Maschek Gregory, Savaraj Niramol, Priebe Waldemar, Braunschweiger Paul, Hamilton Kara, Tidmarsh George F, De Young Linda R, Lampidis Theodore J
Department of Cell Biology and Anatomy, University of Miami, School of Medicine, Miami, Florida 33101, USA.
Cancer Res. 2004 Jan 1;64(1):31-4. doi: 10.1158/0008-5472.can-03-3294.
Slow-growing cell populations located within solid tumors are difficult to target selectively because most cells in normal tissues also have low replication rates. However, a distinguishing feature between slow-growing normal and tumor cells is the hypoxic microenvironment of the latter, which makes them extraordinarily dependent on anaerobic glycolysis for survival. Previously, we have shown that hypoxic tumor cells exhibit increased sensitivity to inhibitors of glycolysis in three distinct in vitro models. Based on these results, we predicted that combination therapy of a chemotherapeutic agent to target rapidly dividing cells and a glycolytic inhibitor to target slow-growing tumor cells would have better efficacy than either agent alone. Here, we test this strategy in vivo using the glycolytic inhibitor 2-deoxy-D-glucose (2-DG) in combination with Adriamycin (ADR) or paclitaxel in nude mouse xenograft models of human osteosarcoma and non-small cell lung cancer. Nude mice implanted with osteosarcoma cells were divided into four groups as follows: (a) untreated controls; (b) mice treated with ADR alone; (c) mice treated with 2-DG alone; or (d) mice treated with a combination of ADR + 2-DG. Treatment began when tumors were either 50 or 300 mm(3) in volume. Starting with small or large tumors, the ADR + 2-DG combination treatment resulted in significantly slower tumor growth (and therefore longer survival) than the control, 2-DG, or ADR treatments (P < 0.0001). Similar beneficial effects of combination treatment were found with 2-DG and paclitaxel in the MV522 non-small cell lung cancer xenograft model. In summary, the treatment of tumors with both the glycolytic inhibitor 2-DG and ADR or paclitaxel results in a significant reduction in tumor growth compared with either agent alone. Overall, these results, combined with our in vitro data, provide a rationale for initiating clinical trials using glycolytic inhibitors in combination with chemotherapeutic agents to increase their therapeutic effectiveness.
实体瘤中生长缓慢的细胞群体难以被选择性靶向，因为正常组织中的大多数细胞复制率也很低。然而，生长缓慢的正常细胞与肿瘤细胞之间的一个显著区别是后者的缺氧微环境，这使得它们极度依赖无氧糖酵解来维持生存。此前，我们已经在三种不同的体外模型中表明，缺氧肿瘤细胞对糖酵解抑制剂表现出更高的敏感性。基于这些结果，我们预测，一种靶向快速分裂细胞的化疗药物与一种靶向生长缓慢的肿瘤细胞的糖酵解抑制剂联合治疗，将比单独使用任何一种药物具有更好的疗效。在此，我们在人骨肉瘤和非小细胞肺癌的裸鼠异种移植模型中，使用糖酵解抑制剂2-脱氧-D-葡萄糖（2-DG）与阿霉素（ADR）或紫杉醇联合，在体内测试了这一策略。将植入骨肉瘤细胞的裸鼠分为以下四组：（a）未治疗的对照组；（b）单独接受ADR治疗的小鼠；（c）单独接受2-DG治疗的小鼠；或（d）接受ADR + 2-DG联合治疗的小鼠。当肿瘤体积达到50或300立方毫米时开始治疗。从大小不同的肿瘤开始，ADR + 2-DG联合治疗导致肿瘤生长明显比对照、2-DG或ADR治疗更慢（因此生存期更长）（P < 0.0001）。在MV522非小细胞肺癌异种移植模型中，2-DG与紫杉醇联合治疗也发现了类似的有益效果。总之，与单独使用任何一种药物相比，使用糖酵解抑制剂2-DG与ADR或紫杉醇联合治疗肿瘤可显著降低肿瘤生长。总体而言，这些结果与我们的体外数据相结合，为启动使用糖酵解抑制剂与化疗药物联合的临床试验以提高其治疗效果提供了理论依据。
