ICRF-187 RESCUE IN ETOPOSIDE TREATMENT IN-VIVO - A MODEL TARGETING HIGH-DOSE TOPOISOMERASE-II POISONS TO CNS TUMORS

The catalytic cycle of topoisomerase II is the target of some of the m ost successful antitumor agents used today, e.g., etoposide (VP-16), i n the treatment of testicular cancer and small-cell lung cancer. The c ell kill mediated by topoisomerase II poisons can be antagonized by di stinct drug types. Thus, we have demonstrated etoposide antagonism wit h the type-II anthracycline aclarubicin, the antimalarial drug chloroq uine, and the cardioprotective agent ICRF-187. In other setups, combin ations of agonist and antagonists have led to high-dose regimens for c ounteracting drug resistance. Thus, the exploitation of folinic acid r escue for methotrexate toxicity and the use of mesna to protect agains t cyclophosphamide toxicity have enabled the use of high-dose methotre xate and cyclophosphamide protocols. Using a similar approach, we have studied possible ways to apply antagonists to topoisomerase II poison s. NDF1-hybrid female mice were treated with the various drugs and dru g combinations. Lethality (LD(10) and LD(50) values) was computed by u se of the maximum-likelihood method, and the antitumor effect of the d rugs was compared in mice inoculated i.p. with either L1210 cells or E hrlich ascites tumor cells. In addition, the compounds were tested on L1210 cells inoculated intracranially. The toxicity of the various dru gs was evaluated by weight and leukocyte counts. ICRF-187 rescues heal thy mice from lethal doses of topoisomerase II poisons. In mice the IC RF-187 LD(10) 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 l ethality. Thus, the LD(10) of etoposide increased from 34 mg/kg for th e single agent to 122 mg/kg for its combination with ICRF-187, corresp onding to a 3.6-fold etoposide dose escalation. In contrast, ICRF-187 did not protect against lethal doses of the non-topoisomerase II-direc ted drug paclitaxel. We further investigated the antitumor effect of e quitoxic schedules in mice inoculated i.p. with L1210 or Ehrlich ascit es tumor cells. The L1210-bearing mice appeared to obtain a larger inc rease in life span from the etoposide and ICRF-187 combination as comp ared with etoposide alone, whereas this was not the case in mice inocu lated with Ehrlich ascites tumor cells. As the hydrophilic ICRF-187 is not expected to cross the blood-brain barrier, in contrast to the lip ophilic etoposide, we investigated the effect of the drug combination in mice inoculated intracranially with L1210 cells. We obtained a sign ificant increase in life span in mice treated with ICRF-187 + etoposid e as compared with mice treated with an equitoxic dose of etoposide al one. Thus, there appear to be potential routes by which one can benefi t from this antagonism. ICRF-187 is a powerful nontoxic protector agai nst the lethality of the topoisomerase II-directed drugs etoposide and m-AMSA in vivo. A brain tumor model demonstrates the superiority of h igh-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 prot ected due to differences in drug; transport across the blood-brain bar rier. ICRF-187 is therefore a promising lead compound for the developm ent of schedules using high-dose topoisomerase II poisons in the treat ment of brain tumors and metastases.