Pastorino Fabio, Mumbengegwi Davis R, Ribatti Domenico, Ponzoni Mirco, Allen Theresa M
Differentiation Therapy Unit, Laboratory of Oncology, G. Gaslini Children's Hospital, 16148-Genoa, Italy.
J Control Release. 2008 Feb 18;126(1):85-94. doi: 10.1016/j.jconrel.2007.11.010. Epub 2007 Nov 28.
Patients with advanced or metastatic melanoma have a very poor prognosis, due to the resistance of melanoma cells to conventional chemotherapy. We previously reported that coated cationic liposomes targeted with a monoclonal antibody against the disialoganglioside GD(2) and containing c-myc antisense oligodeoxynucleotides (alpha GD(2)-CCL[c-myc-as]) induced partial tumor growth arrest in melanoma xenografts. Here we addressed the role of c-myc-asODN treatment in the susceptibility to doxorubicin (DXR) in human melanoma cells. Cytotoxicity studies revealed that growth of melanoma cells was inhibited to a greater extent by alpha GD(2)-CCL[c-myc-as] than by the corresponding non-targeted formulations or by free c-myc-as. Targeted c-myc-as sensitized cells to DXR, reducing the IC(50) by approximately 10-fold. Scrambled ODNs had no effect on the IC(50) of DXR. Compared to either treatment alone, combination of targeted c-myc-as and DXR resulted in earlier apoptosis and in cell death after 2 days of treatment. In vivo experiments revealed that liposomal formulations of c-myc-as and DXR, both targeted via GD(2), led to the most pronounced delay in tumor growth when administered in a sequential manner. As a result, their combination translates into a statistically significant suppression of blood vessel density and an enhanced apoptosis, compared to all treatments given separately. Our data indicate the increasing cell sensitivity to DXR by c-myc-asODNs as a promising basis for developing novel anti-tumor strategy against advanced melanoma.
晚期或转移性黑色素瘤患者预后很差，这是由于黑色素瘤细胞对传统化疗具有抗性。我们之前报道过，用抗双唾液酸神经节苷脂GD(2)的单克隆抗体靶向且含有c-myc反义寡脱氧核苷酸的包被阳离子脂质体（α GD(2)-CCL[c-myc-as]）可使黑色素瘤异种移植瘤的肿瘤生长部分停滞。在此，我们探讨了c-myc反义寡脱氧核苷酸（c-myc-asODN）处理在人黑色素瘤细胞对阿霉素（DXR）敏感性中的作用。细胞毒性研究表明，与相应的非靶向制剂或游离的c-myc-as相比，α GD(2)-CCL[c-myc-as]对黑色素瘤细胞生长的抑制作用更强。靶向的c-myc-as使细胞对DXR敏感，将半数抑制浓度（IC(50)）降低了约10倍。乱序寡脱氧核苷酸对DXR的IC(50)没有影响。与单独的任何一种处理相比，靶向的c-myc-as与DXR联合使用导致更早出现凋亡，且在处理2天后出现细胞死亡。体内实验表明，通过GD(2)靶向的c-myc-as和DXR的脂质体制剂以序贯方式给药时，导致肿瘤生长的延迟最为显著。因此，与单独给予的所有处理相比，它们的联合使用在统计学上显著抑制了血管密度并增强了凋亡。我们的数据表明，c-myc-asODN使细胞对DXR的敏感性增加，这是开发针对晚期黑色素瘤的新型抗肿瘤策略的有前景的基础。
