Anti-MUC-1 immunoliposomal doxorubicin in the treatment of murine models of metastatic breast cancer

Abstract

The fate of breast cancer patients is dependent upon elimination or control of metastases. We studied the effect of antibody-targeted liposomes containing entrapped doxorubicin (DXR) on development of tumours in two models of breast cancer, pseudometastatic and metastatic, in mice. The former used the mouse mammary carcinoma cell line GZHI, which expresses the human MUC-1 gene (L. Ding, E.N. Lalani, M. Reddish, R. Koganty, T. Wong, J. Samuel, M.B. Yacyshyn, A. Meikle, P.Y.S. Fung, J. Taylor-Papadimitriou, B.M. Longenecker, Cancer Immunol. Immunother. 36 (1993) 9--17). GZHI cells seed into the lungs of Balb/c mice following intravenous injection. The latter used the 4T1-MUC1 cell line, a MUC-1 transfectant of the mouse mammary carcinoma cell line 4T1, which metastasizes from a primary mammary fatpad (mfp) implant to the lungs (C.J. Aslakson, F.R. Miller, Cancer Res. 52 (1992) 1399--1405). B27.29, a monoclonal antibody against the MUC-1 antigen, was used to target sterically stabilized immunoliposomes (SIL[B27.29]) to tumour cells. In vitro, SIL[B27.29] showed high specific binding to both GZHI and 4T1-MUC1 cells. The IC(50) of DXR-loaded SIL[B27.29] was similar to that of free drug for GZHI cells. In the pseudometastatic model, mice treated with a single injection of 6 mg DXR/kg in DXR-SIL[B27.29] at 24 h after cell implantation had longer survival times than those injected with non-targeted liposomal drug. In the metastatic model, severe combined immune deficiency mice given weekly injectionsx3 of 2.5 mg DXR/kg encapsulated in either targeted or non-targeted liposomes were almost equally effective in slowing growth of the primary tumour and reducing development of lung tumours. Surgical removal of the primary tumour from mfp, followed by various chemotherapy regimens, was attempted, but removal of the primary tumour was generally incomplete; tumour regrowth occurred and metastases developed in the lungs in all treatment groups. DXR-SL reduced the occurrence of regrowth of the primary tumour, whereas neither targeted liposomal drug or free drug prevented regrowth. We conclude that monoclonal antibody-targeted liposomal DXR is effective in treating early lesions in both the pseudometastatic and metastatic models, but limitations to the access of the targeted liposomes to tumour cells in the primary tumour compromised their therapeutic efficacy in treating the more advanced lesions.

Determination of Doxorubicin Levels in Whole Tumor and Tumor Nuclei in Murine Breast Cancer Tumors

“…Tumors were orthotopically implanted in female BALB/c mice as previously described (23). Briefly, a small incision was made in the lower right abdominal region of anesthetized mice, and 1 Â 10 5 4T1 cells, in full medium, were injected into the right 4 mammary fat pad.…”

Anti-tumor effects of the bacterium caulobacter crescentus in murine tumor models

“…The cells were incubated with FITC labelled B27.29 Mab (10 µg/ml) for 45 min at 4˚C. 19 After washing, the cells were analysed to ensure MUC1 expression on a FACScan (Becton Dickinson, Mountain View, CA) under standard conditions. Animal studies.…”

“…with 1 x 10 6 cells of the Lewis lung carcinoma cell line transfected with MUC1 antigen (LLC-MUC1). 19,20 Murine mammary carcinoma model. BALB/c mice preimmunized with C. crescentus were challenged with 1 x 10 6 EMT-6 cells subcutaneously (s.c.) into the nape of the neck on day 0.…”

Anthracyclines: Molecular Advances and Pharmacologic Developments in Antitumor Activity and Cardiotoxicity

“…The formulation was effective in treating early lesions in both the pseudometastatic and metastatic models, but limitations in the access to tumor cells in the primary tumor compromised its therapeutic efficacy in treating the more advanced lesions (Moase et al, 2001). Other investigators assessed the therapeutic applicability of using liposome-encapsulated DOX targeted against the internalizing CD19 antigens present on human multiple myeloma cells.…”