was carried out by placing the leg with the tumor into a water bath of a temperature of 43.5±0.1°C. The second hyperthermic treatment was given in the same manner after 48 hours. MGBG and DFMO were administered for 4 successive days from the previous day of the first hyperthermia. In mice treated with DFMO plus MGBG, either tumor growth or tumor tripling time was much the same as in the control, while in mice given MGBG, DFMO plus heat, there was a diminution in tumor growth. Hyperthermia together with MGBG, DFMO plus ACNU brought about remarkable antiproliferative effects on ST-2 tumor growth, compared to three regimens with MGBG, DFMO plus heat, MGBG, DFMO plus ACNU, as well as ACNU plus heat. These data suggest that a combination of MGBG with DFMO leads to a favorable thermosensitization to the antitumor efficacy of ACNU.     

Combined therapy of polyamine antimetabolites and antitumor drugs for human gastric cancer xenotransplanted into nude mice

Antitumor therapies using polyamine antimetabolites combined with 1-(4-amino-2-methyl-5-pyrimidyl)methyl-3(2-chloroethyl)-3-nitrosourea (ACNU) or fluorinated pyrimidines for human gastric cancer xenotransplanted into nude mice were studied to determine inhibiting post-therapeutic regrowth of the tumor after cessation of antitumor treatments with polyamine antimetabolites alone. ACNU 20 mg/kg, fluorinated pyrimidine, 5-FU 52.8 mg/kg and 5'-deoxy-5-fluorouridine (5'-DFUR) 100 mg/kg as well as polyamine antimetabolites, alpha-difluoromethylornithine (DFMO) 1000 mg/kg and methylglyoxal-bis-guanylhydrazone (MGBG) 50 mg/kg were given intraperitoneally for 5 successive days. When DFMO and MGBG were combined with ACNU, the post-therapeutic regrowth was definitely inhibited, while combined treatments with 5-FU or 5'-DFUR did not inhibit the regrowth. Post-therapeutic DNA biosynthesis was suppressed in mice given DFMO, MGBG plus ACNU. On the contrary, in mice treated with DFMO, MGBG plus 5-FU or 5'-DFUR, suppression of DNA biosynthesis was not observed. Tumor tissue spermine levels in the DFMO, MGBG plus 5-FU or 5'-DFUR group remained unchanged, compared to those in the DFMO + MGBG group. In mice given DFMO, MGBG plus ACNU, however, spermine levels were markedly depressed; and the ACNU alone depressed also the tissue spermine levels. These different results between nitrosourea and fluorinated pyrimidines may relate to mechanisms of action of these antitumor drugs.     

Combined therapy of polyamine antimetabolites and antitumor drugs for human gastric cancer xenotransplanted into nude mice

Antitumor therapies using polyamine antimetabolites combined with 1-(4-amino-2-methyl-5-pyrimidyl)methyl-3(2-chloroethyl)-3-nitrosourea (ACNU) or fluorinated pyrimidines for human gastric cancer xenotransplanted into nude mice were studied to determine inhibiting post-therapeutic regrowth of the tumor after cessation of antitumor treatments with polyamine antimetabolites alone. ACNU 20 mg/kg, fluorinated pyrimidine, 5-FU 52.8 mg/kg and 5′-deoxy-5-fluorouridine (5′-DFUR) 100 mg/kg as well as polyamine antimetabolites, alpha-difluoromethylornithine (DFMO) 1000 mg/kg and methylglyoxal-bis-guanylhydrazone (MGBG) 50 mg/kg were given intraperitoneally for 5 successive days. When DFMO and MGBG were combined with ACNU, the post-therapeutic regrowth was definitely inhibited, while combined treatments with 5-FU or 5′-DFUR did not inhibit the regrowth. Post-therapeutic DNA biosynthesis was suppressed in mice given DFMO, MGBG plus ACNU. On the contrary, in mice treated with DFMO, MGBG plus 5-FU or 5′-DFUR, suppression of DNA biosynthesis was not observed. Tumor tissue spermine levels in the DFMO, MGBG plus 5-FU or 5′-DFUR group remained unchanged, compared to those in the DFMO + MGBG group. In mice given DFMO, MGBG plus ACNU, however, spermine levels were markedly depressed; and the ACNU alone depressed also the tissue spermine levels. These different results between nitrosourea and fluorinated pyrimidines may relate to mechanisms of action of these antitumor drugs.     

Polyamines, polyamine antimetabolites and urogenital tumors. State of research and clinical results

The polyamine metabolism is pathologically changed in tumor tissues, and especially putrescine and spermidine demonstrate abnormally high values in kidney, bladder, and prostate cancer. The inductive processes which activate the biosynthetic polyamine enzymes in cancer are completely unknown. Of therapeutic interest is the fact that increased enzyme activities through irreversible inhibitors become significantly reduced, which consequently slows the tumor growth. Experimental therapy, especially in transplantable bladder and prostate cancer, displayed a 50% tumor destruction. In clinical studies using inhibitors of the polyamine biosynthesis, the dose had to be significantly reduced because of expressed toxicity. Additional investigations which tried a combination of reversible and irreversible inhibitors proved a similar antitumor activity, but less severe side effects.     

Cardiovascular effects produced by a combination of d-tubocurarine and pancuronium in dogs

The effect on the cardiovascular system of a combination of pancuronium (0.048 mg/kg) and d-tubocurarine (0.288 mg/kg) was studied in five conditioned dogs anesthetized with fentanyl. Changes in heart rate, mean arterial pressure, central venous pressure, mean pulmonary artery pressure, pulmonary capillary wedge pressure, stroke volume, cardiac output, systemic vascular resistance and pulmonary vascular resistance were recorded 2, 5, 10, 20, 30, 40 and 50 minutes after administration of the drug combination. Arterial blood samples were assayed for estimation of histamine levels. There was a significant fall in central venous pressure and mean arterial pressure at 2 minutes (p less than 0.05) and a significant rise in heart rate at 2 and 5 minutes (p less than 0.05). These changes were not significant at 10 minutes. There was no significant change in the other parameters measured and no significant release of histamine. It is concluded that the smaller doses of pancuronium and d-tubocurarine used in combination in dogs do not completely attenuate the cardiovascular effects of either drug when used independently, but that the changes are transient and no longer significant at 10 minutes.     

DNA疫苗与DC疫苗抗肿瘤作用的研究进展

肿瘤是21世纪医学界面临的难题之一,肿瘤疫苗以其低毒、持久和特异性强等特点成为肿瘤治疗研究的热点,有效的肿瘤抗原被识别、递呈是建立抗肿瘤免疫应答的基础,在这个基础的不断理解和深化研究下,新型肿瘤疫苗不断涌现,并展现出一定的抗肿瘤效果,其中DNA疫苗以其独特的肿瘤抗原提供方式及DC在肿瘤抗原呈递中的重要作用,成为了肿瘤免疫治疗的有力工具,本文就目前这两类疫苗作用的机制、进展及存在问题进行综述.     

胃癌细胞对化疗药物和α-干扰素的敏感性试验

目的　探讨人胃癌细胞株对不同化疗药物、α 干扰素及其相互配伍的敏感性。方法　向体外培养的人胃癌细胞 (MGC80 - 3)中加入不同配伍及不同浓度的化疗药物和α 干扰素 ,作用一定时间后 ,采用MTT法检测癌细胞对不同配伍药物的敏感性。结果　联合用药较单一用药的相对抑制率明显增高 ,尤其以氟尿嘧啶、丝裂霉素和表阿霉素 3药联合作用的抑制率最高 ;随药物剂量的增加 ,各组的抑制率有所增高 ,α 干扰素与化疗药物合用时 ,有协同抑制作用 ,尤其在先用α 干扰素 2 4小时后 ,再加用化疗药物 ,抑制率明显增高。结论　联合用药化疗疗效优于单一用药 ,加用α 干扰素具有协同抑制作用 ,尤以先用α 干扰素后 ,再联合用化疗药 ,疗效最佳。     

TACE联合抗肿瘤药物在原发性肝细胞癌治疗中的现状及进展

原发性肝细胞癌(HCC)是世界范围内的一种常见疾病,经导管动脉化疗栓塞术(TACE)已成为不能手术切除的中晚期肝细胞癌的首选治疗方法.但是,TACE有其本身的局限性,例如肿瘤复发率高、并发症较多等,且栓塞治疗后局部组织缺血、缺氧,促进了血管内皮生长因子的活化,进而促进新生血管形成,导致肿瘤复发,降低疗效.TACE联合抗肿瘤血管生成治疗能弥补对方的缺点,两者有良好的协同作用,明显降低肝细胞癌复发率,近年成为非手术治疗肝细胞癌的热点.     

TACE联合抗肿瘤药物在原发性肝细胞癌治疗中的现状及进展

原发性肝细胞癌(HCC)是世界范围内的一种常见疾病,经导管动脉化疗栓塞术(TACE)已成为不能手术切除的中晚期肝细胞癌的首选治疗方法.但是,TACE有其本身的局限性,例如肿瘤复发率高、并发症较多等,且栓塞治疗后局部组织缺血、缺氧,促进了血管内皮生长因子的活化,进而促进新生血管形成,导致肿瘤复发,降低疗效.TACE联合抗肿瘤血管生成治疗能弥补对方的缺点,两者有良好的协同作用,明显降低肝细胞癌复发率,近年成为非手术治疗肝细胞癌的热点.     

Effect of antineoplastic drugs on cell proliferation--individually and in combination

Three antineoplastic agents, bleomycin, cytosine arabinoside and 5-fluorouracil, were studied individually and in combination to determine their effectiveness in controlling cell growth in the presence of fetal bovine serum. All three drugs were effective individually in specifically controlling proliferation (as measured by 3H-thymidine uptake) of human Tenon's capsule fibroblasts while bleomycin is effective at the lowest concentration. However, bleomycin alone rather than in combination with cytosine arabinoside or 5-fluorouracil was most effective in preventing division by these fibroblasts.     

A low concentration of nitrous oxide reduces dyspnoea produced by a combination of hypercapnia and severe elastic load

We have measured how a low concentration of nitrous oxide affected respiratory sensation and ventilation. Severe dyspnoea was induced in nine normal subjects by a combination of hypercapnia and inspiratory elastic load (50 cm H2O litre-1). Subjects were asked to rate their sensation of respiratory discomfort using a visual analogue scale (VAS) while breathing either 20% nitrous oxide or 20% nitrogen gas mixture. We compared the effects of each gas mixture on respiratory sensation and ventilation using steady-state values of ventilatory variables and VAS scores obtained before, during and after inhalation of each gas mixture. Inhalation of 20% nitrous oxide reduced the sensation of respiratory discomfort from a median VAS score of 6.5 (range 5.0-8.1) before inhalation to 3.6 (2.4-5.9) during inhalation (P < 0.05). There was no significant change in minute ventilation but tidal volume increased during inhalation of 20% nitrogen did not alter VAS scores or ventilatory variables. We found that a low concentration of nitrous oxide greatly alleviated the intensity of dyspnoea without changing respiratory load compensation.      

Detection of cellular DNA strand breaks induced by antitumor drug and heat using in situ nick translation

Cellular DNA strand break induced by an alkylating agent: Carboquone (CQ), and heat (43 degrees C) was detected in HeLa cells in vitro and mouse sarcoma-180 cells in vivo. The break sites in the DNA were translated artificially in the presence of Escherichia coli DNA polymerase I and [3H]-labeled dTTP and sites in the DNA were visualized by autoradiographic observation of grains in the nuclei. These breaks increased in a dose and time dependent manner, compared to findings in the control cells. Our findings show that the surviving response of cells decreases while the level of DNA strand breaks increases following exposure to CQ or heat. The nick translation method is a rapid in situ assay for determining drug and heat induced DNA damage of tumor cells, under in vitro and in vivo conditions and in a semi-quantitative manner.     

异体大鼠骨肉瘤细胞RNA电转染树突状细胞瘤苗诱导的特异性抗骨肉瘤免疫学效应

目的 本研究旨在探讨异体大鼠骨肉瘤细胞RNA电转染树突状细胞(dendritic cells,DC)瘤苗在大鼠肿瘤动物模型诱导的抗骨肉瘤免疫学效应.方法 本研究采用UMR108细胞RNA通过电穿孔的方法 转染至SD大鼠骨髓来源的DCs制备瘤苗.将该瘤苗应用于骨肉瘤荷瘤大鼠,观察其特异性抗肿瘤效应,并对瘤苗诱导的细胞毒性T淋巴细胞(cytotoxic T lymphocytes,CTLs)杀瘤效应加以评估.结果 异体骨肉瘤RNA转染DC瘤苗可诱导UMR106特异性的CTLs效应,其杀瘤效果显著.在体内实验中,80%的异体RNA-DC瘤苗接种大鼠可以有效地抵抗肿瘤细胞攻击,而得以长期存活,存活大鼠产生了长效免疫效应,可以抵抗同一肿瘤的二次攻击,但是对其他肿瘤细胞不具有免疫性.结论 该研究为异体骨肉瘤细胞RNA转染DCs瘤苗可以有效地刺激T淋巴细胞增殖及诱导显著的细胞毒T淋巴杀瘤活性提供了证据,并通过动物实验证实了该瘤苗良好的主动免疫治疗效应,从而表明异体瘤苗为以树突状细胞为基础的免疫治疗领域提供了新的策略,针对临床骨肉瘤患者具有广阔的应用前景.