Growth Of Human Tumor Xenografts Research Articles

A potent protein-tyrosine kinase inhibitor which selectively blocks proliferation of epidermal growth factor receptor-expressing tumor cells in vitro and in vivo.

A calculated 3-D model of the kinase domain of the epidermal growth factor receptor (EGF-R) protein-tyrosine kinase (PTK) was used to develop a pharmacophore model for ATP-competitive inhibitors and, subsequently, a new class of selective EGF-R kinase inhibitors. CGP 59326A, a highly selective and potent inhibitor of the EGF-R in vitro, inhibited the proliferation of EGF-R-expressing epithelial lines, while having little anti-proliferative activity against EGF-R-negative lines. In contrast to previously described inhibitors, CGP 59326A had potent and selective in vivo anti-tumor activity at well-tolerated doses against EGF-R-expressing tumors (e.g., ED50 of 0.78 to 1.5 mg/kg for inhibition of A431 tumor growth). CGP 59326A inhibited growth of human tumor xenografts expressing the EGF-R but showed little activity against EGF-R-negative xenografts. Combination of CGP 59326A with cytotoxic agents resulted in tumor regression and cures. The high selectivity and attractive biological profile of CGP 59326A suggest that it could have therapeutic value in the treatment of proliferative diseases which involve mitogenic signaling from the EGF-R.

Monoclonal antibody therapy of human cancer: Taking the HER2 protooncogene to the clinic

The HER2 protooncogene encodes a 185-kDa transmembrane protein (p185HER2) with extensive homology to the epidermal growth factor (EGF) receptor. Clinical and experimental evidence supports a role for overexpression of the HER2 protooncogene in the progression of human breast, ovarian, and non-small cell lung carcinoma. These data also support the hypothesis that p185HER2 present on the surface of overexpressing tumor cells may be a good target for receptor-targeted therapeutics. The anti-p185HER2 murine monoclonal antibody (muMAb) 4D5 is one of over 100 monoclonals that was derived following immunization of mice with cells overexpressing p185HER2. The monoclonal antibody is directed at the extracellular (ligand binding) domain of this receptor tyrosine kinase and presumably has its effect as a result of modulating receptor function. In vitro assays have shown that muMAb 4D5 can specifically inhibit the growth of tumor cells only when they overexpress the HER2 protooncogene. MuMAb 4D5 has also been shown to enhance the TNF-alpha sensitivity of breast tumor cells that overexpress this protooncogene. Relevant to its clinical application, muMAb 4D5 may enhance the sensitivity of p185HER2-overexpressing tumor cells to cisplatin, a chemotherapeutic drug often used in the treatment of ovarian cancer. In vivo assays with a nude mouse model have shown that the monoclonal antibody can localize at the tumor site and can inhibit the growth of human tumor xenografts which overexpress p185HER2. Modulation of p185HER2 activity by muMAb 4D5 can therefore reverse many of the properties associated with tumor progression mediated by this putative growth factor receptor. Together with the demonstrated activity of muMAb 4D5 in nude mouse models, these results support the clinical application of muMAb 4D5 for therapy of human cancers characterized by the overexpression of p185HER2.

Effects of IL-6, alone and in combination with chemotherapeutic agents or radiotherapy, on the growth of human tumor xenografts

Effects of IL-6, alone and in combination with chemotherapeutic agents or radiotherapy, on the growth of human tumor xenografts

Anti-epidermal growth factor receptor monoclonal antibodies as potential anti-cancer agents

The EGF receptor is a potential target for antitumor therapy, because it is expressed at high levels on many human tumor cells and appears to be involved in autocrine stimulation of cell growth in a number of experimental studies. Anti-EGF receptor MAbs, which block ligand binding, can prevent the growth in culture of cells that are stimulated by EGF or TGF-α. Growth of human tumor xenografts bearing high levels of EGF receptors is also inhibited. A Phase I trial in patients with squamous cell carcinoma of the lung has demonstrated the capacity of a single dose of 120 mg anti-EGF receptor MAb to localize in such tumors and to achieve saturating concentrations in the blood for more than 3 days, without causing toxicity.

Recombinant interleukin-2 inhibits growth of human tumor xenografts in congenitally athymic mice

Administration of human recombinant interleukin-2 (RIL-2) into congenitally athymic (nu/nu) mice carrying subcutaneous transplants of HeLa, HU 609T and T24B human carcinoma cells partially inhibited growth of the human tumor xenografts. In vitro activation of nu/nu spleen cells with human RIL-2 resulted in generation of killer cells showing in the 51Cr cytotoxicity assay similar levels of cytolysis as RIL-2-activated spleen cells from heterozygous (nu/+) mice. The RIL-2-activated (LAK) cells were cytotoxic for a variety of mouse and human tumors, reaching the peak of their cytotoxic activity after 3 days of cultivation in the RIL-2-containing medium. The cytotoxic activity of activated nu/nu spleen cells was significantly reduced by treatment with antibody against glycolipid asialo GM1, the differentiation antigen of natural killer (NK) cells. This finding suggests that in addition to the conventional, asialo GM1 − LAK cells, asialo GM1 + activated NK cells participated in the cytotoxicity displayed by the IL-2-activated nu/nu killer spleen cells.

Clonal growth of human tumor xenografts. First experiences in drug testing.

Human tumors growing as nude mice xenografts were investigated for growth in a clonogenic assay. Colony formation of more than 30 colonies per plate was obtained in 47 of 63 tumors examined (74.6%). The growth rate was enhanced by raising the concentration of fetal calf serum in the culture medium. Plating efficiency ranged from 0.0003% to 5.5%. To study the applicability of this model for screening new anticancer drugs, preliminary studies in drug sensitivity were conducted with continuous incubation of different anticancer drugs in a dose range of 1/10 to 10 times the maximum achievable plasma level. The highest concentration almost always led to a complete suppression of colony growth. In our opinion the procedure described may be a useful combination of two methods in predictive drug testing, provided drug concentration and mode of drug incubation are adequately considered.

Polar solvents: a novel class of antineoplastic agents.

It has been known for many decades that certain murine and human cancers can spontaneously mature to benign tissue. These observations have stimulated investigators to attempt to induce a state of more normal or benign differentiation in cancer cells using biologic substances or chemicals. Polar solvents including dimethylsulfoxide, dimethylformamide, and monomethylformamide have proven to be good inducers of maturational events in murine and human cancer cells. Moreover, several laboratories have demonstrated that polar solvents inhibit the growth of human tumor xenografts in nude mice. These findings have resulted in the entry of monomethylformamide into phase I clinical trials in America and Europe. Preclinical work further suggests that polar solvents may be useful agents in combination with conventional treatment modalities. The use of drugs such as monomethylformamide that can convert neoplastic cells to benign cells rather than kill the tumor cells represents an important conceptual departure from standard cytotoxic chemotherapy. The use of maturational-agent therapy should be considered as an important new development in the design of cancer treatment protocols.

Growth of human tumors in mice after short-term immunosuppression with procarbazine, cyclophosphamide, and antilymphocyte serum.

A simple combine treatment with immunosuppressive agents permitting the growth of human tumor xenografts in conventional mice is presented. It consists of two simultaneous applications of 90 mg of procarbazine (PCH) per kg and 30 mg of cyclophosphamide (CY) per kg, alternating with two doses of 0.15 ml/10 g of antilymphocyte serum (ALS) for 4 days before grafting. No postgraft treatment is used. With a take rate of 100%, at 60 days after subcutaneous transplantation into male C3H mice, fragments of a human colon adenocarcinoma had grown (on the average) into cherry-sized tumors. Two osteosarcomas, an Ewing sarcoma, and a bronchogenic carcinoma were also studied and grew similarly. Tumors could be established in the three tested mouse strains but grew better in male animals. Synergy of PCH and CY and ALS depends upon the alternating sequence of both drugs and ALS. The histology of the colon carcinoma and the Ewing sarcoma was unchanged as compared to the tumors growing in nude mice. In contrast, the osteosarcoma developed in a more differentiated fashion in the immunosuppressed mice. The presented model may serve as a screening system for anticancer drugs.

N:NIH(S)II-<italic>nu/nu</italic> Mice With Combined Immunodeficiency: A New Model for Human Tumor Heterotransplantation<xref ref-type="fn" rid="fn2">2</xref>

A new "nude" mouse model was developed by successive crossings and backcrossings between athymic nu/nu mice, on an N:NIH(S) background, and female CBA/N mice that have an X-linked immune defect in B-lymphocyte function. The resulting doubly congenic N:NIH(S(II-nu/nu mice maintained the marked thymic hypoplasia and poor development of hair of the nu/nu mice. In contrast to nu/nu and CBA/N mice, in this new mouse model both T-cell zones of lymph nodes and the spleen were depleted of lymphocytes. Lymphocytic follicles were rare and diminutive; not germinal centers were noted. The nodal cortical and paracortical areas were represented principally by connective tissue, endothelial cells, and macrophages, including giant multinucleated cells. No medullary cords were recognized. The mice with combined immunodeficiency supported the growth of human tumor xenografts and were susceptible to murine viral hepatitis.

Human tumour xenografts established and serially transplanted in mice immunologically deprived by thymectomy, cytosine arabinoside and whole-body irradiation.

Mice immunologically deprived by thymectomy, cytosine arabinoside treatment and whole-body irradiation were used to study the growth of human tumours as xenografts. 10/16 melanoma biopsies, 4/13 ovarian carcinoma biopsies and 3/6 uterine cancer biopsies grew as serially transpllantable xenograft lines. The tumour lines were studied through serial passages by histology, histochemistry, electron microscopy, chromosome analysis, immune fluorescence, growth rate measurement and mitotic counts. They retained the characteristics of the tumours of origin, with the exception of loss of pigmentation in two melanomas, histological dedifferentiation in the uterine carcinomas, and increased mitotic frequency and growth rate in some melanomas. It was concluded that this type of animal preparation is as useful as alternative methods of immunological deprivation, or as athymic nude mice, for the growth of human tumour xenografts, at least for some experimental purposes.

Growth of human tumor xenografts implanted under the renal capsule of normal immunocompetent mice.

The subrenal capsule technique proved effective in demonstrating that the growth of human tumors in normal, immunocompetent animals for 6 days was quantifiable in ocular micrometer units. Positive growth was demonstrable not only with human tumors that had been established in serial transplantation in athymic nude mouse hosts, but also with primary surgical explants. Growth rates of transplantation-established xenograft systems were similar whether implanted in athymic nude or in normal immunocompetent animals indicating that the 6-day time-frame successfully evades growth inhibitory effects of immunologic origin. Immunosuppression with a single dose of cyclophosphamide did not appear to affect growth rate, but permitted the tumors to grow larger extending the time to reach peak size. Significantly, xenografts of primary surgical explants showed positive growth more frequently in 6 days (82%) in the immunocompetent animal than in 11 days (30%) in the immunodeficient athymic nude mouse.

Metastatic growth of human tumour xenografts in thymectomised irradiated mice reconstituted with syngeneic bone marrow cells

Human tumour xenografts were grown by s.c. implantation in thymectomised irradiated mice reconstituted with syngeneic bone marrow cells. Sixty-three tumour specimens were implanted into 462 mice, and tumour survivals of 1 to 20 weeks were recorded. At autopsy, a comprehensive macroscopic and microscopic examination was made. Eighteen cases of metastasis were observed from 5 different tumour types.