Djeha A H, Thomson T A, Leung H, Searle P F, Young L S, Kerr D J, Harris P A, Mountain A, Wrighton C J
Cobra Therapeutics Ltd., The Science Park, Keele, Staffordshire, ST5 5SP, United Kingdom.
Mol Ther. 2001 Feb;3(2):233-40. doi: 10.1006/mthe.2000.0250.
Gene-directed enzyme prodrug therapy (GDEPT) is a refinement of cancer chemotherapy that generates a potent cell-killing drug specifically in tumor cells by enzymatic activation of an inert prodrug. We describe in vivo studies that evaluate the efficacy and safety of intratumoral (i.t.) injection of an adenovirus vector (CTL102) expressing Escherichia coli nitroreductase (NTR) combined with systemic prodrug (CB1954) treatment. A single i.t. injection of CTL102 (7.5 x 10(9) to -2 x 10(10) particles) followed by CB1954 treatment produced clear anti-tumor effects in subcutaneous (s.c.) xenograft models of four cancers that are likely candidates for GDEPT (i.e., primary liver, head and neck, colorectal and prostate). Virus dose-response studies (s.c. liver model) revealed a steep increase and subsequent rapid plateauing of both NTR gene delivery and anti-tumor efficacy. Evidence of minor virus spread (toxicity) was observed in a s.c. head and neck xenograft model. This was eliminated by passive immunization with neutralizing anti-Ad5 antibodies prior to virus injection without reducing the magnitude of the anti-tumor effect. Preexisting anti-Ad5 neutralizing antibodies may therefore be an advantage rather than an issue in the clinical use of this new therapy.
基因导向酶前药疗法（GDEPT）是癌症化疗的一种改进方法，它通过对惰性前药进行酶促活化，在肿瘤细胞中特异性地产生一种强效的细胞杀伤药物。我们描述了体内研究，该研究评估了瘤内（i.t.）注射表达大肠杆菌硝基还原酶（NTR）的腺病毒载体（CTL102）与全身前药（CB1954）联合治疗的疗效和安全性。在四种可能适用于GDEPT的癌症（即原发性肝癌、头颈癌、结直肠癌和前列腺癌）的皮下（s.c.）异种移植模型中，单次瘤内注射CTL102（7.5×10⁹至2×10¹⁰个颗粒），随后进行CB1954治疗产生了明显的抗肿瘤效果。病毒剂量反应研究（皮下肝癌模型）显示，NTR基因传递和抗肿瘤疗效均急剧增加，随后迅速趋于平稳。在皮下头颈异种移植模型中观察到了轻微的病毒扩散（毒性）迹象。在病毒注射前用中和抗Ad5抗体进行被动免疫消除了这种情况，且未降低抗肿瘤效果的强度。因此，预先存在的抗Ad5中和抗体在这种新疗法的临床应用中可能是一个优势而非问题。
