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Biomedical subjects

A J Hiller

Publications and source records attributed to A J Hiller.

8 recordsLinked to original sources
PubMed1999

Antitumor activity of Herceptin in combination with STEALTH liposomal cisplatin or nonliposomal cisplatin in a HER2 positive human breast cancer model.

Single agent antitumor activity of Herceptin, a humanized monoclonal antibody directed against HER2, has been demonstrated in numerous preclinical and clinical studies. Additionally, combination therapy with Herceptin and chemotherapy (CRx) has demonstrated additive antitumor activity in both preclinical models and early clinical trials. STEALTH (pegylated) liposomal (PL) cisplatin, also known as SPI-077, is currently in clinical trials for a variety of solid tumors. The three studies reported here discuss the antitumor activity of the combination of Herceptin and nonliposomal cisplatin or PL-cisplatin in two xenograft tumor models, initiated from the cell lines, BT474 and MDA453, that overexpress the oncogene, HER2. Herceptin alone had significant antitumor activity in all three experiments (p < 0.0001). Nonliposomal cisplatin and PL-cisplatin were both effective antitumor agents but, at tolerable dose levels, PL-cisplatin was superior to nonliposomal cisplatin (p < 0.0003). The effect of combining Herceptin with the chemotherapeutic cisplatin or PL-cisplatin, was most significant at moderate doses of H (0.5 mg/kg, p < 0.0001), but tended to be greater than either agent alone in all experiments. The combination of PL-cisplatin with Herceptin had statistically similar antitumor activity to that of nonliposomal cisplatin with Herceptin in all experiments. We conclude that combination therapy with PL-cisplatin and Herceptin results in significant antitumor activity with the potential for reducing toxicity in metastatic breast cancer patients.

Animals↗
PubMed1995

Outgrowth of BT-474 human breast cancer cells in immune-deficient mice: a new in vivo model for hormone-dependent breast cancer.

The effect of co-inoculation of basement membrane matrix, Matrigel and two human breast cancer cell lines, BT-474 and SK-BR-3, was tested in immune-deficient mice. Both cell lines strongly overexpress c-ErbB-2 protein, whereas only BT-474 is reported to be oestrogen receptor positive. Co-inoculation of Matrigel and BT-474 cells but not of Matrigel and SK-BR-3 cells resulted in tumour formation in bg-nu-xid mice. Oestrogen supplementation greatly enhanced tumorigenicity, but did not seem to be an absolute requirement. In vivo, BT-474 cells grow as a poorly differentiated adenocarcinoma with a doubling time of 9.4 +/- 1.1 days after inoculation into the neck region. A high proliferative activity appears to be compensated by a relatively high rate of cell loss, as BT-474 tumours contain many cells with the typical morphology of apoptotic cell death. Wild-type p53, known to participate in the induction of apoptosis, is absent from the tumours, whereas Bcl-2, known to inhibit apoptosis, is expressed at intermediate levels. BT-474 tumours tend to metastasise to the regional lymph nodes and are capable of forming micrometastatic lesions in the lung. Flow cytometrical analysis of DNA ploidy demonstrated no change in tumours compared with the cell line. Immunohistochemical and flow cytometrical detection of a number of hormone and growth factor receptors, transcription factors, cell adhesion molecules and proteins involved in proliferation and cell death demonstrated no major changes in ploidy and phenotype of tumours compared with the cell line. High expression of the cell-surface molecules c-ErbB-2 and episialin make it a potentially useful model for research in immune therapy.

Animals↗
PubMed1988

Specificity of tumor necrosis factor toxicity for human mammary carcinomas relative to normal mammary epithelium and correlation with response to doxorubicin.

By using a unique short-term culture system capable of growing both normal and malignant breast epithelial tissue, human recombinant tumor necrosis factor (TNF) showed preferential cytotoxicity to malignant cells as compared to the corresponding nonmalignant cells. Most of the malignant specimens were sensitive to TNF with 13 of 18 specimens showing 90% inhibition of clonal growth (ID90) by less than 500 units of TNF per ml of culture fluid. In contrast, all 13 nonmalignant specimens tested clustered at the resistant end of the TNF response spectrum, with ID90 values being greater than 5000 units of TNF per ml of culture fluid. This differential sensitivity to TNF was seen in three cases in which malignant and nonmalignant breast epithelial tissues from the same patient were studied. To investigate the mechanism of resistance to TNF by normal cells, the presence of receptors for TNF was determined. Five of six cultures showed specific binding of 125I-labeled TNF and there was no relationship between the degree of resistance and the degree of specific binding. Simultaneous comparison of tumor responsiveness to doxorubicin and TNF revealed a positive correlation in ID90 values; these results may have important implications for the clinical use of TNF in cancer patients heavily pretreated with doxorubicin.

Breast↗
PubMed1985

Response to doxorubicin of cultured normal and cancerous human mammary epithelial cells.

Epithelial cells were isolated and cultured from a number of human mammary specimens of both cancerous and noncancerous origin. Doxorubicin (Dx) sensitivity was measured at second passage with the use of a highly efficient clonogenic assay. For 23 different tumor specimens derived from patients without previous chemotherapy, the drug concentrations required to kill 50% of the cells varied approximately 35-fold. In contrast, for 11 tumor specimens from patients who relapsed after regimens containing Dx, the drug concentration for 50% survival varied only fivefold and the dose-response curves for these specimens clustered at the more resistant end of the spectrum. A wide range of sensitivities was also observed among 13 noncancerous mammary specimens; however, tumor tissue and noncancerous tissue from the same donor were similar. When cultures were subjected to drug incubation periods of 1 and 4 hours, dose-response curves were superimposable when plotted as a function of drug concentration multiplied by time.

Breast↗
PubMed1976

The biology of human cells in tissue culture. I. Characterization of cells derived from osteogenic sarcomas.

We have extensively characterized cell lines derived from six human osteosarcomas. The growth properties of these cultures were compared to those of fibroblastic cultures derived from skin of osteosarcoma patients and skin of bone-marrow of normal individuals. Each tumor-derived line showed some but not all of the abnormal growth properties usually associated with malignant transformation, indicating that tumor cells rather than normal stromal cells had in fact been cultured. The parameters measured included saturation density, cell morphology, growth pattern, growth on contact inhibited monolayers of normal fibroblastic or epithelial cells and tumorigenicity in immunosuppressed mice. Although the skin fibroblasts from the osteosarcoma patients appeared normal in vitro, they showed a greater ability to grow in immunosuppressed mice than did normalfibroblasts. This observation suggests that all fibroblasts of osteosarcoma patients may have an increased propensity for malignant transformation.

Adolescent↗