Use of a human tumor cloning system to evaluate analogs of methotrexate and mitoxantrone.

We have utilized a human tumor cloning system to compare the antitumor activity of trimetrexate ( TMQ ), a new dihydrofolate reductase inhibitor, and ametantrone , a new anthracenedione, with that of analogs already in clinical trial (methotrexate and mitoxantrone). Sixty-nine of 136 tumors plated for the TMQ study and 84 of 228 tumors plated for the ametantrone study were evaluable for drug-sensitivity assays. The overall in vitro response rates (defined as a less than or equal to 50% survival of tumor colony-forming units) for TMQ were 20% and 23% at 0.1 and 1 microgram/ml, respectively; for ametantrone they were 13%, 21%, and 26% at 0.1, 1, and 10 micrograms/ml, respectively. The overall in vitro activity for both new compounds was similar to that of their clinically used analogs, but TMQ was active in eight of 47 methotrexate-resistant specimens and ametantrone in nine of 62 mitoxantrone-resistant specimens. A comparison of these in vitro results with the results of phase II clinical trials with both drugs should allow an evaluation of the utility of the human tumor cloning system for predicting clinical antitumor activity of analogs of currently available antineoplastic agents.