Moase E H, Qi W, Ishida T, Gabos Z, Longenecker B M, Zimmermann G L, Ding L, Krantz M, Allen T M
Department of Pharmacology, University of Alberta, Edmonton, Canada.
Biochim Biophys Acta. 2001 Feb 9;1510(1-2):43-55. doi: 10.1016/s0005-2736(00)00334-5.
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.
乳腺癌患者的命运取决于转移灶的消除或控制。我们研究了包载阿霉素（DXR）的抗体靶向脂质体对两种小鼠乳腺癌模型（假转移模型和转移模型）中肿瘤发展的影响。前者使用表达人MUC - 1基因的小鼠乳腺癌细胞系GZHI（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）。静脉注射后，GZHI细胞会在Balb/c小鼠的肺部形成种植灶。后者使用4T1 - MUC1细胞系，它是小鼠乳腺癌细胞系4T1的MUC - 1转染细胞系，会从原发性乳腺脂肪垫（mfp）植入部位转移至肺部（C.J. Aslakson，F.R. Miller，Cancer Res. 52 (1992) 1399 - 1405）。针对MUC - 1抗原的单克隆抗体B27.29被用于将空间稳定免疫脂质体（SIL[B27.29]）靶向至肿瘤细胞。在体外，SIL[B27.29]对GZHI和4T1 - MUC1细胞均表现出高特异性结合。负载DXR的SIL[B27.29]对GZHI细胞的半数抑制浓度（IC50）与游离药物相似。在假转移模型中，细胞植入后24小时单次注射6 mg DXR/kg于DXR - SIL[B27.29]中的小鼠，其存活时间比注射非靶向脂质体药物的小鼠更长。在转移模型中，每周注射x3、剂量为2.5 mg DXR/kg且包裹于靶向或非靶向脂质体中的重度联合免疫缺陷小鼠，在减缓原发性肿瘤生长和减少肺部肿瘤发展方面几乎同样有效。尝试从mfp手术切除原发性肿瘤，随后采用各种化疗方案，但原发性肿瘤的切除通常不彻底；所有治疗组均出现肿瘤复发且肺部发生转移。DXR - SL减少了原发性肿瘤复发的发生，而靶向脂质体药物或游离药物均未能阻止复发。我们得出结论，单克隆抗体靶向脂质体DXR在假转移模型和转移模型中治疗早期病变均有效，但靶向脂质体进入原发性肿瘤中肿瘤细胞的受限性损害了它们在治疗更晚期病变时的疗效。
