Kleibl K, Margison G P
Cancer Research Institute, Slovak Academy of Sciences, Bratislava.
Neoplasma. 1998;45(4):181-6.
Resistance of tumor cells to alkylating anticancer agents that produce adducts at the O6 position of guanine in DNA, the O6-alkylating agents, correlates with the expression of O6-alkylguanine-DNA alkyltransferase (ATase). O6-benzylguanine and related pseudosubstrates are able to inactivate human ATase in vitro and in vivo and they are being tested as chemotherapeutic adjuvants for enhancing the effectiveness of O6-alkylating drugs. On the other hand, the clinical consequences of ATase depletion may be fatal for some sensitive systems e.g. hematopoiesis. To overcome this problem, strategies for the protection of primary bone marrow cells by targeted transfer of pseudosubstrate-resistant ATase genes have been considered and recently achieved at the laboratory level. This approach could therefore be now extended to a clinical cancer gene therapy program.
肿瘤细胞对在DNA中鸟嘌呤的O6位置产生加合物的烷化抗癌剂（即O6-烷化剂）的耐药性与O6-烷基鸟嘌呤-DNA烷基转移酶（ATase）的表达相关。O6-苄基鸟嘌呤及相关假底物能够在体外和体内使人类ATase失活，并且它们正作为化疗佐剂进行测试，以提高O6-烷化药物的疗效。另一方面，ATase耗竭的临床后果对某些敏感系统（如造血系统）可能是致命的。为克服这一问题，通过靶向转移抗假底物ATase基因来保护原代骨髓细胞的策略已被考虑，并且最近在实验室水平上得以实现。因此，这种方法现在可以扩展到临床癌症基因治疗方案中。
