CI-921, the 5-methyl-4-carboxamide analog of
amsacrine, in combination with
cisplatin produced a 6-fold better cell kill in vitro than expected based on additive effects. The combination of
CI-921 and
cisplatin was subsequently evaluated in three in vivo model systems: intraperitoneally (TP) and intravenously (IV) implanted
P388 leukemia, and advanced stage subcutaneously (SC) implanted LC-12
squamous cell carcinoma. All
drug treatments were administered IP on an intermittent treatment schedule which was optimal for both agents. Combination
therapy was superior to
therapy with the best single agent alone,
CI-921, in all three model systems. Against IP implanted
P388 leukemia, combination
therapy produced greater than 8 logs of net
tumor cell kill with 60-day survivors (cures). This level of activity was 50-fold greater (1.7 log) than that obtained with
CI-921 alone. An IV implant of
P388 leukemia was used in a confirmatory study to provide a more rigorous evaluation against disseminated disease. Combination
therapy against IV implanted
P388 leukemia produced greater than 7.7 logs of net
tumor cell kill, which was 630-fold greater (2.8 logs) than that obtained with
CI-921 therapy alone. Against advanced stage LC-12 (200-1000 mg
tumors at initial treatment), combination
therapy improved
tumor cell kill by 0.6 log (4-fold) over that obtained with
CI-921 therapy alone and also produced greater numbers of 120-day survivors than did single agent
therapy with
CI-921. The combination of
carboplatin and
CI-921 was also evaluated against IV implanted
P388 leukemia to determine if the enhanced
therapeutic effect of
CI-921 and
cisplatin could be extended to include
CI-921 and
carboplatin. Combination
therapy with
CI-921 and
carboplatin increased net log
tumor cell kill by 0.8 and 1.5 log in two separate tests (6- and 32-fold, respectively) over that obtained with
CI-921 therapy alone. The data indicate that combination
therapy with
CI-921 and
platinum containing
anticancer agents may have clinical application.