Hormone dependency of a serially transplantable human prostatic cancer (HONDA) in nude mice

Human prostatic cancer (HONDA) serially transplanted in nude mice grew well in male mice but not at all in untreated female mice or in castrated male mice. Progressive growth in female mice was obtained by i.m. administration of 1 mg of testosterone twice a week. Estradiol inhibited the growth of the tumor in male mice to some extent; however, some growth was observed. The tumor in untreated male mice retained the histological features of poorly differentiated adenocarcinoma. Tumors in castrated male mice showed reduction in size of tumor cell nests with relative overgrowth of stroma. The tumor in androgenized female mice consisted of columnar epithelial cells with large nuclei and more abundant cytoplasms and a large glandular lumen, showing histology of moderately differentiated adenocarcinoma. High levels of human prostatic acid phosphatase (PAP) were detected in sera from untreated male mice. Testosterone markedly increased the content of serum PAP of androgenized female mice. Estradiol reduced the levels of PAP in sera from untreated male mice regardless of the tumor weight. High-affinity androgen receptors were present in cytosol and in nuclear extract of the tumor in untreated male mice. No measurable amount of progesterone or estrogen receptors was present in cytosol from untreated male mice.     

裸鼠的人原发性胃癌移植瘤生物学及分子遗传学性质研究

A human primary gastric cancer tissue (adenocarcinoma II-III) was transplanted into nude mice (SWISS/DF. nu/nu). It has been transferred for 8 generations at 56 sites in 28 nude mice with transplantable rate of 100%. The transplanted tumor is designated as transplantable human primary gastric cancer-1 in nude mice (THPGC-1). The growth of THPGC-1 is rather rapid and the size of transplanted tumor reaches 1 cm2, 4-5 weeks after transfer. The morphology and histochemistry of the original tumor were retained well in the initial and serial transplanted tumors. THPGC-1 could secret carcinoembryonic antigen (CEA). After intravenous or intraperitoneal injection of 131I-antiCEA monoclonal antibody into the THPGC-1 bearing nude mice, the radiolabeled antibody was concentrated and localized in the tumor as shown by gamma-camera analysis. Similar pattern of lactate dehydrogenase isoenzyme was observed both in primary gastric cancer tissue and THPGC-1 tissue. Chromosomal examination revealed that THPGC-1 was human aneuploid ones. Southern blot analysis showed that the pattern of repetitive DNA bands and the structures of 28s, rDNA, c-H-ras and c-myc genes in THPGC-1 were identical to the original primary gastric cancer DNA. The results suggest that THPGC-1 be a reliable model for the research of the molecular biology of cancer cells and experimental gastric cancer diagnosis and treatment.     

Tumor-bone interaction induced by transplantable human tumors in nude mice

Tumor-bone interactions were experimentally studied using four transplantable human urogenital tumors in nude mice. The method consisted of subcutaneously (SC) inoculating tumor cells over the calvaria in nude mice after the periosteum has been disrupted. This resulted in a local tumor causing fragmentation of the bone. The degree of tumor-bone interaction also varied with the type of implanted tumors as shown in radiographic and histologic examinations. All tumors were associated with histologic patterns of classical bone remodeling, including bone destruction with osteoclast proliferation and reactive new bone formation. The evidence presented here suggests that the majority of tumor-bone interaction showed a combination of both features, bone destruction and new bone formation, and the mechanisms whereby tumors interact with bone may vary with the biological properties of the tumor. Our new system would be suitable for studying the biology of local interaction between bone and tumor cells and searching out a method to protect the bone from cancer cells.     

Establishment and characterization of a human adenoid cystic carcinoma line of the salivary gland which is serially transplantable and spontaneously metastasises to the lung in nude mice.

Adenoid cystic carcinoma (ACC) is a rare malignant tumour of the head and neck occurring in the salivary glands. We established a human ACC line which is serially transplantable in nude mice and designated it as KOA-1. The KOA-1 tumour doubled in 9.3 days and retained the histological characteristics of a solid pattern of ACC even after 22 serial passages. The KOA-1 metastasised to the lung when transplanted subcutaneously into the back. This tumour line may serve as a useful model for exploration of the biological behaviour and treatment of human ACC.     

Cell kinetics and chemosensitivity of human carcinomas serially transplanted into nude mice

Six human carcinoma xenografts serially transplanted into nude mice were used for the study of chemosensitivity and cell kinetics. Three gastric carcinomas (St-4, St-40 and H-111), two colon carcinomas (Co-3 and Co-4) and one breast carcinoma (MX-1) were inoculated into the subcutaneous tissue of BALB/cA nude mice. The maximum tolerable doses of mitomycin C (MMC), adriamycin (ADM), cyclophosphamide (CPA) and 5-fluorouracil (5-FU) were administered when the tumor weights reached 100-300 mg. The response rates of the tumor to these drugs were found to be 3/6 for MMC, 2/6 for 5-FU and 1/6 for ADM and CPA. Percent labeled mitosis curves obtained from 3H-thymidine pulse labeling were analyzed by the method of Quastler and Sherman. It was found that the antitumor effect of MMC was closely correlated with the growth fractions of the tumors (r = -0.98, P less than 0.001), and it appeared that the tumor cells were more sensitive to MMC in the resting stages during the proliferating phase than in the other cell cycle phases. Cell kinetics is considered to be an important factor in determining chemosensitivity, and the system of human tumor xenografts-nude mice seems to be a suitable experimental model for investigating the correlation between cell kinetics and chemosensitivity in vivo.     

Karyology of a human colonic carcinoma (GW-39) serially xenografted in hamsters and in nude mice.

A karyological analysis of the G-banded chromosomes of the serially transplantable GW-39 human colonic carcinoma was undertaken. GW-39 cells harvested from hamsters, nude (athymic) mice and cell cultures from 1972 to 1976 revealed a hypodiploid stemline of 45 human chromosomes, with a consistent loss of a 21-chromosome. No apparent alterations of the near-diploid stemline resulted during long-term xenogeneic propagation of this human cancer line.     

Human neuroblastoma serially transplanted in nude mice and metastases

A human neuroblastoma from a female patient was directly transplanted into nude mice and serial transplantation was established. Histology of the transplanted tumor was almost the same as that of the patient. During serial transplantation, a high frequency of metastasis to distant organs such as ovaries, lymph node and cerebrum was observed, especially in the ovaries where the metastatic rate reached to 66%. Regarding the distribution of organs involved, there is close similarity between that in the patient with neuroblastoma and tumor-bearing mice. This transplantable human neuroblastoma provided a unique research tool for studies on its morphological and biological nature, including metastasis.     

Experimental combined hormone therapy on human breast carcinomas serially transplanted into nude mice

Experimental combined hormone therapy with tamoxifen, aminoglutethimide and medroxyprogesterone acetate was investigated using three hormone-dependent human breast carcinomas serially transplanted into nude mice. The antitumor effect of combined tamoxifen and aminoglutethimide was better than that of either tamoxifen or aminoglutethimide alone. Since aminoglutethimide significantly reduced the level of estrogen and the uterine weight in normal female mice, the antitumor effect of combined tamoxifen and aminoglutethimide was assumed to be a result of the low estrogen level produced by aminoglutethimide, favoring the competition of tamoxifen with estrogen receptors. There was no additive antitumor effect of the combination of tamoxifen and medroxyprogesterone acetate, although serum medroxyprogesterone acetate levels in nude mice were almost equivalent to those of humans. These results indicate that combination hormone therapy, especially with and aminoglutethimide, might be a promising method for clinical application.     

Primary human breast carcinomas transplantable in the nude mouse.

Of 19 primary human breast carcinomas implanted into noninbred female nude mice, 3 produced transplantable tumors. Membrane components specific for human mammary epithelial cells were demonstrated in the cells from heterotransplants even after four or five passages in nude mice.     

Endocrine sensitivity of the receptor-positive T61 human breast carcinoma serially grown in nude mice

A study was made on the effect of ovariectomy, 17 beta-oestradiol, and tamoxifen on the oestrogen and progesterone receptor-positive T61 human breast carcinoma grown in nude mice. The effect of the treatment was evaluated by the specific growth delay calculated on the basis of Gompertz growth curves, and by the changes in the cell cycle distribution monitored by flow cytometric DNA analysis. The results demonstrated that both oestradiol and tamoxifen induced a temporary growth delay, whereas ovariectomy of the host had no effect on the growth of the tumour. The oestradiol-induced tumour growth delay was accompanied by a decrease in the G1 fraction, an accumulation of cells in the S-phase, and polyploidy, whereas neither treatment with tamoxifen nor ovariectomy influenced cell cycle distribution. The results indicate that oestradiol and tamoxifen have different mechanisms of action. In addition, they were interpreted as indicating different mechanisms regulating ovarian-dependent tumour growth, on the one hand, and oestrogen and tamoxifen-induced tumour growth inhibition, on the other. The results support the view that the presence of receptors may be of importance but is not a sufficiently clear marker to allow prediction of the endocrine sensitivity of individual breast tumours.     

Radiation therapy for human renal cell carcinoma transplantable to the nude mice

Efficacy of radiation therapy was studied using human renal cell carcinoma strain (AM-RC-3) implantable in nude mice. Cobalt 60 gamma-ray was used dosage of 5 Gy, 10 Gy, 15 Gy and 20 Gy in single, localized exposures of subcutaneously implanted tumors of the lower right femoral region. Therapeutic efficacy was determined using the Battelle Columbus Standard and evaluation of histological changes based on National Cancer Research Institute (Shimosato's classifications). Conclusion based on the obtained data are as follows: I) The T RW/C RW ratio on the tumor growth curve was 42% or less for all dosage groups except the 5 Gy group; dosages other than 5 Gy are believed effective. The 15 and 20 Gy dosage were particularly effective and the respective groups had RW of 0.96 and 0.95. II) Although Grade IIa and IIb changes were observed in the 15 and 20 Gy dosage groups, respectively, two weeks after irradiation, four weeks after irradiation all groups exhibited microscopic tissue formations that could be considered regrowth of tumor cells. Determination of histopathological effectiveness two weeks after irradiation is thought most suitable. III) Radiation therapy is appropriate as an adjuvant treatment in cases of renal cell carcinoma and should be used in combination with other therapies.     

Establishment of transplantable human colon cancer cell lines, chemosensitivity of colon carcinomas and the serially transplantable strains with MTT assay

Three human colon carcinoma xenografts serially transplantable into nude mice were established and named Co-6, Co-7, and Co-8. The chemosensitivity of these stains were assessed by MTT assay of the fresh surgical specimens (primary MTT assay) and the serially passaged xenografts (xenografts MTT assay), in vivo chemosensitivity test in nude mice (nude mouse system) and clinical responses. Drugs used for the experiments are mitomycin C (MMC), adriamycin (ADM), 5-fluorouracil (5-FU) and cisplatin (DDP). The primary MTT assay revealed true negative with MMC and 5-FU on Co-7 and Co-8 cases. The chemosensitivity of the tumor cells seemed to be increased in the xenografts MTT assay and nude mouse system, in which MMC and DDP were evaluated to be positive on Co-6 and Co-7. However, the chemosensitivity pattern of the tumor cells seemed to be stable in these chemosensitivity tests, indicating better to choose the agent with the highest inhibition rate among various tested agents, even when none have an inhibition rate equal to or more than 50%.     

人绒癌裸鼠皮下移植瘤模型的放射免疫显像

目的 探讨放射免疫显像对人绒癌裸鼠皮下移植瘤的显像效果。方法 应用＾１３１Ｉ标记的小鼠抗ｈＣＧ单克隆抗体,对人绒癌裸鼠皮下移植瘤模型进行放射免疫显像,以正常小鼠ＩｇＧ作为对照,观察放射免疫显像效果,并测定不组织中的放射性活度,计算肿瘤／非肿瘤放射活性比（Ｔ／ＮＴ比值）。结果 在注入标记抗体后２４小时,移植瘤部位即可见放射性浓聚,并随时间的推移而浓聚增强,７２－９６小时后肿瘤可以清晰显像,可显像的最     

Human endometrial carcinomas serially transplanted in nude mice and established in continuous cell lines.

Three out of five human endometrial carcinomas were successfully grafted into nude mice (BALB/c/nu/nu). Two of these tumors could be maintained by serial transplantation. The morphological characteristics displayed by the grafted tumors were comparable to those of the original carcinomas. Permanent cell lines were established from these two tumors. Reinjection of cells grown in vitro into nude mice produced nodules of identical histology as compared to original solid transplants. The influence of medroxyprogesterone acetate on tumor growth in vivo and cell proliferation in vitro was studied. This hormonal treatment did not produce any significant effect on tumor cells, either in vitro or in vivo, for the two endometrial carcinomas. After medroxyprogesterone administration, a slight but non-significant growth inhibition of the tumor cells in vitro was observed and the tumor transplants in vivo did not appear to be influenced. The experiments illustrate the possible use of this model for testing potential anti-cancer agents.     

CIK细胞对脾虚型人胃癌裸鼠腹膜移植模型抗肿瘤作用及其机制的实验研究

目的 :探讨CIK细胞对脾虚型人胃癌裸鼠腹膜移植模型的抗肿瘤作用及机制。方法 :在成功制备CIK细胞、建立脾虚型人胃癌裸鼠腹膜移植模型的基础上 ,观察CIK细胞对脾虚型人胃癌裸鼠腹膜移植模型的体内抗肿瘤作用。用放射免疫方法 (RIA )、酶联免疫方法(ELISA)检测CIK细胞在体内抗肿瘤过程中血清和腹水中CEA以及血清IL 2、TNF α、IFN γ、GM CSF含量的变化。结果 :NS对照组裸鼠腹水继续生长 ,与其相比 ,CD3AK组体质量、腹围、腹水量均明显减少 ,P <0 0 1。CIK组较CD3AK组上述指标有进一步显著减少 ,腹水均全部消失 ,其腹水抑制率达 10 0 % ,P <0 0 1;NS对照组裸鼠血清、腹水中CEA含量均保持较高水平 ,与其相比 ,CD3AK组明显减少 ,CIK组较CD3AK组血清中CEA含量进一步显著减低 ,P <0 0 1;另外 ,与NS对照组相比 ,CIK组裸鼠血清中IL 2、TNF α、INF γ、GM CSF含量均显著增加 ,P <0 0 1。结论 :CIK细胞对脾虚型人胃癌腹膜移植裸小鼠模型有更强的体内抗肿瘤活性 ;并可显著减少胃癌细胞CEA的分泌 ,继续分泌IL 2、TNF α、INF γ、GM CSF等细胞因子而发挥直接或间接的抗肿瘤作用。