ICRF-187 rescue in etoposide treatment in vivo. A model targeting high-dose topoisomerase II poisons to CNS tumors
ICRF-187 rescue in etoposide treatment in vivo. A model targeting high-dose topoisomerase II poisons to CNS tumors
复制标题
ICRF-187在体内依托泊苷治疗中的救援。
DOI：
--
复制
发表时间：
1996
影响因子：
3
通讯作者：
M. Sehested
中科院分区：
文献类型：
--
作者：
B. Holm;P. B. Jensen;M. Sehested
摘要：拓扑异构酶 II 的催化循环是当今使用的一些最成功的抗肿瘤药物的靶标，例如依托泊苷 (VP-16)，用于治疗睾丸癌和小细胞肺癌。拓扑异构酶 II 毒物介导的细胞杀伤作用可以被不同的药物类型拮抗。因此，我们证明了依托泊苷与 II 型蒽环类阿克拉霉素、抗疟药氯喹和心脏保护剂 ICRF-187 具有拮抗作用。在其他设置中，激动剂和拮抗剂的组合导致了对抗耐药性的高剂量方案。因此，利用亚叶酸解救甲氨蝶呤毒性以及使用美司钠来预防环磷酰胺毒性使得高剂量甲氨蝶呤和环磷酰胺方案的使用成为可能。使用类似的方法，我们研究了应用拓扑异构酶 II 毒物拮抗剂的可能方法。 NDF1 杂交雌性小鼠接受各种药物和药物组合治疗。采用最大似然法计算致死率（LD10和LD50值），比较药物腹腔注射小鼠的抗肿瘤作用。 L1210 细胞或艾利希腹水肿瘤细胞。此外，这些化合物还在颅内接种的 L1210 细胞上进行了测试。通过体重和白细胞计数评价各种药物的毒性。 ICRF-187 可将健康小鼠从致命剂量的拓扑异构酶 II 毒物中拯救出来。在小鼠中，ICRF-187 LD10 为 500 mg/kg。在 ICRF-187 的广泛无毒剂量范围 (50–250 mg/kg) 内，我们发现了针对 m-AMSA 和依托泊苷致死性的保护作用。因此，依托泊苷的 LD10 从单药的 34 mg/kg 增加到与 ICRF-187 组合的 122 mg/kg，相当于依托泊苷剂量增加了 3.6 倍。相比之下，ICRF-187 不能防止致命剂量的非拓扑异构酶 II 导向药物紫杉醇。我们进一步研究了等毒性方案对腹腔注射小鼠的抗肿瘤作用。与L1210或艾氏腹水肿瘤细胞。与单独使用依托泊苷相比，携带 L1210 的小鼠似乎从依托泊苷和 ICRF-187 组合中获得了更大的寿命延长，而在接种艾氏腹水肿瘤细胞的小鼠中情况并非如此。由于亲水性 ICRF-187 预计不会穿过血脑屏障，与亲脂性依托泊苷相比，我们研究了药物组合在颅内接种 L1210 细胞的小鼠中的效果。与单独使用等毒剂量的依托泊苷治疗的小鼠相比，使用 ICRF-187 + 依托泊苷治疗的小鼠的寿命显着延长。因此，似乎存在可以从这种对抗中受益的潜在途径。 ICRF-187 是一种强大的无毒保护剂，可抵抗拓扑异构酶 II 导向药物依托泊苷和 m-AMSA 的体内致死作用。脑肿瘤模型表明，与单独使用依托泊苷治疗相比，采用 ICRF-187 保护的高剂量依托泊苷治疗具有优越性。这意味着细胞毒性药物剂量可以到达大脑中的肿瘤，并且由于药物跨血脑屏障转运的差异可以保护正常组织。因此，ICRF-187 是一种很有前途的先导化合物，可用于开发使用高剂量拓扑异构酶 II 毒物治疗脑肿瘤和转移瘤的方案。
Abstract The catalytic cycle of topoisomerase II is the target of some of the most successful antitumor agents used today, e.g., etoposide (VP-16), in the treatment of testicular cancer and small-cell lung cancer. The cell kill mediated by topoisomerase II poisons can be antagonized by distinct drug types. Thus, we have demonstrated etoposide antagonism with the type-II anthracycline aclarubicin, the antimalarial drug chloroquine, and the cardioprotective agent ICRF-187. In other setups, combinations of agonist and antagonists have led to high-dose regimens for counteracting drug resistance. Thus, the exploitation of folinic acid rescue for methotrexate toxicity and the use of mesna to protect against cyclophosphamide toxicity have enabled the use of high-dose methotrexate and cyclophosphamide protocols. Using a similar approach, we have studied possible ways to apply antagonists to topoisomerase II poisons. NDF1-hybrid female mice were treated with the various drugs and drug combinations. Lethality (LD10 and LD50 values) was computed by use of the maximum-likelihood method, and the antitumor effect of the drugs was compared in mice inoculated i.p. with either L1210 cells or Ehrlich ascites tumor cells. In addition, the compounds were tested on L1210 cells inoculated intracranially. The toxicity of the various drugs was evaluated by weight and leukocyte counts. ICRF-187 rescues healthy mice from lethal doses of topoisomerase II poisons. In mice the ICRF-187 LD10 was 500 mg/kg. Within a wide nontoxic dose range (50–250 mg/kg) of ICRF-187 we found protection against m-AMSA and etoposide lethality. Thus, the LD10 of etoposide increased from 34 mg/kg for the single agent to 122 mg/kg for its combination with ICRF-187, corresponding to a 3.6-fold etoposide dose escalation. In contrast, ICRF-187 did not protect against lethal doses of the non-topoisomerase II-directed drug paclitaxel. We further investigated the antitumor effect of equitoxic schedules in mice inoculated i.p. with L1210 or Ehrlich ascites tumor cells. The L1210-bearing mice appeared to obtain a larger increase in life span from the etoposide and ICRF-187 combination as compared with etoposide alone, whereas this was not the case in mice inoculated with Ehrlich ascites tumor cells. As the hydrophilic ICRF-187 is not expected to cross the blood-brain barrier, in contrast to the lipophilic etoposide, we investigated the effect of the drug combination in mice inoculated intracranially with L1210 cells. We obtained a significant increase in life span in mice treated with ICRF-187 + etoposide as compared with mice treated with an equitoxic dose of etoposide alone. Thus, there appear to be potential routes by which one can benefit from this antagonism. ICRF-187 is a powerful nontoxic protector against the lethality of the topoisomerase II-directed drugs etoposide and m-AMSA in vivo. A brain tumor model demonstrates the superiority of high-dose etoposide treatment with ICRF-187 protection as compared with etoposide treatment alone. This implies that tumors in the brain can be reached by cytotoxic drug doses and that normal tissues can be protected due to differences in drug transport across the blood-brain barrier. ICRF-187 is therefore a promising lead compound for the development of schedules using high-dose topoisomerase II poisons in the treatment of brain tumors and metastases.
影响因子：
56.9
作者：
TEWEY, KM;ROWE, TC;LIU, LF
通讯作者：
LIU, LF
DOI：
10.1073/pnas.91.5.1781
发表时间：
1994-03-01
影响因子：
11.1
作者：
ROCA, J;ISHIDA, R;WANG, JC
通讯作者：
WANG, JC