[99mTc]Human telomerase reverse-transcriptase antisense mRNA oligonucleotide

Excerpt

Telomerase is an enzyme that synthesizes telomeric DNA at the terminal end of a chromosome, and its activation is one of the mechanisms for the progression of cancer (1). Telomerase, in conjunction with the telomere-binding proteins, maintains stability of the chromosomal terminal end by replicating the DNA, but inhibition of this activity results in a shortened telomere and ultimately leads to replicative senescence or even cell death (2). The repression and close regulation of this enzyme is considered to be one of the mechanisms for tumor suppression in humans, and there is much evidence that a shortened telomere is an indication for the development of a cancer or other degenerative disease, especially in older individuals (3-6). In addition, telomerases are specifically expressed in most cancer cell types and therefore are targets for the development of many anticancer drugs (2). Also, tumors are less likely to develop resistance to anti-telomerase drugs compared to other anticancer treatments because maintenance of the telomere and immortality is crucial for tumor progression (2). Several clinical trials for drugs, vaccines, and antibodies that target the telomerases as a treatment for cancer have been approved by the United States Food and Drug Administration.

Telomerase consists of the telomerase RNA (hTR), the telomerase reverse-transcriptase (hTERT), and the associated proteins (1). Although hTR is expressed without telomerase activity both in normal cells and in malignant cells, only tumor cells express hTERT. As a consequence, hTERT is the target for the development of many anticancer therapies (7), and its expression levels may have prognostic value (8). Investigators have used only indirect methods such as immunohistochemistry, reverse-transcription polymerase chain reaction (RT-PCR), fluorescence, bioluminescence, and radionuclide imaging to determine the expression levels of hTERT in various cell types with reasonable results (9, 10). This approach may not, however, yield the exact nature of the change(s) that alter the genotype and, ultimately, the cell phenotype that result in the development of a cancer. Liu et al. envisioned that antisense oligonucleotides (ASON) would be an excellent in vivo tool to determine the level of expression of a gene during the early stages of tumor development because of their high specificity for binding to nucleotides (11). The authors investigated the in vitro activity and biodistribution of ASON directed toward the hTERT gene and labeled with radioactive technetium (^99mTc) in mice bearing xenograft tumors.