Halldén G
Centre for Molecular Oncology and Imaging, Institute of Cancer, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
J BUON. 2009 Sep;14 Suppl 1:S61-7.
Replication-selective oncolytic adenoviruses are promising anti-tumour therapeutic agents that have been proven safe in hundreds of patients. While clinical efficacy was limited with the viral mutants alone, outcomes were improved in combination with chemotherapeutics. To further increase efficacy of viral-based therapies it is necessary to explore the cellular mechanisms responsible for enhanced tumour elimination in combination with cytotoxic drugs and to develop mutants with higher potency. To this end we generated a set of novel adenoviral mutants with deletions of the anti-apoptotic E1B19K-gene and the pRb-binding E1ACR2-region. Mutants with the E1B19K deletion significantly increased tumour cell killing in combination with cytotoxic drugs including gemcitabine, 5-fluorouracil (5-FU), docetaxel and mitoxantrone through enhancement of drug-induced apoptosis but did not sensitise normal cells to drugs. The double-deleted AdDeltaDelta (DeltaE1ACR2 and DeltaE1B19K) mutant had high cell killing activity in prostate and pancreatic carcinoma models. Replication was similar to the parental Ad5 and DeltaCR2 viruses in all tumour cells and was attenuated in normal cells. In combination with chemotherapeutics AdDeltaDelta synergistically enhanced cell death in all tested cancer cell lines and in prostate and pancreatic xenografts in vivo. These data suggest that the AdDeltaDelta mutant is a candidate for targeting of solid tumours specifically in combination with cytotoxic factors. Our findings imply that less toxic doses than currently practised in the clinic could efficiently target adenocarcinomas when combined with the AdDeltaDelta mutant.
复制选择性溶瘤腺病毒是很有前景的抗肿瘤治疗药物，已在数百名患者中证明其安全性。虽然单独使用病毒突变体时临床疗效有限，但与化疗药物联合使用时疗效有所改善。为了进一步提高基于病毒的治疗效果，有必要探索与细胞毒性药物联合使用时增强肿瘤清除的细胞机制，并开发更高效的突变体。为此，我们构建了一组新型腺病毒突变体，缺失了抗凋亡的E1B19K基因和与pRb结合的E1ACR2区域。缺失E1B19K的突变体与包括吉西他滨、5-氟尿嘧啶（5-FU）、多西他赛和米托蒽醌在内的细胞毒性药物联合使用时，通过增强药物诱导的凋亡显著增加了肿瘤细胞杀伤，但未使正常细胞对药物敏感。双缺失的AdDeltaDelta（DeltaE1ACR2和DeltaE1B19K）突变体在前列腺癌和胰腺癌模型中具有高细胞杀伤活性。在所有肿瘤细胞中的复制与亲本Ad5和DeltaCR2病毒相似，在正常细胞中复制减弱。与化疗药物联合使用时，AdDeltaDelta在所有测试的癌细胞系以及体内前列腺和胰腺异种移植模型中协同增强细胞死亡。这些数据表明，AdDeltaDelta突变体是特别是与细胞毒性因子联合使用时靶向实体瘤的候选药物。我们的研究结果表明，与AdDeltaDelta突变体联合使用时，比目前临床实践中使用的剂量毒性更低的剂量可以有效地靶向腺癌。
