Pharmacokinetics, antifolate activity and tissue distribution of PT523 in SCC VII tumor-bearing mice.

Purpose: To monitor the pharmacokinetics of PT523 and methotrexate in C3H mice with transplanted SCC VII tumors; to compare the impact of PT523 and methotrexate on tumor and normal host 5,10-methylenetetrahydrofolate levels; and to synthesize [14C]PT523 and determine its time-dependent tissue distribution in tumor and host tissues.

Methods: C3H mice bearing SCC VII tumors were given i.p.

Leucovorin and folic acid regimens for selective expansion of murine 5,10-methylenetetrahydrofolate pools.

Mice bearing subcutaneously implanted EMT6 mammary adenocarcinoma were treated with leucovorin or folic acid by continuous subcutaneous infusion or bolus intraperitoneal injection. (6R)-5,10-Methylenetetrahydrofolate pools in cytosolic extracts of the tumor, marrow, and gut were measured by analysis of the ternary complex with thymidylate synthase (5,10-methylenetetrahydrofolate: dUMP C-methyltransferase, EC 2.1.