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 non-toxic 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 anti-
tumor 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.