Telomerase as a new target for the treatment of hormone-refractory prostate cancer.
Prostate cancer is the leading cause of cancer-related deaths in men. Androgen ablation is the mainstay of treatment for advanced prostate cancer. This therapy is very effective in androgen-dependent cancer; however, these cancers eventually become androgen independent, rendering anti-androgen therapy ineffective. The exploration of novel modalities of treatment is therefore essential to improve the prognosis of this neoplasia. Telomeres are specialized heterochromatin structures that act as protective caps at the ends of chromosomes. Telomere maintenance in the majority of tumor cells is achieved by telomerase, a reverse transcriptase enzyme that catalyzes the synthesis of further telomeric DNA. Telomerase is detected in the majority of prostate cancers, but not in normal or benign prostatic hyperplasia tissue. Moreover, the human telomerase reverse transcriptase (hTERT) gene, the catalytic subunit of telomerase, is regulated by androgens as well as by different oncogenes including Her-2, Ras, c-Myc and Bcl-2, which seem to play an important role in prostate cancer progression. Thus, telomerase may represent a very good candidate for targeted therapy in prostate tumors. To inhibit telomere maintenance by telomerase, approaches that directly target either telomerase and telomeres or the telomerase regulatory mechanisms have been used. Moreover, strategies targeting telomerase-positive cells as a means to directly kill the tumor cells have been tested. This review summarizes the most promising results achieved by anti-telomerase strategy in different solid tumors. Most of the telomerase-associated therapies described here have proved very promising for the treatment of prostate cancer. On the basis of the good results obtained and considering the multigenic defects of human tumors, including prostate cancer, the combination of anti-telomerase strategies with conventional drugs and/or molecules capable of interfering with oncogenic pathways could efficiently improve the response of this neoplasia.
Biroccio
Annamaria
A
Experimental Chemotherapy Laboratory, Regina Elena Cancer Institute, Via delle Messi d'Oro 156, 00158 Rome, Italy.
Leonetti
Carlo
C
D006801:Humans; D008297:Male; D009376:Neoplasms, Hormone-Dependent / Q000201:enzymology / Q000473:pathology / Q000628:therapy*; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000473:pathology / Q000628:therapy*; D019098:Telomerase / Q000037:antagonists & inhibitors*
D019098:Telomerase