Dual addressing of thymidine synthesis pathways for effective targeting of proliferating melanoma. (13th June 2017)

• Record Type: Journal Article
• Authors: Miran, Tara; Vogg, Andreas T. J.; El Moussaoui, Laila; Kaiser, Hans‐Jürgen; Drude, Natascha; von Felbert, Verena; Mottaghy, Felix M.; Morgenroth, Agnieszka
• Is Part Of: Cancer medicine. Volume 6:Number 7(2017:Jul.)
• Page Start: 1639
• Page End: 1651
• Publication Date: 2017-06-13
• Subjects: Auger electron emitter -- endogenous radiation -- malignant melanoma -- nucleoside synthesis pathway -- thymidylate synthase; 616.994005
• DOI: 10.1002/cam4.1113
• Languages: English
• ISSNs: 2045-7634

Abstract

Abstract: Here, we examined the potential of blocking the thymidine de novo synthesis pathways for sensitizing melanoma cells to the nucleoside salvage pathway targeting endogenous DNA irradiation. Expression of key nucleotide synthesis and proliferation enzymes thymidylate synthase (TS) and thymidine kinase 1 (TK1) was evaluated in differentiated (MITF high [microphthalmia‐associated transcription factor] IGR1) and invasive (MITF medium IGR37) melanoma cells. For inhibition of de novo pathways cells were incubated either with an irreversible TS inhibitor 5‐fluoro‐2′‐deoxyuridine (FdUrd) or with a competitive dihydrofolate‐reductase (DHFR) inhibitor methotrexate (MTX). Salvage pathway was addressed by irradiation‐emitting thymidine analog [ 123/125 I]‐5‐iodo‐4′‐thio‐2′‐deoxyuridine ( 123/125 I‐ITdU). The in vivo targeting efficiency was visualized by single‐photon emission computed tomography. Pretreatment with FdUrd strongly increased the cellular uptake and the DNA incorporation of 125 I‐ITdU into the mitotically active IGR37 cells. This effect was less pronounced in the differentiated IGR1 cells. In vivo, inhibition of TS led to a high and preferential accumulation of 123 I‐ITdU in tumor tissue. This preclinical study presents profound rationale for development of therapeutic approach by highly efficient and selective radioactive targeting one of the crucial salvage pathways in melanomas. Abstract : FdUrd increases mitotic activity in melanoma cells and inhibits pyrimidine de novo synthesis pathway, leading to efficient uptake of salvage thymidine synthesis pathway targeting Auger electron‐emitting thymidine analog 123/125I‐ITdU. The DNA‐incorporated 123/125I‐ITdU induces severe DNA damages (double‐strand breaks) and consequently cell apoptosis.