Telomere homolog oligonucleotides induce apoptosis in malignant but not in normal lymphoid cells: mechanism and therapeutic potential.
Human B- or T-cell lymphoma lines and primary murine lymphomas were treated with DNA oligonucleotides homologous to the telomere (TTAGGG repeat; "T-oligo"), either alone or in combination with standard, widely-used anticancer chemotherapeutic agents. T-oligo induces cell cycle arrest and apoptosis in cultured human or murine B or T-lymphoma cell lines and primary tumor cells, but exerts no detectable toxicity on normal human or murine primary lymphocytes. Exposure to T-oligo is hypothesized to mimic exposure of the 3' telomere repeat sequence, activating the ataxia telangiectasia mutated kinase, which phosphorylates downstream effectors such as p53, but effects are not dependent solely on functional p53. T-oligo causes early S-phase arrest and cooperates well with G(2)- or M-phase-specific anticancer agents; when combined at 1/10th of the conventional dose, vincristine and T-oligo produce greater-than-additive killing of human or murine lymphoma cells (78% of cells undergoing apoptosis after 6 hr vs. 5% of control cells). In mice, 1/10th of the conventional dose of a standard combination of cyclophosphamide, adriamycin, vincristine and prednisone is twice as effective when used in combination with low dose T-oligo. Thus, T-oligo sensitizes tumors to traditional anticancer agents and represents a potentially important new addition to the therapeutic arsenal for aggressive lymphomas.
Longe
Harold O
HO
Department of Medicine, Cancer Research Center, Boston University School of Medicine (BUSM), Boston, MA 02118, USA.
Romesser
Paul B
PB
Rankin
Andrew M
AM
Faller
Douglas V
DV
Eller
Mark S
MS
Gilchrest
Barbara A
BA
Denis
Gerald V
GV
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D008214:Lymphocytes / Q000378:metabolism* / Q000473:pathology; D008223:Lymphoma / Q000378:metabolism* / Q000473:pathology; D020714:Maximum Tolerated Dose; D051379:Mice; D009841:Oligonucleotides / Q000737:chemistry*; D010766:Phosphorylation; D016615:Telomere / Q000648:ultrastructure*
D009841:Oligonucleotides; D053148:Caspase 3