@entity10976 ( @entity10976 ) is a catalytic inhibitor of the nuclear enzyme DNA topoisomerase II (topo II). It protects cells against topo II poisons, such as @entity2879 and @entity2663 , by hindering the DNA cleavage reaction of the target enzyme. We have previously shown that this antagonism also extends to an in vivo model. Thus, @entity10976 protected @entity19 against supralethal doses of @entity2879 and @entity5257 , and the @entity2879 LD10 dose increased as much as 3.6-fold when combined with @entity10976 (B. Holm, Cancer Chemother. Pharmacol., 38: 203-209, 1996). We describe here how scheduling of this drug combination can be optimized and used. Interestingly, @entity10976 can protect when it is given after @entity2879 . Although timing is very critical here, @entity10976 was able to completely protect when given 10 min after @entity2879 . This rescue principle resembles methotrexate rescue by @entity4181 . We also found scheduling to be crucial because @entity10976 did not protect when @entity2879 was given once a day for five days, whereas effective protection was seen when @entity2879 was used three times, once every four days. Similar investigations were performed with @entity2663 in combination with @entity10976 . The combination with @entity10976 allowed a 3.4-fold @entity2663 dose escalation. Such dose escalations could be advantageous in specific situations. One such case is when the @entity5 is situated in a pharmacological sanctuary, e.g., in the brain. @entity10976 is hydrophilic and does not cross the blood-brain barrier, whereas the lipophilic @entity2879 and @entity2663 do. Therefore, @entity10976 would protect normal tissues and allow a cytotoxic dose of @entity2879 to reach the central nervous system (CNS). We therefore studied the combinations using L1210 or EHR2 cells inoculated into the CNS of @entity19 . L1210 presented a leukemic CNS model with leptomeningeal spread and infiltration of liver, spleen, and lymph nodes, whereas EHR2 cells acted as a solid @entity5 with no evidence of @entity66 . In all experiments, the combination of high-dose @entity2879 and @entity10976 was significantly superior to an equitoxic dose of @entity2879 alone. Such superiority was also seen when treatment was given on days 4, 8, and 12 after @entity5 inoculation. Here @entity2879 alone resulted in a mean increased life span of 12.3%, whereas the rescue regimen yielded an increase of 47% (P < 0.0001). In conclusion, DNA topo II rescue by catalytic inhibitors is a new strategy enabling significant epipodophyllotoxin dose escalations; in this study, we have demonstrated the superiority of this strategy in two in vivo @entity1221 models. This concept is now being tested in a clinical trial.

Improved targeting of brain tumors using dexrazoxane rescue of topoisomerase II combined with supralethal doses of @entity2879 and XXXX .

@entity4181 :: ('MESH:D002955', 'Chemical') :: ['folinic acid'] @entity66 :: ('MESH:D004194', 'Disease') :: ['extracerebral disease'] @entity5257 :: ('MESH:D000677', 'Chemical') :: ['amsacrine'] @entity2663 :: ('MESH:D013713', 'Chemical') :: ['teniposide'] @entity19 :: ('10090', 'Species') :: ['mice'] @entity5 :: ('MESH:D009369', 'Disease') :: ['tumor'] @entity1221 :: ('MESH:D016543', 'Disease') :: ['CNS tumor'] @entity2879 :: ('MESH:D005047', 'Chemical') :: ['etoposide'] @entity10976 :: ('MESH:D011929', 'Chemical') :: ['Dexrazoxane', 'ICRF-187']
@entity2663 :: (MESH:D013713,Chemical) :: ['teniposide']
