TUMOR AND TISSUE DISTRIBUTION OF A METHOTREXATE ANTI-EL4 IMMUNOGLOBULIN CONJUGATE IN EL4 LYMPHOMA-BEARING MICE

Abstract

The uptake and tissue distribution of [3H]methotrexate ([3H]MTX) at doses of 5 mg/kg i.p. either free or linked to anti-EL4 immunoglobulin G (AELG) or normal rabbit globulin (NRG) was studied in EL4 lymphoma-bearing C57BL/6J mice. When the uptakes of MTX-AELG, MTX-NRG and free MTX were assayed as cell-associated 3H activity, comparison 3 h after administration showed that uptake of MTX administered as the AELG conjugate was 2.5 times the uptake of MTX administered as the NRG conjugate and 6 times the uptake of MTX administered free. In contrast to the difference in the uptake of MTX-AELG and MTX-NRG by tumor cells, the pattern of uptake in all the other tissues studied was generally similar for the 2 conjugates. Conjugated MTX persisted in all tissues and serum and ascites fluid, whereas free MTX declined rapidly after reaching peak levels around 1 h, except in EL4 cells where 45% was retained at 24 h. The levels of intracellular MTX after administration of these 3 agents exceeded the intracellular dihydrofolate reductase level and correlated with the relative tumor-inhibitory effect in vivo of the agent (MTX-AELG > MTX-NRG > MTX).