ODN 491, a novel antisense oligodeoxynucleotide that targets thymidylate synthase, exerts cell-specific effects in human tumor cell lines.

Thymidylate synthase (TS) is essential for DNA replication and is a target for cancer chemotherapy. However, toxicity to normal cells and tumor cell drug resistance necessitate development of new therapeutic strategies. One such strategy is to use antisense (AS) technology to reduce TS mRNA and protein levels in treated cells.

Antisense targeting of thymidylate synthase (TS) mRNA increases TS gene transcription and TS protein: effects on human tumor cell sensitivity to TS enzyme-inhibiting drugs.

Thymidylate synthase (TS) catalyses the only de novo pathway to produce thymidylate for DNA replication and repair and is an important target for cancer chemotherapy. Preexisting or acquired drug resistance in tumor cells limits clinical efficacy of TS-targeting drugs. Cells selected for higher TS protein activity have decreased sensitivity to TS-targeting chemotherapeutic agents (5-FUdR and raltitrexed).

Therapeutic potential of antisense oligodeoxynucleotides to down-regulate thymidylate synthase in mesothelioma.

Malignant mesothelioma is an aggressive tumor of the serosal surfaces of the lungs, heart, and abdomen. Survival rates are poor and effective treatments are not available. However, recent therapeutic regimens targeting thymidylate synthase (TS) in malignant mesothelioma patients have shown promise.

Toxicology of antisense therapeutics.

Targeting unique mRNA molecules using antisense approaches, based on sequence specificity of double-stranded nucleic acid interactions should, in theory, allow for design of drugs with high specificity for intended targets. Antisense-induced degradation or inhibition of translation of a target mRNA is potentially capable of inhibiting the expression of any target protein. In fact, a large number of proteins of widely varied character have been successfully downregulated using an assortment of antisense-based approaches.

A "combination oligonucleotide" antisense strategy to downregulate thymidylate synthase and decrease tumor cell growth and drug resistance.

Thymidylate synthase (TS) catalyzes de novo production of thymidylate for DNA synthesis and cell proliferation. As such, TS has been a target of antitumor chemotherapy for many years. Our laboratory has identified several antisense oligodeoxynucleotides (ODNs) that downregulate TS mRNA and protein, inhibit cell proliferation, and sensitize cells to TS-directed chemotherapeutic drugs.

The means to an end of tumor cell resistance to chemotherapeutic drugs targeting thymidylate synthase: shoot the messenger.

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.