Combination chemotherapy with a new folate analog: activity of 10-ethyl-10-deaza-aminopterin compared to methotrexate with 5-fluorouracil and alkylating agents against advanced metastatic disease in murine tumor models

Abstract

A new folate analog, 10-ethyl-10-deaza-aminopterin (10EDAM), was compared to methotrexate (MTX) in combination with 5-fluorouracil (5-FU) and/or alkylating agents against three models of advanced metastatic (E0771 mammary adenocarcinoma and T241 fibrosarcoma) or disseminated (L1210 leukemia) disease in BD2F1 mice. Of all the agents examined on a schedule of every 3 days X 3, 10EDAM and cyclophosphamide (CPA) were the most active overall against the tumor models employed. Against the E0771 tumor, antitumor potency was in the descending order of CPA, 10EDAM, cisplatin (Cis Pt), melphalan (L-PAM), MTX, and 5-FU. Similar ranking in relative potency was also derived with the T241 tumor. Against both of these models, MTX and 5-FU were only minimally active. Against the L1210 leukemia, 10EDAM was the most active agent followed in descending order by MTX, CPA, 5-FU, L-PAM, and Cis Pt. All two-drug combinations required attenuation to one-half the LD10 dosage for each. The results show that 10EDAM with CPA was the most effective combination employed in all three tumor models. Therapeutic activity was far greater than that obtained with each agent alone, with a substantial number of long-term survivors. 10EDAM was also highly active in combination with L-PAM and Cis Pt against the E0771 tumor and with Cis Pt against the L1210 leukemia. Some increase in therapeutic activity beyond that obtained with each agent alone, but to a substantially lesser extent, was documented for MTX and each of the three alkylating agents against the L1210 tumor. MTX with 5-FU was not an effective combination, but against the E0771 tumor gave therapeutic effects beyond that obtained with each agent alone when 5-FU was given 7 hours after MTX. Similar effects were seen with 10EDAM and 5-FU on these schedules, but 10EDAM alone was more effective than MTX and 5-FU given together against this tumor. A combination of either antifolate with 5-FU and CPA was ineffective against all three tumor models, in part because of the further attenuation of dosage required in this mouse strain and the minimal overall activity of 5-FU in these models. Results documented with 10EDAM and CPA and, perhaps, other alkylating agents are interpreted as indicative of therapeutic synergism between these agents. These results appear to suggest substantial potential for 10EDAM in clinically employed combination therapy currently including MTX.