The Means to an End of Tumor Cell Resistance to Chemotherapeutic Drugs Targeting Thymidylate Synthase: Shoot the Messenger

Authors: Berg R.W.; Ferguson P.J.; DeMoor J.M.; Vincent M.D.; Vincent M.D.; Koropatnick J.

Source: Current Drug Targets, Volume 3, Number 4, August 2002 , pp. 297-309(13)

Publisher: Bentham Science Publishers

Abstract:

Thymidylate synthase (TS) is an essential enzyme in de novo synthesis of thymidylate, and is required for DNA synthesis and cell proliferation in the absence of exogenous thymidine. As a consequence, TS is a target for anticancer chemotherapy by several drugs, including 5-fluorouracil (5-FU) and raltitrexed (Tomudex), in treatment of colorectal and other tumors. TS overexpression due to increased gene transcription and mRNA translation can mediate drug resistance. Decreased cellular uptake and polyglutamylation of TS-targeting drugs (raltitrexed, for example), increased drug efflux, altered metabolism of cytotoxic drugs (for example, 5-FU), and other events can decrease the effectiveness of TS-targeting drugs. Recent preclinical and clinical studies have addressed the resistance problem by using combinations of different drugs that target TS,or by combining TS-targeting and non-TS-targeting drugs. Our approach has been to circumvent and / or prevent TS overexpression-mediated drug resistance by employing antisense oligodeoxynucleotides (ODNs) to downregulate TS mRNA and protein levels. These studies have revealed that targeting the 3' end of human TS mRNA downregulates TS mRNA and protein, inhibits cell proliferation, and sensitizes HeLa cells to raltitrexed, 5-FU, and 5-fluorodeoxyuridine (5-FUdR) in vitro (Ferguson et al., Br. J. Pharmacol. 127, 1777-1786, 1999). In addition, growth of human HT29 colon carcinoma cell explants in immunocompromised mice is inhibited by antisense downregulation of TS (Berg et al., J.Pharmacol. Exp. Therap. 298, 477-484, 2001). TS-overexpressing, 5-FUdR-resistant HeLa cells have been established in order to examine resistance mechanisms and cross-resistance to 5-FU and raltitrexed. Treatment of 5-FUdR-resistant HeLa cells with TS antisense ODN effectively reduces TS mRNA and protein levels, and decreases the IC50 of 5-FUdR by up to 80% (Ferguson et al., Br. J. Pharmacol., 134, 1437-1446, 2001). These results indicate that antisense ODN treatment improves the efficacy of anti-TS chemotherapeutic drugs in vitro and in vivo , and is effective in overcoming tumor cell resistance to these drugs. However, cellular responses to antisense targeting of different TS mRNA domains are complex. In fact, targeting the translation start site (but not other TS mRNA regions) stimulates TS gene transcription (DeMoor et al., Exp. Cell Res., 243, 11-21, 1998). Distinctive cellular responses to targeting of specific TS mRNA regions provide exciting therapeutic opportunities. Antisense ODN treatment to modulate TS activity, in combination with TS-targeting chemotherapeutic drugs, has the potential to be an effective anti-tumor therapy.

Keywords: Tumor Cell; Chemotherapeutic; raltitrexed; TS-targeting drugs

Language: English

Document Type: Review article

DOI: http://dx.doi.org/10.2174/1389450023347605

Publication date: 2002-08-01

• Current Drug Targets aims to cover the latest and most outstanding developments on the medicinal chemistry and pharmacology of molecular drug targets e.g. disease specific proteins, receptors, enzymes, genes. Each issue of the journal will be devoted to a single timely topic, with series of in-depth reviews, written by leaders in the field, covering a range of current topics on drug targets. These issues will be organized and led by a guest editor who is a recognized expert in the overall topic. As the discovery, identification, characterisation and validation of novel human drug targets for drug discovery continues to grow; this journal will be essential reading for all pharmaceutical scientists involved in drug discovery and development.

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