Telomerase inhibitors for the treatment of brain tumors and the potential of intranasal delivery.
A fundamental limitation in the treatment of brain tumors is that < 1% of most therapeutic agents administered systemically are able to cross the blood-brain barrier (BBB). The development of new strategies that circumvent the BBB should increase the likelihood of tumor response to selected therapeutic agents. Intranasal delivery (IND) is a practical, noninvasive method of bypassing the BBB to deliver therapeutic agents to the brain. This technique has demonstrated promising results in the treatment of neurological disorders. Telomerase is a reverse transcriptase that is expressed in the vast majority of malignant gliomas, although not in the healthy brain. Telomerase inhibition can therefore be used as a therapeutic strategy for selectively targeting malignant gliomas. The first successful IND of a telomerase inhibitor as a therapy for brain tumors was GRN-163, an oligonucleotide N3'-->5' thiophosphoramidate telomerase inhibitor, which was successfully administered into intracerebral tumors in rats with no apparent toxicity. GRN-163 exhibited favorable tumor uptake and inhibited tumor growth, leading to prolonged lifespan in treated animals. The IND of telomerase inhibitors represents a new therapeutic approach that appears to selectively kill tumor cells, without inducing toxic effects in the surrounding healthy brain tissue.
Hashizume
Rintaro
R
University of California San Francisco, Hellen Diller Family Cancer Research Center, Mission Bay, 1450 3rd Street, HD 200, San Francisco, CA 94158-0520, USA. rintaro.hashizume@ucsf.edu
Gupta
Nalin
N
D000281:Administration, Intranasal; D000818:Animals; D001812:Blood-Brain Barrier / Q000502:physiology; D001932:Brain Neoplasms / Q000188:drug therapy*; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use; D009369:Neoplasms / Q000201:enzymology / Q000235:genetics; D009434:Neural Pathways / Q000033:anatomy & histology; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use; D009841:Oligonucleotides / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use; D019098:Telomerase / Q000037:antagonists & inhibitors*
D004791:Enzyme Inhibitors; C479222:GRN163; D007211:Indoles; D009841:Oligonucleotides; D009536:Niacinamide; D019098:Telomerase; C519562:imetelstat