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

The fate of breast cancer patients is dependent upon elimination or control of metastases. We studied the effect of antibody-targeted liposomes contai ning entrapped doxorubicin (DXR) on development of tumours in two models of breast cancer, pseudometastatic and metastatic, in mice. The former used t he mouse mammary carcinoma cell line GZHI, which expresses the human MUG-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. Longeneck er, Cancer Immunol. Immunother. 36 (1993) 9-17). GZHI cells seed into the l ungs of Balb/c mice following intravenous injection. The latter used the 4T 1-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). B 27.29, a monoclonal antibody against the MUC-1 antigen, was used to target sterically stabilized immunoliposomes (SIL[B27.29]) to tumour cells. In vit ro, SIL[B27.29] showed high specific binding to both GZHI and 4T1-MUC1 cell s. The IC50 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 inje ction of 6 mg DXR/ kg in DXR-SIL[B27.29] at 24 h after cell implantation ha d longer survival times than those injected with non-targeted liposomal dru g. In the metastatic model, severe combined immune deficiency mice given we ekly injections X 3 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 o f the primary tumour from mfp, followed by various chemotherapy regimens, w as attempted, but removal of the primary tumour was generally incomplete; t umour regrowth occurred and metastases developed in the lungs in all treatm ent 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. (C) 2001 Elsevier Science B.V. All rights reserved.