Gallicchio M A, van Sinderen M, Bach L A
Department of Medicine, University of Melbourne, Austin Hospital, Studley Rd, Heidelberg, Victoria, 3084, Australia.
Horm Metab Res. 2003 Nov-Dec;35(11-12):822-7. doi: 10.1055/s-2004-814153.
Rhabdomyosarcomas secrete high levels of insulin-like growth factor-II, suggesting this autocrine growth factor plays a major role in the unregulated growth of this childhood cancer. Treatment of Rh30 rhabdomyosarcoma cells with insulin-like growth factor binding protein-6 (IGFBP-6; 1000 ng/ml), which binds insulin-like growth factor-II with high affinity, inhibited growth in vitro (p < 0.001). Co-incubation of cells with rapamycin (1.56 ng/ml), an inhibitor of p70 S6 kinase, and IGFBP-6 (200 ng/ml) resulted in a significant reduction in Rh30 cell number compared to rapamycin or IGFBP-6 alone (p < 0.05 for both). Co-treatment of Rh30 cells with CCI-779 (5 and 50 ng/ml), an ester analogue of rapamycin, and IGFBP-6 (200 or 1000 ng/ml) also inhibited growth in vitro relative to CCI-779 alone (p < 0.01 and p < 0.001, respectively). In a nude mouse model, xenografts of Rh30 cells transfected with a recombinant vector encoding IGFBP-6 (phBP6-E3) showed delayed growth relative to vector control xenografts (27 days vs. 19 days to reach an average tumour volume of 0.5 cm (3); p < 0.001). Treatment with CCI-779 (10 mg/kg) of mice inoculated with vector control xenografts, also delayed growth (to 31 days; p = 0.0055) relative to untreated mice with vector control xenografts. Co-treatment with CCI-779 (10 mg/kg) reduced phBP6-E3 transfected xenograft growth even further (to 45 days) compared to vector control xenografts (p < 0.001, day 33). CCI-779 thus acts additively with IGFBP-6 to reduce rhabdomyosarcoma growth both in vitro and in vivo.
横纹肌肉瘤分泌高水平的胰岛素样生长因子-II，这表明这种自分泌生长因子在这种儿童癌症的失控生长中起主要作用。用与胰岛素样生长因子-II具有高亲和力的胰岛素样生长因子结合蛋白-6（IGFBP-6；1000 ng/ml）处理Rh30横纹肌肉瘤细胞，可抑制其体外生长（p<0.001）。将细胞与p70 S6激酶抑制剂雷帕霉素（1.56 ng/ml）和IGFBP-6（200 ng/ml）共同孵育，与单独使用雷帕霉素或IGFBP-6相比，Rh30细胞数量显著减少（两者p均<0.05）。用雷帕霉素酯类似物CCI-779（5和50 ng/ml）和IGFBP-6（200或1000 ng/ml）共同处理Rh30细胞，相对于单独使用CCI-779，也能抑制其体外生长（分别为p<0.01和p<0.001）。在裸鼠模型中，用编码IGFBP-6的重组载体（phBP6-E3）转染的Rh30细胞异种移植瘤相对于载体对照异种移植瘤生长延迟（达到平均肿瘤体积0.5 cm³分别为27天和19天；p<0.001）。用CCI-779（10 mg/kg）处理接种载体对照异种移植瘤的小鼠，相对于未处理的接种载体对照异种移植瘤的小鼠，生长也延迟（至31天；p = 0.0055）。与载体对照异种移植瘤相比，用CCI-779（10 mg/kg）共同处理可进一步降低phBP6-E3转染的异种移植瘤生长（至45天）（第33天p<0.001）。因此，CCI-７７９与IGFBP-6具有相加作用，可在体外和体内降低横纹肌肉瘤的生长。
