Therapeutic synergy of trimetrexate (CI-898) in combination with doxorubicin, vincristine, cytoxan, 6-thioguanine, cisplatin, or 5-fluorouracil against intraperitoneally implanted P388 leukemia.

In order to support planning of clinical trials of trimetrexate (CI-898) in combination chemotherapy regimens, several studies were carried out to determine the potential for therapeutic synergy between CI-898 and several clinically proven agents including doxorubicin, cytoxan, FUra, 6-thioguanine (6-TG), vincristine, methotrexate, and cisplatin. F1 hybrid mice bearing either early or advanced stage P388 leukemia were treated with either the single agents or with various combination regimens and observed for lifespan. These studies demonstrated a high degree of therapeutic synergism between CI-898 and doxorubicin, cytoxan, and 6-TG. Combinations of CI-898 with FUra, vincristine, and cisplatin also produced enhanced tumor cell kill, although the results were less dramatic than those mentioned above. The host toxicities of CI-898 and methotrexate were synergistic and appeared to negate any potential therapeutic benefit of the combination. The synergistic effect of the doxorubicin, vincristine, and cytoxan combinations may have been due to a lack of overlapping host toxicities, but the synergy observed with 6-TG was obtained in spite of synergistic host toxicity.