Lönn U, Lönn S
Radiumhemmet, Karolinska Hospital, Stockholm, Sweden.
Cancer Res. 1988 Jun 15;48(12):3319-23.
The antineoplastic agents methotrexate and 5-fluorodeoxyuridine induce DNA lesions, although the drugs are not incorporated into DNA. The lesions arise as a result of reduced repair of damage occurring in DNA independently of the treatment with antineoplastic agents. When cells containing DNA lesions are treated with calmodulin inhibitors (W-7, phenothiazine, promethazine), the amount of lesions is increased, in all probability due to reduced DNA repair. This is paralleled by increased growth inhibition. Hence by inhibiting calmodulin, one can modulate the levels of DNA lesions and change the growth-inhibitory effect induced by methotrexate or 5-fluorodeoxyuridine. This strongly supports the importance of this type of DNA lesion in the toxic effects induced by the drugs.
抗肿瘤药物甲氨蝶呤和5-氟脱氧尿苷可诱导DNA损伤，尽管这些药物并不掺入DNA中。这些损伤是由于DNA中独立于抗肿瘤药物治疗而发生的损伤修复减少所致。当用钙调蛋白抑制剂（W-7、吩噻嗪、异丙嗪）处理含有DNA损伤的细胞时，损伤数量增加，很可能是由于DNA修复减少。这与生长抑制增加相平行。因此，通过抑制钙调蛋白，可以调节DNA损伤水平，并改变甲氨蝶呤或5-氟脱氧尿苷诱导的生长抑制作用。这有力地支持了这类DNA损伤在药物诱导的毒性作用中的重要性。
