Laboratory Animal Science

APPLICATION OF IMMUNODEFICIENCY ANIMAL IN THE STUDY OF TUMOR INVASION

Gao Jin Institute of Basic Medical Sciences,Chinese Academy of Medical Sicenees,Beijing,100005

1992, 9(04): 1-6.

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In recent 10 years, we have employed immuno-deficiency animal to observe the invasiveness of human tumors from different point of view. In summary, the following works were undertaken. (1) Establishment of animal models of invasion, six in vivo iuvasion models were set up,including dorsal-lateral subcutaneous, intramuscular, intra-peritoneal, subrenal capsule, subtesticular capsule and footpadal subcutaneous imptantation. These models could be used for different purpose. All the six models could be employed for comparative study of tumor invasiveness. (2) Observation on the relationship between invasion and metastasis. The footpadal subcutaneous implantation model was used in the study. Local tumor was eradicated at different time interval. The relationship between local invasion and metastasis of tumor were inve-stigatedeither by sacrifying the animal at different time or after keeping the animal as long as they could survive. Our results indicate that metastasis can form only after local invasion reached Ⅲ-degree. So Ⅲ-degree local invasion is the critical stage. (3) Primary evaluation of quantitation of tumor invasion. (4) Observation on the relationship between the invasiveness of tumor cells and organ microenviroment. The results suggested the invasiveness of tumor cells, like metastasis of them, is also organspecific. (5) Our investigation also proved that the expression of tumor cell invasion is closely related with the ways they were implanted. In a word, our experimental results in 10 years were summed up and analysed. Problems worth further investigation was raised. These observations lay good foundation for further study of the mechanism and experimental treatment of tumor cell invasion.

HUMAN TUMOR HETEROTRANSPLANTATION AND ANTICANCER DRUG RESEARCH

Zhen Yongsu Institute of Medicinal Biotechnology,Chinese Academy of Medical Sciences,Beijing,100050

1992, 9(04): 7-9.

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Human tumor heterotransplantation in immunodeficient animals provides experimental models for various human cancers. It has been demonstrated that there exists a good correlation between the drug effect on tumor xenografts and the clinical efficacy of the drug against the correspondent tumors. Therefore, human tumor xenografts have been widely used in the research of anticancer drugs. As experimental models, human tumor xenografts are of particular importance in the screening of new drugs for specified types of tumor, in the evaluation of experimental therapeutic effects of drugs on human tumors and in the study of targeted tumor therapy.

EXPERIMENTAL STUDIES ON ORTHOTOPIC XENOTRANS-PLANTATION OF HUMAN PULMONARY CARCINOMAS IN NUDE MICE

Zheng Jie Qi Maosong Xu Rong Department of Pathology,Bejing Medical University,Beijing,100083

1992, 9(04): 10-13.

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A highly metastatic giant cell carcinoma (PG) and a poorly metastatic adenocarcinoma (PAa) were orthotopically implanted into nude mice, and the take rates were 74% for PG and 56% for PAa. Invasive tumors located in hilar region or peripheral part of lung, or spread diffusely, which were quite similar to three macroscopic types of primary lung carcinomas and different from well-circumscribed masses of ectopically implanted tumors. It is interesting to point out that the metastatic incidence of PAa cells in regional lymph nodes was 56% when implanted orthotopically which was even higher than the metastatic incidence in beige nude mice bearing subcutaneous tumors. Collectly, the results demonstrate that the orthotopic implantation of human lung carcinomas favour the expression of metastatic phenotype suitable for experimental study of metastasis. The comparation of expressions of oncogenes and antioncogenes in orthotopically implanted tumors with those in subcutaneously implanted tumors of the same kind will contribute to searching for molecular basis of tumor invasion and metastasis.

INVESTIGATION OF THE FORMATION OF LIVER METASTASIS AND ITS MECHANISM AFTER INTRAS-PLENIC IMPLANTATION OF HUMAN AND MOUSE TUMOR INTO NORMAL AND IMMUNODIFICIENT MICE

Xue Kexun Gao Jin Zhao Xuemei Gu Pei Institute of Basic Medical Sciences,Chinese Academy of Medical Sciertees,Beijing

1992, 9(04): 14-16.

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Trying to elucidate the mechamism and biological charateristics of metastatic formation of tumor cell in liver, human nasopharygeal carcinoma (CNE-2Z) and mice uterine cervical carcinoma (U14) were intrasplenicly innoculeted into nude mice and inbred 615 mice respectively. Forty three to fifty days after implantation tumor nodules in spleen and hepatic metastasis were detected in 8/10 cases of CNE-2Z group, of them four cases concurred with pulmonary metastasis. For the U14 group, the mice were sacrificed on the 13rd or 14th day, hepatic metastasis occurred in 73% cases with various degree of pulmonary or/and lymphatic metastasis, of those with primary nodule resection one day or three days after implantation, 11% and 63% demostrated hepatic metastasis respectively. It is suggested that once there is enough tumor cells innoculated into the spleen, a primary tumor would occur in it, and then spreading via blood circulation, secodary metastatic tumor would formed in liver.

ESTABLISHMENT OF TRANSPLANTABLE MODELS OF HUMAN ESOPHAGEAL CARCINOMA IN NUDE MICE AND THEIR THERAPEUTIC CHARACTERISTICS

Cai Haiying Wei Longxing Yie Yanli,et al Cancer Center,Sun Yatsen University of Medical Sciences

1992, 9(04): 17-23.

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We have successfully established two human esophageal carcinoma models in nude mice by transplantation of surgical specimen from patients with esophageal cancer Histopathological study revealed that one of these to be squamous call carcinoma (HEC_2) and the other adeno-squamous cell carcinoma (HEC_6). Light and electron microscopy showed that they were similar to that of the original human tumors. The transplanted tumors have been maintained for more than three years through more than 40 passages. The tumors grew steadily and fast. The rate of inoculation was 100%. Bleomycin A5 and 5-Fluorouracil (5-Fu) were used for treatment of HEC_6. Results showed that Bleomycin A5 exhibited a remarkable growth inhibition on the HEC_6. The inhibitory rates of two separate experiments were 56.5% and 87.8% respectively comparing with the control group (P<0.01). The inhibitory rates of 5-Fu were 6.5% and 36.6% respectively, there was no statistic difference compared to the control group. HEC_2 was treated by X-ray or X-ray combined with Hematoporphyrin derivative (HPD), the tumor inhibitory rates were 57.7% and 85.4% respectively The results showed that combination of HPD with orthovoltage X-ray irradiation exhibited enhanced effect, and the result was repeatble.

STUDY OF HUMAN PRIMARY HEPATOCARCINOMA IN NUDE MICE SECRETING AFP & HBsAG

Yang Shanmin Zhao Yuhua Chen Fu Cancer Research Center,Xiamen University,xiamen,Fujian

1992, 9(04): 24-28.

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The hetrotransplanted human hepatocellular carcinoma (HCC) secreting both AFP &-HBsAg was first established in Fujian province. The nude mice bearing tumor grew well and kept up 5th passage. Under histological examination, supported by electron microscopy and immunohistochemistry, the transplanted tumor retained approximately the morphological characteristics of original tumor. Shown by TEM, the transplanted tumor cells displayed some figures seen in normal liver cells, such as bile canilicull, junctionai complexes which were incomplete. HBsAg-like crystal structure was seen within RER and SER in some tumor cells. It is suggested that the close relationship between HBV and HCC be presented.It is reasonable that the development of double marked tumor in nude mice is an-useful animal model for the studies of cell biology, chemosensitivity and immunotherapy in HCC. A transfer solution, which is suitable for the survival of tumor cells, was presented in this paper. Owing to the limited passages of nude mice, the further efforts will andoubtedly be directed toward the schedule of biochemistry, growth dynamics and chromosome characteristics in hetrotransplanted HCC.

THE ANTI-EXPERIMENTAL METASTASIS EFFECTS OF HIGHLY METASTATIC TUMOUR LINES BY HUMAN LAK CELLS IN THE BLOOD CIRCULATION OF NUDE MICE

Zhang Binxue Wang Jieliang Zhou Kexiang, Department of Pathology,Beijing Medical University,Beijing,100083

1992, 9(04): 32-34.

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The blood circulatory system of nude mice has been used to study the anti-experimental metastasis effects of LAK cells activated in vitro with interleukin-2 on the highly metastatic tumor lines moving in blood. On the first day of the test, 3×10~7 LAK cells and 1×10~6 tumor cells were mixed and injected tailveinly to each of the mice in test group (n=5), at the effectors/targets ratio of 30:1; while in the controlled group, each mouse was only injected tailveinly with 1×11~8 tumor cells. All of the mice were injected (ip) with rIL-2 300 cu/gram body weight dayly for seven days. As a result, none of the mice in test group was seen with tumor growth (0/5), eight weeks after injection; and all of the mice in controlled group were fount out with metastatic tumor formation in lungs, lymphonodes, rachis and subskin (5/5). The results indicated that LAK cells could not only exhibit the antitumor effecs in vitro, but also catch and kill metastatic cancer cells in the blood circulation.

EFFECTS OF THE CONJUGATE COMPOSED OF MONOCLONAL ANTIBODY FAB FRAGMENT AND ANTITUMOR ANTIBIOTIC C1027 ON HUMAN HEPATOMA XENOGRAFTS IN NUDE MICE

Li Junzhi Jiang Min Xue Yuchuan Zhen Yongsu Institilte of Medieinal Biotcchnology,Chinese Acadcmy of Medical Sciences, Beijing,100050

1992, 9(04): 35-38.

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Fab fragment of 3A5, a monoclonal antibody directed against human hepatoma BEL-7402 cells, was prepared by digestion of the McAb and purification through the Sepharose 4B-Mark3 affinity column. By ELISA, McAb 3A5 and the Fab fragment were strongly reactive with hepatoma BEL-7402 cells and weakly reactive with KB cells. Using SPDP as the linker agent, McAb 3A5 and its Fab fragment were conjugated to antitumor antibiotic C1027 separately. As determined by clonogenic assay against hepatoma BEL-7402 cells, the IC50 values for McAb-C1027, Fab-C1027 and C1027 were 4.2x10~(-14)M, 8.6x10~(-16)M and 6.5x10~(-16)M, respectively. Fab-C1027 was 32-fold more potent in cytatoxicity to hepatoma cells than to KB cells, indicatng selective cytotoxicity of Fab-C1027 conjugate to the target cells. Therapeutic effects of the conjugates were evaluated with hepatoma BEL-7402 xenografts in nude mice. After sc transplantation of the tumor, treatment started on day 3, iv, with equivalent dose of C1027, 0.1mg/kg ×6.Fab-C1027 and free C1027 inhibited the tumor growth by 85% and 59% respectively.

EFFECTS OF RADIATION COMBINED WITH β-CAROTENE ON HUMAN NASOPHARYNGEAL CARCINOMA XENOGRAFTS IN NUDE MICE

Hu Changkun Cao Shilong Huang Kangmei Cancer Hospital,Shanghai Medical University,Shanghai,200032

1992, 9(04): 39-43.

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The effects of radiation and/or β-carotene on the 36th passage human nasopharyngeal carcinoma xenografts in nude mice were studied by tumor volume and flow cytometry. The xenografts were implanted subcutaneously into the posterior limb of the animals, β-carotene (12mg/kg, p.o., q.d.) and/or a single does of 5 Gy ~(60)Co γ-ray was given to the nude mcie, and 0.9%NaCl (4mg/kg, p.o., q.d.) was used as control group. In 4 weeks after treatment, the relative tumor volume in radiation or radiaton combined with β-carotene goup. The factorial analysis indicated that radiation was the main factor of inhibiting tumor growth (p<0.05 or 0.01), but β-carotene had no statistically effect on tumor growth (p<0.05). The flow cytometric analysis showed that the S% of tumors in the grouos of control, β-carotene, radiation and radiation combined with β-carotene was 10.0, 9.9, 14.4 and 15.9% respectively. It indicated that radiation cause a significant rise in S% (P<0.01) and G_2+ M%(P<0.05). The S% of bone marrow in above 4 groups was 10.1 ,13.7,16.8 and 15.0% respectively; and G_2+M% was 11.0, 12.7, 17.4 and 14.2% respectively. A significant rise of G_2+M% (P<0.05) in bone marrow had been obtained by radiation, but the effect was inhibited by β-carotene (P<0.05).

RADIOIMMUNOIMAGING AND TARGETING TREATMENT OF ~(131)I-LABELED MONOCLONAL ANTIBODY MC_3 IN NUDE MICE BEARING HUMAN RECTAL CANCER

Xu Shenhua Mu Hanzhou Qian Lijuan, Cancer Res.Inst of Zhejiang Cancer Hospital,Hangzhou,310022

1992, 9(04): 44-50.

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Radioimmunoimaging and targeting treatment of ~(131)I-labeled specific monoclonal antibody MC_3 against human colon mucoid adenocarcinoma in tumor-bearing nude mice were studied. The specific binding rate of the monoclonal antibody MC_3 to rectal cancer cells in vitro was 37.5% and 32.1%. In nude mice bearing human rectal cancer xenografts a clear image of tumor was obtained by ECT camera between 48-120 hours after injection of laoeled MC_3 and the concentration of MC_3 in tumor increased with time. The optimal imaging time was 96-120 hrs. after injection. Where as injection of ~(131)I-NMIgG in to the nude mice resulted in an equal distribution in the whole body. 120 hours after injection of ~(131)I-MC_3 the tumor/liver and tumor/normal colon distribution raties were 3.61 and 9.81 respectively and the localization index of tumor was 4.26. Targeting treatment of ~(131)I-MC_3 was found to be able to inhibit 90.14% of tumor growth at 14th day after injection as compared with the control groups. The difference was very significant (P<0.01) as compared with the ~(131)I-NMIgG control group. The difference in the amount of CEA in blood serum of nude mice at 32th day after injection of ~(131)I-MC_3 was significant (P<0.05) as compared with the ~(131)I-NMIgG control group. Histopathological examination showed that in the ~(131)I-MC_3 group at 8th day after injection the tumor showed large areas of necrosis, and only a few round cancer cells werw found near the capsule of the tumor. Inradiation damage was observed in other tissues. The results showed that monoclonal antibody MC_3 may be used in localization and targeting treatment of human colon-rectal cancers.

DISTRIBUTION AND RADIOIMMUNOIMAGING OF ~(131)I-ANTI-HUMAN BLADDER CARCINOMA McAb IN NUDE MICE WITH TUMOR XENOGRAFTS

Zhang Chunli Pan Zhongyun Wan Zhaozhuo, Dept.of Nucl.Meb.,First Hosp.of Beijing Medical University,100034

1992, 9(04): 51-54.

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Anti human bladder carcinoma monoclonal antibody (Anti BIU-87 McAb) was radioiodinated using Ch-T method with satisfied lebelling efficiency and immune activity. After injection of the antibody into nude mice with tumor xenografts, the radioactivity ratio of target to nontarget tissues increased with time. 72 hours post intravenous injection, tumor/blood ratio was 0.99, tumor/muscle 8.43, tumor/bladder 4.04. 120 hours post injection, tumor/blood ratio was 1.38, tumor/muscle 12.31, tumor/bladder 5.24. Tumor imaging with γ camera was clear 3 days post injection, and it was mors clear during 5-7 days post injection. Contrasted with non-specific imaging indicated that anti BIU-87 McAb has high specificity. The results suggest that anti BIU-87 McAb be useful for guiding diagnosis and therapy of bladder carcer and its matastatic focus.

CARCINOGENESIS OF EPSTEIN-BARR VIRUS AND CHEMICAL CARCINOGEN DNP ON TRANSPLANTS OF HUMAN FETAL NASOPHARYNGEAL MUCOSA IN NUDE MICE

Guo Zhongmin Wu Feng Shen Shujing Onclogy Laboratory in Guangdong medical Collogy,Zhanjiang.524023

1992, 9(04): 58-62.

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The study presented investigates the separate or corporate carcinogencsis of EBV, DNP and PMA on human fetal nasopharyngeal mucosa transplants in nude mice and effects of the factors above on the formation of human experimental NPC. The results show that the transplant epithelia sucessfully express EBNA in EBV transfected groups. General hyperplasia were observed in control group, whereas precancerous lesions in other experimental groups. 8 cases of carcinomas were found, which included: 4 cases of car, in situ in EBV, DNP, EBV +DNP and DNP+PMA groups separately, 1 of early infiltrating car.in EBV+PMA group, 3 of typical infiltrating car. in EBV+DNP, DNP+PMA and EBV+DNP+PMA groups respectively. From the results above, it is estimated that EBV play a role in carcinogenesis of experimental NPC and also suggested that DNP be an important carcinogen in NPC carcinogenesis which is closely related to the corporation of different carcinogenic factors.

STUDY ON M.Leprae INFECTION OF NUDE MICE BY MULTIPLE ROUTES OF THE INOCULATION

Wang Heying Zhang Weiyun Yu Linchong Shi Meiqin\ Institite of Dermatology,Chinese Academy of Medical Scienees,Nanjing 210042

1992, 9(04): 63-66.

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The immune-deficient nude mice were inoculated with nude mouse-derived Mycobacterium leprae by the multiple routes of the inoculation (intravenously, subcutaneously at the foot pads and ears). The results showed that these animals inoculated were capable of supporting a great number of Mycobacterium leprae to level 10~(11~12) per g of tissue, and were detected histopathologically to have more heavy lepromatous lesions. The dissemination of the infection was found, particularly in the sites with lower body temperature. The organisms have a partiality for the striate muscle and peripheral nerves. The authors suggest that the experimental leprosy in the nude mice is a very useful tool for leprosy research, especially in countries without the armaillo. In comparison with the inoculation by single route reported previousy, the inoculation by the multiple routes is more available.

A MODEL OF SPONTANEOUS TUMOR WITH LYMPHATIC METASTASIS IN NUDE MOUSE

Li Side Cheng Huaxu Ma Jiqing Shanghai Cancer Institute,Shanghai 200032

1992, 9(04): 67-71.

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Spontaneous tumor nodes were discovered by accident in a nude mouse (BA-BL/c nu/nu). These nodes were implanted subcutaneously with more than ten passages in more than one hundred nude mice. The primary and metastatic tumor nodes were observed by means of anatomy, light and electronic microscopy. Results showed that this tumor (LMLM) was a murine tumor with widespread lymph node metastasis which could be transplanted stably. Tumor appeared on the 5th to 15th days after transplantation, tumor occurrence rate was more than 95%. Life span of the mice bearing the LMLM tumor was 25 to 35 days after transplantation. There was no visible tumor node in mouse's lungs, liver, stomach, gut, kidneys, spleen, etc. This tumor can grow in the heterozygous nude mouse (BALB/c nu/+) when implanted subcutaneously.

FACILITIES AND MANAGEMENT ON A SMALL SCALE BARRIER

Wand Zhaochuo Xiao Xuguang Wang jieliang Beijing Medical University,Beijing,100083

1992, 9(04): 76-79.

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This paper recommends experience on both production and experiment of nudes. It includes distribution of facilities, using method and monitoring requirement on isolators, lamina air flow units, clean room, plastic cages with sealed air filter and autoclaves. The results indicate that when the small scale farrier system and essential equipments had been set up, mass production of nude mice and the high-quality experimental studies can be carried out.

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