Southgate Thomas D, Garside Elloise, Margison Geoffrey P, Fairbairn Leslie J
Cancer Research UK Gene Therapy Group, Paterson Institute for Cancer Research, Christie Hospital NHS Trust, Wilmslow Road, Manchester M20 4BX, UK.
J Gene Med. 2006 Aug;8(8):972-9. doi: 10.1002/jgm.914.
Tumour resistance to chemotherapeutic agents results in most chemotherapy being administered in a multi-agent fashion that is often associated with a high level of toxicity in highly proliferative tissues such as the haematopoietic compartment. Thus, whilst many genetic manipulation strategies aim to protect normal tissue against a single component of a multi-agent regime, it is clearly preferable to protect normal cells against all toxicities. In this study we have used retroviral gene transfer to achieve co-expression of either p-glycoprotein (MDR1) or multi-drug resistance-related protein 1 (MRP1) with the P140K mutant form of O6-methylguanine-DNA-methyl transferase (MGMT) which, unlike the wild-type protein, is insensitive to inactivation by tumour sensitisers such as O6-benzylguanine (O6-BeG) or PaTrin2. The combination of certain MDR1/MRP1 substrate drugs with O6-alkylating agents (against which MGMT confers resistance) is particularly myelotoxic. We show here that haematopoietic progenitors co-expressing mutant MGMT with an ABC-transporter exhibit resistance to combination chemotherapy in vitro. This combination of drug transporter and DNA repair function may provide an effective in vivo protection of the haematopoietic compartment during tumour ablation using combination chemotherapy.
肿瘤对化疗药物产生耐药性，导致大多数化疗以多药联合的方式进行，而这通常会在高增殖组织（如造血系统）中产生高水平的毒性。因此，尽管许多基因操作策略旨在保护正常组织免受多药联合方案中单一成分的影响，但显然保护正常细胞免受所有毒性更为可取。在本研究中，我们利用逆转录病毒基因转移技术，使P140K突变形式的O6-甲基鸟嘌呤-DNA甲基转移酶（MGMT）与P-糖蛋白（MDR1）或多药耐药相关蛋白1（MRP1）共表达，与野生型蛋白不同，该突变型蛋白对O6-苄基鸟嘌呤（O6-BeG）或PaTrin2等肿瘤增敏剂的失活不敏感。某些MDR1/MRP1底物药物与O6-烷基化剂（MGMT对其具有耐药性）联合使用时，骨髓毒性尤其严重。我们在此表明，共表达突变型MGMT与ABC转运蛋白的造血祖细胞在体外对联合化疗具有抗性。药物转运蛋白和DNA修复功能的这种组合可能在使用联合化疗进行肿瘤消融期间为造血系统提供有效的体内保护。
