[SP-4-3-(R)]-[1,1-cyclobutanedicarboxylato(2-)](2-methyl-1,4-
butane-
diamine-N,N')
platinum (CI-973) is a
cisplatin analogue that is currently in clinical trial. Preclinically,
CI-973 retained activity against L1210, P388, K562, and human ovarian
carcinoma sublines resistant to
cisplatin in vitro.
CI-973 also retained substantial activity [ratio of median life span of treated to control groups x 100% (%T/C) > 190] against
cisplatin resistant L1210 and P388 sublines in vivo. Good activity (stasis or
tumor burden reduction) was also obtained against five murine solid
tumors including breast, colon, and
sarcoma. Binary combination
therapy with
CI-973 and seven clinically utilized
anticancer agents was evaluated against murine
tumors in vivo for the ability of each combination to produce a superior therapeutic response compared to optimal single agent
therapy alone at tolerated doses. The seven agents combined with
CI-973 were
mitomycin C,
cyclophosphamide,
doxorubicin,
vinblastine,
etoposide,
ifosfamide, and
methotrexate. Of the combination regimens evaluated, only the combination of
CI-973 and
methotrexate was therapeutically superior to single agent
therapy. Against i.v. inoculated
P388 leukemia, combination
therapy with
CI-973 at 32 mg/kg/injection and
methotrexate at 43 mg/kg/injection produced 5.3 logs greater cell kill (%T/C = 284, with one cell surviving
therapy) than either
methotrexate therapy (%T/C = 208, with 2.5 x 10(5) cells surviving
therapy) or
CI-973 therapy (%T/C = 193 with 2.5 x 10(6) cells surviving
therapy) alone. The combination toxicity index of 1.0 indicated additive normal host tissue toxicity with the same target organs for dose limiting toxicity. To better understand the enhanced cell kill in vivo, the combination of
CI-973 and
methotrexate was evaluated against
P388 leukemia in vitro. Clonogenic survival studies showed that the combination of
CI-973 and
methotrexate was additive rather than synergistic with respect to cell killing in vitro. The lack of greater than additive cell kill in vitro suggested that the mechanism responsible for synergistic kill in vivo was not operative in vitro. The in vivo results suggest that the combination of
CI-973 and
methotrexate may be useful in the clinic.