Comparative effects on the immune system of methotrexate and trimetrexate

Methotrexate (MTX) is an antimetabolite commonly used in the treatment of neoplastic disease, while trimetrexate (TMQ) is an investigational antifolate which is currently advocated as a potential alternative to MTX. The cytotoxic properties of antifolates to rapidly proliferating cells suggests that the immune system would be a significant and undesirable target for these drugs. We examined the comparative effects of these two chemotherapeutic agents on the murine immune system using in vivo and in vitro methods. Both drugs were potent suppressors of T-dependent antibody formation in vitro as well as in vivo. While TMQ appeared to be more immunosuppressive than MTX following in vitro addition of the drugs, the converse appeared to be true when dosing was performed in vivo. The drug induced suppression of T-dependent antibody formation was dose dependent for both antifolates. Lymphoproliferative studies demonstrated marked suppressive effects on LPS and PHA induced 3H-uridine and 3H-deoxyuridine incorporation following addition of both drugs in vitro suggesting effects on both RNA and thymidylate biosynthesis. Timed addition studies demonstrated a particularly susceptible time period (hours 24-48 after addition of the mitogen LPS) in stimulated lymphocytes with respect to inhibition of 3H-uridine incorporation. Following in vivo administration of either antifolate, natural killer cell activity was significantly decreased with no substantial differences between the two drugs.(ABSTRACT TRUNCATED AT 250 WORDS)