Cargando…

Effect of Hammerhead Ribozyme against Human Thymidylate Synthase on the Cytotoxicity of Thymidylate Synthase Inhibitors

One of the resistance mechanisms to folate‐based thymidylate synthase (TS) inhibitors is the increase in TS activity in tumor cells. Human B lymphoblastoid cell line (W1L2) was made resistant to a lipophilic non‐polyglutamatable TS inhibitor (ZM249148), and the subline (W1L2:R179) showed a 20‐fold i...

Descripción completa

Detalles Bibliográficos
Autores principales: Kobayashi, Hiroyuki, Takemura, Yuzuru, Miyachi, Hayato, Skelton, Lorraine, Jackman, Ann L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Blackwell Publishing Ltd 1995
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5920622/
https://www.ncbi.nlm.nih.gov/pubmed/8567390
http://dx.doi.org/10.1111/j.1349-7006.1995.tb03014.x
_version_ 1783317863932624896
author Kobayashi, Hiroyuki
Takemura, Yuzuru
Miyachi, Hayato
Skelton, Lorraine
Jackman, Ann L.
author_facet Kobayashi, Hiroyuki
Takemura, Yuzuru
Miyachi, Hayato
Skelton, Lorraine
Jackman, Ann L.
author_sort Kobayashi, Hiroyuki
collection PubMed
description One of the resistance mechanisms to folate‐based thymidylate synthase (TS) inhibitors is the increase in TS activity in tumor cells. Human B lymphoblastoid cell line (W1L2) was made resistant to a lipophilic non‐polyglutamatable TS inhibitor (ZM249148), and the subline (W1L2:R179) showed a 20‐fold increase in TS enzyme activity with concomitant overexpression of TS mRNA. To overcome the resistance, we designed a ribozyme that can cleave the CUC sequences in a triple tandemly repeated sequence of TS mRNA. Expression of this ribozyme in W1L2:R179 cells transfected with Epstein Barr virus‐based expression vector resulted in sensitization to TS inhibitors concomitantly with a decrease of TS expression. The ribozyme expressed in transfectants was shown to be functional in cleaving artificial TS RNA in vitro.
format Online
Article
Text
id pubmed-5920622
institution National Center for Biotechnology Information
language English
publishDate 1995
publisher Blackwell Publishing Ltd
record_format MEDLINE/PubMed
spelling pubmed-59206222018-05-11 Effect of Hammerhead Ribozyme against Human Thymidylate Synthase on the Cytotoxicity of Thymidylate Synthase Inhibitors Kobayashi, Hiroyuki Takemura, Yuzuru Miyachi, Hayato Skelton, Lorraine Jackman, Ann L. Jpn J Cancer Res Rapid Communication One of the resistance mechanisms to folate‐based thymidylate synthase (TS) inhibitors is the increase in TS activity in tumor cells. Human B lymphoblastoid cell line (W1L2) was made resistant to a lipophilic non‐polyglutamatable TS inhibitor (ZM249148), and the subline (W1L2:R179) showed a 20‐fold increase in TS enzyme activity with concomitant overexpression of TS mRNA. To overcome the resistance, we designed a ribozyme that can cleave the CUC sequences in a triple tandemly repeated sequence of TS mRNA. Expression of this ribozyme in W1L2:R179 cells transfected with Epstein Barr virus‐based expression vector resulted in sensitization to TS inhibitors concomitantly with a decrease of TS expression. The ribozyme expressed in transfectants was shown to be functional in cleaving artificial TS RNA in vitro. Blackwell Publishing Ltd 1995-11 /pmc/articles/PMC5920622/ /pubmed/8567390 http://dx.doi.org/10.1111/j.1349-7006.1995.tb03014.x Text en
spellingShingle Rapid Communication
Kobayashi, Hiroyuki
Takemura, Yuzuru
Miyachi, Hayato
Skelton, Lorraine
Jackman, Ann L.
Effect of Hammerhead Ribozyme against Human Thymidylate Synthase on the Cytotoxicity of Thymidylate Synthase Inhibitors
title Effect of Hammerhead Ribozyme against Human Thymidylate Synthase on the Cytotoxicity of Thymidylate Synthase Inhibitors
title_full Effect of Hammerhead Ribozyme against Human Thymidylate Synthase on the Cytotoxicity of Thymidylate Synthase Inhibitors
title_fullStr Effect of Hammerhead Ribozyme against Human Thymidylate Synthase on the Cytotoxicity of Thymidylate Synthase Inhibitors
title_full_unstemmed Effect of Hammerhead Ribozyme against Human Thymidylate Synthase on the Cytotoxicity of Thymidylate Synthase Inhibitors
title_short Effect of Hammerhead Ribozyme against Human Thymidylate Synthase on the Cytotoxicity of Thymidylate Synthase Inhibitors
title_sort effect of hammerhead ribozyme against human thymidylate synthase on the cytotoxicity of thymidylate synthase inhibitors
topic Rapid Communication
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5920622/
https://www.ncbi.nlm.nih.gov/pubmed/8567390
http://dx.doi.org/10.1111/j.1349-7006.1995.tb03014.x
work_keys_str_mv AT kobayashihiroyuki effectofhammerheadribozymeagainsthumanthymidylatesynthaseonthecytotoxicityofthymidylatesynthaseinhibitors
AT takemurayuzuru effectofhammerheadribozymeagainsthumanthymidylatesynthaseonthecytotoxicityofthymidylatesynthaseinhibitors
AT miyachihayato effectofhammerheadribozymeagainsthumanthymidylatesynthaseonthecytotoxicityofthymidylatesynthaseinhibitors
AT skeltonlorraine effectofhammerheadribozymeagainsthumanthymidylatesynthaseonthecytotoxicityofthymidylatesynthaseinhibitors
AT jackmanannl effectofhammerheadribozymeagainsthumanthymidylatesynthaseonthecytotoxicityofthymidylatesynthaseinhibitors