Pratesi G, De Cesare M, Zunino F
Isituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy.
Cancer Chemother Pharmacol. 1996;38(2):123-8. doi: 10.1007/s002800050459.
Lonidamine is an antitumor agent with a peculiar mechanism of action, since it differentially impairs the energy metabolism of normal and neoplastic cells. We investigated the effects of lonidamine on the activity of DNA-damaging antitumor agents against the MX-1 human breast carcinoma xenograft. Athymic mice bearing measurable s.c. tumors were treated by a single injection of doxorubicin (i.v.), cyclophosphamide (i.v.), or cisplatin (i.p.) followed by repeated daily injections of lonidamine (i.p. or p.o.). A potentiation of the activity of all these DNA-damaging drugs was achieved when each was given in combination with lonidamine, but for doxorubicin and cyclophosphamide the increase in antitumor activity paralleled the increase in lethal toxicity. In contrast, a therapeutic advantage of the combination was achieved for cisplatin and lonidamine as compared with cisplatin alone. Indeed, 6 mg/kg of cisplatin plus lonidamine cured all tumors, whereas the maximum tolerated dose of cisplatin alone (12 mg/kg) cured only six of eight tumors. In addition, the study indicated that the duration of lonidamine administration after injection of the cytotoxic drug influenced the tumor response and that prolonged treatment resulted in greater efficacy. These results document the ability of lonidamine to modulate the pharmacological activity of DNA-damaging drugs, thus suggesting that lonidamine may be a clinically useful cisplatin modulator.
氯尼达明是一种具有独特作用机制的抗肿瘤药物，因为它对正常细胞和肿瘤细胞的能量代谢有不同程度的损害。我们研究了氯尼达明对DNA损伤抗肿瘤药物抗MX - 1人乳腺癌异种移植瘤活性的影响。对携带可测量皮下肿瘤的无胸腺小鼠，单次静脉注射阿霉素、静脉注射环磷酰胺或腹腔注射顺铂，随后每天重复腹腔或口服注射氯尼达明。当这些DNA损伤药物与氯尼达明联合使用时，其活性均得到增强，但对于阿霉素和环磷酰胺，抗肿瘤活性的增加与致死毒性的增加平行。相比之下，与单独使用顺铂相比，顺铂与氯尼达明联合使用具有治疗优势。事实上，6mg/kg顺铂加氯尼达明可治愈所有肿瘤，而单独使用顺铂的最大耐受剂量（12mg/kg）仅能治愈8个肿瘤中的6个。此外，研究表明，在注射细胞毒性药物后给予氯尼达明的持续时间会影响肿瘤反应，延长治疗可提高疗效。这些结果证明了氯尼达明调节DNA损伤药物药理活性的能力，因此表明氯尼达明可能是一种临床上有用的顺铂调节剂。
