Asparaginase-methotrexate in combination chemotherapy: schedule-dependent differential effects on normal versus neoplastic cells.

In a variety of cell culture and in vivo experiments with normal and tumor-bearing animals, the antecedent or simultaneous use of protein synthesis inhibitors with antimetabolites or alkylating agents will significantly attenuate the cytotoxic effects of the latter. The protein synthesis inhibitor asparaginase shares this potential. In murine leukemia L5178Y which is sensitive to both asparaginase and methotrexate (MTX), the prior use of asparaginase or the simultaneous administration of both drugs results in subadditive effects. In tumor-bearing mice, multiple courses of sequential MTX followed by asparaginase cured 55% of the leukemic mice whereas the converse sequence cured none. Partial explanation for this pharmacologic antagonism includes asparaginase-induced decrease in cellular uptake of MTX and delay in cell cycle traverse. It is of importance to recognize such pharmacologic antagonism for the proper design of clinical trials. Studies with human leukemic lymphoblasts suggest that the optimal time interval between asparaginase and a subsequent dose of MTX was 9-10 days. A 24-hour interval between methotrexate and a subsequent dose of asparaginase permits at least an additive therapeutic effect. The repeated use of this 2-day tandem schedule (MTX AsNase) permits the host to tolerate increasingly larger doses of MTX. These larger doses of MTX may have therapeutic benefit for the following reasons: 1) the steep dose-response relationship for MTX, 2) larger doses may overcome "transport-resistant" populations, and 3) larger doses may penetrate pharmacologic sanctuaries such as the blood-brain barrier. Trials of this combination in adults and children with advanced lymphoblastic leukemia, many of whom were previously treated with asparaginase and were refractory to conventional doses of MTX, resulted in complete remissions of 64% and 50%, respectively.