IMPROVED TARGETING OF BRAIN-TUMORS USING DEXRAZOXANE RESCUE OF TOPOISOMERASE-II COMBINED WITH SUPRALETHAL DOSES OF ETOPOSIDE AND TENIPOSIDE

Dexrazoxane (ICRF-187) is a catalytic inhibitor of the nuclear enzyme DNA topoisomerase II (topo II). It protects cells against topo II pois ons, such as etoposide and teniposide, by hindering the DNA cleavage r eaction of the target enzyme. We have previously shown that this antag onism also extends to an in vivo model. Thus, ICRF-187 protected mice against supralethal doses of etoposide and amsacrine, and the etoposid e LD,, dose increased as much as 3.6-fold when combined with ICRF-187 (B, Helm, Cancer Chemother. Pharmacol., 38: 203-209, 1996), We describ e here how scheduling of this drug combination can be optimized and us ed. Interestingly, ICRF-187 can protect when it is given after etoposi de, Although timing is very critical here, ICRF-187 was able to comple tely protect when given 10 min after etoposide, This rescue principle resembles methotrexate rescue hy folinic acid. We also found schedulin g to be crucial because ICRF-187 did not protect when etoposide was gi ven once a day for five days, whereas effective protection was seen wh en etoposide was used three times, once every four days. Similar inves tigations were performed with teniposide in combination with ICRF-187, The combination with ICRF-187 allowed a 3.4-fold teniposide dose esca lation. Such dose escalations could be advantageous in specific situat ions. One such case is when the tumor is situated in a pharmacological sanctuary, e.g., in the brain. ICRF-187 is hydrophilic and does not c ross the blood-brain barrier, whereas the lipophilic etoposide and ten iposide do. Therefore, ICRF-187 would protect normal tissues and allow a cytotoxic dose of etoposide to reach the central nervous system (CN S), We therefore studied the combinations using L1210 or EHR2 cells in oculated into the CNS of mice. L1210 presented a leukemic CNS model wi th leptomeningeal spread and infiltration of liver, spleen, and lymph nodes, whereas EHR2 cells acted as a solid tumor with no evidence of e xtracerebral disease. In all experiments, the combination of high-dose etoposide and ICRF-187 was significantly superior to an equitoxic dos e of etoposide alone. Such superiority was also seen when treatment wa s given on days 4, 8, and 12 after tumor inoculation. Here etoposide a lone resulted in a mean increased life span of 12.3%, whereas the resc ue regimen yielded an increase of 47% (P < 0.0001), In conclusion, DNA topo II rescue by catalytic inhibitors is a new strategy enabling sig nificant epipodophyllotoxin dose escalations; in this study, we have d emonstrated the superiority of this strategy in two in vivo CNS tumor models, This concept is now being tested in a clinical trial.