The effect of co-inoculation of membrane matrix, Matrigel and two human breast cancer cell lines, was (Cornil et al., 1989;Fu et al., 1991Fu et al., , 1992 (Elledge et al., 1992) and has been reported to be an important prognostic factor in node-negative breast ancer (Pavelic et al., 1992). Stable and exclusive c-erbB-2 overexpression by malignant cells (Niehans et al., 1993) and profound effects of signal transduction through the c-ErbB-2 pathway (Harwerth et al., 1993; Lupu and Lippman 1993) (Boston, MA, USA). These mice lack natural killer cell activity owing to the beige (bg) mutation, are athymic owing to the nude mutation (nu) and have a lack of T cell-independent B cells because of their X-linked immun deficiency. The animals were kept in isolator cages which were changed twice weekly. They were Correspondence: H-J van Slooten,

Pegylated liposomal doxorubicin (PL-DOX or DoxiP ) is currently being used in the clinic to treat solid tumors in humans (ovarian and breast cancer and Kaposi's sarcoma). Previous preclinical studies comparing the antitumor activity of nonliposomal doxorubicin and PL-DOX have shown that PL-DOX has significantly greater antitumor activity at equivalent doses, but these studies have not reported the degree of increase in antitumor potency associated with liposome encapsulation at lower doses of PL-DOX. The studies presented here were designed to determine the dose of PL-DOX that produces the same antitumor activity as the maximum tolerated dose (MTD) of nonliposomal doxorubicin. Conventional mice were inoculated with Lewis lung or C26 colon cells, and nude mice were inoculated with BT474 or MCF7 human breast cancer cells. Tumor-bearing mice were treated with nonliposomal doxorubicin at the MTD or with PL-DOX at the same or lower doses. As in previously published studies, PL-DOX had significantly greater antitumor activity than nonliposomal doxorubicin at the same dose levels (p < 0.05). In Lewis Lung and C26 Colon carcinoma, antitumor activity of nonliposomal doxorubicin (9 Journal of Liposome Research Downloaded from informahealthcare.com by Kungliga Tekniska Hogskolan on 08/11/15For personal use only. COLBERN ET AL.mg/kg, the MTD for conventional mice) was equivalent to antitumor activity of PL-DOX at 2 mg/kg, a 4.5-fold increase in antitumor potency. In human breast cancer xenografts (BT474 and MCF7) in nude mice, antitumor activity of nonliposomal doxorubicin (4 mg/kg, the MTD for nude mice) was equivalent to PL-DOX at 2 mg/kg, a 2-fold increase in potency. Based on results of these studies, the potency of PL-DOX is increased from 2to 4.5-fold conipared to nonliposomal doxorubicin.

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.

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By using a unique short-term culture system capable ofgrowing 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 ofthe malignant specimens were sensitive to TNF with 13 of 18 specimens showing 90% inhibition of clonal growth (IED9) by <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 >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.