Open AccessDual addressing of thymidine synthesis pathways for effective targeting of proliferating melanoma
Author(s) -
Miran Tara,
Vogg Andreas T. J.,
El Moussaoui Laila,
Kaiser HansJürgen,
Drude Natascha,
Felbert Verena,
Mottaghy Felix M.,
Morgenroth Agnieszka
Publication year - 2017
Publication title -
cancer medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.403
H-Index - 53
ISSN - 2045-7634
DOI - 10.1002/cam4.1113
Subject(s) - thymidylate synthase , thymidine , thymidine kinase , nucleotide salvage , deoxyuridine , nucleoside analogue , biology , dna synthesis , cancer research , thymidine phosphorylase , in vivo , dihydrofolate reductase , chemistry , nucleoside , microbiology and biotechnology , biochemistry , enzyme , in vitro , nucleotide , dna , cancer , fluorouracil , genetics , virus , herpes simplex virus , gene
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 ( TK 1) was evaluated in differentiated ( MITF high [microphthalmia‐associated transcription factor] IGR 1) and invasive ( MITF medium IGR 37) 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‐ IT dU). 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‐ IT dU into the mitotically active IGR 37 cells. This effect was less pronounced in the differentiated IGR 1 cells. In vivo, inhibition of TS led to a high and preferential accumulation of 123 I‐ IT dU 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.