Biological Chemistry 2014-12-01

Methotrexate-gelonin conjugate - an inhibitor of MCF-7 cells expressing the dihydrofolate receptor.

Mohamed Badr, Christian Kopp, Sandra Theison, Jennifer Meyer, Wolfgang E Trommer

Index: Biol. Chem. 395(12) , 1461-6, (2014)

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Abstract

An immunotoxin composed of gelonin, a basic ribosome-inactivating protein, type I of 30 kDa, isolated from the seeds of the Indian plant Gelonium multiflorum and methotrexate (MTX) has been studied as a potential tool of gelonin delivery into the cytoplasm of MTX-responsive cells. On the average, about five molecules of methotrexate were chemically coupled to gelonin via an N-hydroxysuccinimide ester of the drug. The MTX-gelonin conjugate was able to reduce the viability of MCF-7 cells in a dose-dependent manner with ID50 of 10 nm, whereas gelonin or MTX alone showed none or very little effects. Besides its ribosome-inactivating activity, which is about ten-fold lower in an in vitro translation assay (IC50 of 50.5 ng/ml as compared to 4.6 ng/ml), the conjugate also significantly induced direct and oxidative DNA damage as shown by the alkaline comet assay. Hence, MTX-gelonin conjugates are promising candidates for the treatment of MTX-responsive cancers.