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

摘要

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[B27.39]) 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 injections * 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 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 therapetutic efficacy in treating the more advanced lesions.