Abbott Laboratories, Cancer Research, Abbott Park, Illinois 60064, USA.
Clin Cancer Res. 2009 Dec 1;15(23):7277-90. doi: 10.1158/1078-0432.CCR-09-1245. Epub 2009 Nov 24.
ABT-888, currently in phase 2 trials, is a potent oral poly(ADP-ribose) polymerase inhibitor that enhances the activity of multiple DNA-damaging agents, including temozolomide (TMZ). We investigated ABT-888+TMZ combination therapy in multiple xenograft models representing various human tumors having different responses to TMZ.
ABT-888+TMZ efficacy in xenograft tumors implanted in subcutaneous, orthotopic, and metastatic sites was assessed by tumor burden, expression of poly(ADP-ribose) polymer, and O(6)-methylguanine methyltransferase (MGMT).
Varying levels of ABT-888+TMZ sensitivity were evident across a broad histologic spectrum of models (55-100% tumor growth inhibition) in B-cell lymphoma, small cell lung carcinoma, non-small cell lung carcinoma, pancreatic, ovarian, breast, and prostate xenografts, including numerous regressions. Combination efficacy in otherwise TMZ nonresponsive tumors suggests that TMZ resistance may be overcome by poly(ADP-ribose) polymerase inhibition. Profound ABT-888+TMZ efficacy was seen in experimental metastases models that acquired resistance to TMZ. Moreover, TMZ resistance was overcome in crossover treatments, indicating that combination therapy may overcome acquired TMZ resistance. Neither tumor MGMT, mismatch repair, nor poly(ADP-ribose) polymer correlated with the degree of sensitivity to ABT-888+TMZ.
Robust ABT-888+TMZ efficacy is observed across a spectrum of tumor types, including orthotopic and metastatic implantation. As many TMZ nonresponsive tumors proved sensitive to ABT-888+TMZ, this novel combination may broaden the clinical use of TMZ beyond melanoma and glioma. Although TMZ resistance may be influenced by MGMT, neither MGMT nor other mechanisms of TMZ resistance (mismatch repair) precluded sensitivity to ABT-888+TMZ. Underlying mechanisms of TMZ resistance in these models are not completely understood but likely involve mechanisms independent of MGMT.
ABT-888 目前处于 2 期临床试验阶段，是一种强效的口服多聚（ADP-核糖）聚合酶抑制剂，可增强多种 DNA 损伤剂的活性，包括替莫唑胺（TMZ）。我们研究了 ABT-888+TMZ 联合治疗在代表不同对 TMZ 反应的各种人类肿瘤的异种移植模型中的疗效。
通过肿瘤负担、多聚（ADP-核糖）聚合物和 O（6）-甲基鸟嘌呤甲基转移酶（MGMT）的表达，评估 ABT-888+TMZ 在皮下、原位和转移性部位植入的异种移植肿瘤中的疗效。
在包括弥漫性大 B 细胞淋巴瘤、小细胞肺癌、非小细胞肺癌、胰腺癌、卵巢癌、乳腺癌和前列腺癌在内的广泛组织学谱模型中，ABT-888+TMZ 的敏感性水平不同（55-100%肿瘤生长抑制），包括许多肿瘤消退。ABT-888+TMZ 在其他 TMZ 无反应性肿瘤中的疗效提示，多聚（ADP-核糖）聚合酶抑制可能克服 TMZ 耐药性。在实验性转移模型中观察到了 ABT-888+TMZ 的显著疗效，这些模型对 TMZ 产生了耐药性。此外，在交叉治疗中克服了 TMZ 耐药性，表明联合治疗可能克服获得性 TMZ 耐药性。肿瘤 MGMT、错配修复或多聚（ADP-核糖）聚合物与对 ABT-888+TMZ 的敏感性程度均无相关性。
ABT-888+TMZ 在广泛的肿瘤类型中表现出强大的疗效，包括原位和转移性植入。由于许多 TMZ 无反应性肿瘤对 ABT-888+TMZ 敏感，这种新型联合治疗可能会扩大 TMZ 的临床应用范围，超越黑色素瘤和神经胶质瘤。尽管 TMZ 耐药性可能受 MGMT 影响，但 MGMT 或其他 TMZ 耐药机制（错配修复）都不排除对 ABT-888+TMZ 的敏感性。这些模型中 TMZ 耐药的潜在机制尚不完全清楚，但可能涉及与 MGMT 无关的机制。
