Antitumor effects of recombinant human tumor necrosis factor against human tumor xenografts transplanted into nude mice

Antitumor activities of recombinant human tumor necrosis factor (rH-TNF) against human tumor xenografts in nude mice were studied. Thirteen human tumor xenografts serially transplanted into nude mice were used for experiments; five gastric, two breast, two gallbladder, one colon and one esophageal carcinoma, one liposarcoma and one squamous carcinoma of the neck. They were inoculated into the subcutaneous tissue of BALB/c nu/nu nude mice and the treatment was started when the estimated tumor weight reached 100-300 mg. rH-TNF was administered intratumorally at schedule of qd X 5 or q3d X 5. rH-TNF showed a marked antitumor activity against various human tumors. The hemorrhagic necrosis was observed in all types of the human tumor xenografts (100 per cent), and the complete regression of the tumor was noted in 4 of 11 tumors (36.4 per cent). On the contrary, intraperitoneal rH-TNF exhibited little antitumor effect. The additive effect in the combination of TNF and Mitomycin C was observed against two Mitomycin C resistant gastric tumors.     

Experimental studies on the combined effects of alpha and gamma interferons against human tumor xenografts transplanted into nude mice

The antitumor activities, resulting from the combined treatment of leukocyte interferon (IFN-α), with recombinant human immune interferon (IFN-γ), against human tumor xenografts in nude mice, were studied. Nine human tumor xenografts, (7 from gastric carcinoma, 1 from gallbladder carcinoma and 1 from breast carcinoma), were serially transplanted into nude mice for the purpose of this experiment. Each human tumor xenograft was inoculated subcutaneously into BALB/c nu/nu nude mice and treatment was started after the estimated tumor had reached 100–300 mg. IFN was administered intramuscularly at a schedule of qd×14. Treatment with either IFN-α or IFN-γ alone, did not produce any antitumor effect against the various human tumor xenografts, however the combination of IFN-α with IFN-γ resulted in achieving significant antitumor effects against the various human tumors. Inhibition of tumor growth was observed in 7 of the 9 tumors (77.8 per cent), and regression of the tumor was noted in 5 of the 9 tumors (55.6 per cent).     

Antitumor effects of bacterial lipopolysaccharide and tumor necrosis factor in mice

The effects of lipopolysaccharide (LPS) against tumor growth and on cellular immunity were studied in comparison with those of tumor necrosis factor (TNF). LPS and TNF, which were administered into mice with tumors, induced hemorrhagic necrosis within 48 hours after the initiation of the treatment. LPS and TNF significantly inhibited the tumor growth, as compared with findings in the controls. There was no significant difference in inhibitory effect on tumor growth between mice treated with LPS or TNF once or twice. Both LPS and TNF prevented the decrease of delayed type hypersensitivity in the tumor bearing mice.     

Growth of human tumor xenografts in nude mice and mice with severe combined immunodeficiency (SCID)

Twenty-three fresh tumor specimens obtained at surgery and 5 serially transferable human tumor xenografts were implanted subcutaneously into nude mice and mice with severe combined immunodeficiency (SCID) to compare the take rates of the fresh surgical specimens and the growth rates of the transferable strains. The overall take rates were 65% for the SCID mice and 60% for the nude mice, without any significant difference, although colon carcinoma seemed to have higher acceptance in the SCID mice with a take rate of 6/8. All the serially transferable strains were successfully accepted in the SCID mice, their growth rates being essentially identical to those in the nude mice. These results indicate that the SCID mouse can be used as a human tumor xenograft-mouse system as well as the nude mouse.     

Antitumor activities of KW-2152, a new isoquinon agent, against human tumor xenografts transplanted into nude mice

The antitumor activities of KW-2152, a new isoquinon derivative, were examined in thirteen human tumor xenografts, transplanted into nude mice. KW-2152 was administered intravenously at a schedule of q4d X 3, in daily doses of 7.3 mg/kg and 3.6 mg/kg, and q2d X 6 with a daily doses of 7.3 mg/kg, respectively. KW-2152 displayed significant antitumor activities against the human tumor xenografts in 3 out of 13 strains (23.1 per cent) at the schedule of q4d X 3, with a daily dose of 7.3 mg/kg. Depending on the schedule of administration, tumor activity was observed in 8 out of 13 strains (61.5 per cent) at a schedule of q2d X 6, with a daily dose of 7.3 mg/kg. SH-2 and SH-9 gastric tumors were sensitive to KW-2152 and growth was completely inhibited with the schedule of q4d X 3, and a daily dose of 7.3 mg/kg. Thus, KW-2152 seems to have a wide antitumor spectrum, and the possible antitumor effects for clinical use, warrant attention.     

Antitumor activities of KW-2152, a new isoquinon agent,against human tumor xenografts transplanted into nude mice

The antitumor activities of KW-2152, a new isoquinon derivative, were examined in thirteen human tumor xenografts, transplanted into nude mice. KW-2152 was administered intravenously at a schedule of q4d×3, in daily doses of 7.3 mg/kg and 3.6 mg/kg, and q2d×6 with a daily dosis of 7.3 mg/kg, respectively. KW-2152 displayed significant antitumor activities against the human tumor xenografts in 3 out of 13 strains (23.1 per cent) at the schedule of q4d×3, with a daily dose of 7.3 mg/kg. Depending on the schedule of administration, tumor activity was observed in 8 out of 13 strains (61.5 per cent) at a schedule of q2d×6, with a daily dose of 7.3 mg/kg. SH-2 and SH-9 gastric tumors were sensitive to KW-2152 and growth was completely inhibited with the schedule of q4d×3, and a daily dose of 7.3 mg/kg. Thus, KW-2152 seems to have a wide antitumor spectrum, and the possible antitumor effects for clinical use, warrant attention.     

The effects of estrogen on human breast carcinomas serially transplanted into nude mice

The effect and mechanisms of 17β-estradiol (E₂) on breast cancer cells were studiedin vivo andin vitro, using 5 human breast carcinomas serially transplanted into nude mice. These carcinoma strains consisted of 4 estrogen receptor (ER) positive tumors and 1 ER negative tumor. Mice bearing these tumors were treated with an intramuscular injection of E₂ at a dosage of 50 mg/kg and the tumor doubling time (Td) was calculated in days. The tumor growth was significantly stimulated by E₂ in 3 out of the 4 ER positive tumors, the Td of the E₂ treated groups being 17.6 days for MCF-7 (control: −17.8 days), 12.8 days for R-27 (control: −12.5 days∼14.5 days) and 10.4 days for Br-10 (control: 14.5 days), however, in the T-61 tumor, the growth was inhibited by E₂ in a dose dependent manner. In the case of the ER-negative MX-1 tumor, the tumor cell growth was not affected by E₂. Discrepancies between the effects of E₂ on ER-positive tumors were further analyzed by examining the steroid hormone receptor status and conductingin vitro growth studies.In vitro clonogenic cell assay reproduced the antitumor activity of E₂, indicating that E₂ directly inhibits part of the cell growth of T-61 tumors. The above results suggest that this experimental system provides a useful tool for analyzing the mechanism of estrogen in breast cancer and that the clonogenic assay using ER positive specimens can help to identify breast cancers sensitive to estrogen therapy.     

Experimental studies on the combined effects of alpha and gamma interferons against human tumor xenografts transplanted into nude mice

The antitumor activities, resulting from the combined treatment of leukocyte interferon (IFN-alpha), with recombinant human immune interferon (IFN-gamma), against human tumor xenografts in nude mice, were studied. Nine human tumor xenografts, (7 from gastric carcinoma, 1 from gallbladder carcinoma and 1 from breast carcinoma), were serially transplanted into nude mice for the purpose of this experiment. Each human tumor xenograft was inoculated subcutaneously into BALB/c nu/nu nude mice and treatment was started after the estimated tumor had reached 100-300 mg. IFN was administered intramuscularly at a schedule of qd X 14. Treatment with either IFN-alpha or IFN-gamma alone, did not produce any antitumor effect against the various human tumor xenografts, however the combination of IFN-alpha with IFN-gamma resulted in achieving significant antitumor effects against the various human tumors. Inhibition of tumor growth was observed in 7 of the 9 tumors (77.8 per cent), and regression of the tumor was noted in 5 of the 9 tumors (55.6 per cent).     

肿瘤坏死因子与可溶性肿瘤坏死因子受体在膀胱肿瘤中的表达

目的探讨肿瘤坏死因子（TNF）和可溶性肿瘤坏死因子受体（STNFR）与膀胱肿瘤生物学行为的关系。方法测定26例膀优移行细胞癌患者和20例正常对照者血清中TNF和STNFR水平。结果发现膀胱肿瘤患者血TNF水平与对照组相比差异无显著性（P＞0．05）,而STNFR水平显著高于对照组（P＜0．001）,并随着临床分期的增加而升高,巨术后2周时显著下降（P＜001）;TNF与STNFR水平之间无显著相关关系。结论STNFR抑制了TNF生物学活性而降低了机体的免疫功能,并可作为评估病情严重程度和预后的指标。     

重组人肿瘤坏死因子抗结肠癌的体外研究

研究重组人肿瘤坏死因子（ｒｈＴＮＦ）体外对人结肠癌细胞株ＳＷ－４８０的抗瘤作用，改良ＭＴＴ地测试表明，ｒｈＴＮＦ在较高剂量时才能瘤细胞表现细胞毒性，而联合应用５－氟脲嘧或丝裂霉素，ｒｈＴＮＦ在很小剂量即可获得增强细胞毒性，＾３Ｈ－ＴｄＲ掺入率测定表明ｒｈＴＮＦ细胞毒性与瘤细胞ＤＮＡ合成受抑具有一致性关系，电镜观察发现，ｒｈＴＮＦ作用瘤细胞先发生线粒体及细胞核的破坏，然后出现细胞膜及细胞裂解。     

The biological characteristics and chemosensitivity of anaplastic thyroid carcinoma transplanted into nude mice

Three xenografts established from three patients with anaplastic thyroid carcinoma were investigated for their biological characteristics and chemosensitivity. The histological and immunohistochemical findings of these tumors were almost the same as those of the original tumors. Although the growth rate of each xenograft was constant, the tumor doubling time varied from 4.8 per 9.0 days, and the labeling indexes, determined using bromodeoxyuridine pulse labeling, varied from 11.4 to 25.1 per cent. The chemosensitivity tests were performed according to the Battle Columbus Laboratories Protocol, with adriamycin, cyclophosphamide, cisplatin, mitomycin C and tegafur administered intraperitoneally to tumor-bearing nude mice in maximum tolerable doses. Tumors with slower growth rates tended to be sensitive to more drugs. Furthermore, cyclophosphamide showed antitumor effects against all the tumors tested. Althouth previous treatments of the original tumors may have affected the results, our results suggest that a more suitable chemotherapy for anaplastic thyroid carcinoma could be developed.     

Differential antiproliferative activities of alpha- and gamma-interferon and tumor necrosis factor alone or in combinations against two prostate cancer xenografts transplanted in nude mice

We have investigated the antiproliferative effects of recombinant human alpha- and gamma-Interferon (IFN) and recombinant human Tumor Necrosis Factor alpha (TNF) against the hormone-independently growing PC3 and DU145 prostatic tumor lines. Subcutaneous, peritumoral administration of the drugs was started 24 hours after subcutaneous implantation of 1–2 mm³ tumor pieces. IFN was given three times per week and TNF five times per week. IFN-alpha (dose-range 0.5–5 ng/gram bodyweight) had significant growth-inhibiting effects against the PC3 tumor, but showed no significant antitumor effects against the DU145 tumor. IFN-gamma monotherapy (dose-range 8–80 ng/gram bodyweight) was less effective than IFN-alpha. 500 ng/gram TNF produced growth inhibition of both tumors, whereas the lower dose (50 ng/g) was only effective against the PC3 tumor. IFN-alpha and -gamma combination treatment had significant antiproliferative effects against the PC3 tumor, but not against the DU145 tumor. Combinations of IFN-alpha and TNF were very effective against both xenografts; some combinations resulted in complete growth inhibition. IFN-gamma and TNF combinations also showed significant antitumor effects against both tumor lines. We therefore conclude that cytokine combination treatment may provide a new approach in the treatment of hormone-escaped prostatic tumors.     

Cell kinetic analysis of human tumor xenografts using anti-bromodeoxyuridine monoclonal antibody

The cell kinetics of human tumor xenografts serially transplanted into nude mice was examined using bromodeoxyuridine (BrdU) and anti-BrdU monoclonal antibody. After various doses of BrdU were given intraperitoneally into tumor bearing nude mice, the tumors were resected and stained immunohistochemically, using the anti-BrdU monoclonal antibody. The number of stained cells was demonstrated as the labeling index (LI). The optimal condition for BrdU staining was assumed to be 300mg of BrdU per kg followed by an incubation period of one hour. Since the LI by BrdU closely correlated with that in autoradiography by³H-TdR, this method is more useful and safer than the conventional autoradiographic study for investigating clinical cell kinetic analysis, as there is no need to use potentially hazardous radioactive compounds and the period of assay is shorter.     

Sensitivity of anticancer agents on human gastric cancers transplanted into nude mice

In the chemotherapy for gastric cancer, the most sensitive anticancer agent against individual tumors should be prescribed. The establishment of a sensitivity test using nude mice as anin vivo model is urgently awaited by clinicians and researchers alike. Seventy-three tumors derived from human gastric cancer were transplanted subcutaneously into nude mice and these mice were then treated intraperitoneally with anticancer agents. Mitomycin C (MMC), 5-fluorouracil (5-FU) and cyclophosphamide (CPM) were used. The doses given were 3 mg/kg of MMC, 75 mg/kg of 5-FU and 200 mg/kg of CPM. In 52 of the 73 cancers, chemosensitivity was evaluated by the microscopic changes in the tumors. The rate of positive sensitivity against gastric cancer was 44.2% in MMC, 34.6% in 5-FU and 30.8% in CPM, respectively. The sensitivity of each agent tested by this method indicated a good correlation with the clinical therapeutic effects. Our results suggest the feasibility of evaluation of the sensitivity of various agents from the microscopic changes on tumors transplanted into nude mice.     

冷冻和重组人肿瘤坏死因子一α在C6大鼠脑胶质瘤治疗中的协同作用

目的 观察冷冻联合重组人肿瘤坏死因子-α( rhTN F-α)治疗C6大鼠脑胶质瘤治疗的协同作用.方法 以原位末端转移酶标记(TUNEL)法检测肿瘤细胞的凋亡,采用免疫组织化学检测增殖细胞核抗原(PCNA)的表达；行核磁共振(MRI)检查,测量肿瘤体积,计算抑瘤率.动态观察各组荷瘤鼠生存期和rhTNF-α对荷瘤鼠的不良反应.结果 联合治疗组肿瘤细胞凋亡、PCNA的表达、肿瘤体积和生存期与其他各组比较差异有统计学意义(P＜0.01),且该组对肿瘤生.长的抑制率(60.38％；89.48％)明显大于冷冻组(42.69％；66.31％)和TNF-α组(21.68％；49.01％),且大于理论抑瘤率(82.82％).rhTNF-α对实验动物有不良反应.结论 冷冻和rhTNF-α对C6联用的抗肿瘤作用进一步加强,具有协同作用.     

超声引导下关节腔内注射重组人Ⅱ型肿瘤坏死因子受体-抗体融合蛋白(益赛普)治疗血友病性关节病

目的 观察超声引导下关节腔内注射重组人Ⅱ型肿瘤坏死因子受体-抗体融合蛋白（益赛普）治疗血友病性关节病（HA）的价值。方法 回顾性分析32例接受超声引导下穿刺关节腔注射益赛普的HA患者，对比观察治疗前及治疗后1个月血友病关节健康评分（HJHS）、视觉模拟评分（VAS），以及超声所示目标关节增生滑膜厚度、血流信号、Melchiorre及中国早期血友病性关节病超声检测（HEAD-US-C）评分，评估其治疗价值。结果 对32例均成功完成超声引导下穿刺关节腔及腔内注射益赛普，共对18例膝关节、7例肘关节及7例踝关节进行治疗。术后未出现感染、出血等并发症。治疗后1个月，目标关节HJHS、VAS、Melchiorre评分、HEAD-US-C评分及增生滑膜最大厚度、平均厚度、血流信号均低于治疗前（P均<0.01）。结论 超声引导下关节腔内注射益赛普治疗HA安全、有效。     

正常妊娠与自然流产小鼠模型蜕膜组织和血清中肿瘤坏死因子及其受体的表达

目的比较正常妊娠与自然流产小鼠模型蜕膜组织肿瘤坏死因子-α(TNF-α)及其受体1(TNFR1)和血清可溶性肿瘤坏死因子受体1(sTNFR1)的表达,探讨其与不明原因自然流产的关系。方法建立正常妊娠小鼠模型CBA×BALB/C和自然流产模型CBA×DBA/2。采用免疫组化SABC法测定两组模型孕13 d蜕膜组织TNF-α、TNFR1表达水平;酶联免疫吸附试验(ELISA)测定两组模型孕13 d血清sTNFR1表达水平。结果与正常妊娠模型相比,自然流产模型蜕膜组织中TNF-α、TNFR1表达显著升高(P<0.01);血清sTNFR1表达水平也高于正常妊娠模型(P<0.05)。结论TNF-α、TNFR1、sTNFR1可能与自然流产的发生发展有关。某些病理情况引发的蜕膜TNF-α、TNFR1表达增加也许是自然流产发生的原因之一,sTNFR1水平升高可能对妊娠具有自我保护和自我稳定的生理意义。