Abstract
Precursor 2'-deoxythymidine 5'-monophosphate for DNA biosynthesis is supplied by thymidylate synthase (TS) (EC 2.1.1.45) through a de novo pathway and the enzyme levels are elevated in malignancy. TS is therefore a key target for cancer chemotherapy. Human leukocyte TS levels in patients with chronic myeloblastic leukemia (CML) and acute lymphoblastic leukemia (ALL) are highly elevated (66- and 33-fold, respectively) compared to the low baseline activity of normal healthy controls. Preliminary screening tests for the antitumor activity of the beta-carboline-benzoquinolizidine alkaloid deoxytubulosine (DTB) (isolated from the Indian medicinal plant Alanguim lamarckii) were performed employing in vitro inhibition studies on the leukemic leukocyte TS as the probe enzyme. Enzyme activity of the leukemic leukocytes was potently inhibited by DTB (IC50 = 50 microM) in both CML and ALL. The emetine alkaloid DTB was assessed for its biochemical and biological evaluation for the first time as a potential antileukemic agent.
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