Radiosensitization of mammary carcinoma cells by telomere homolog oligonucleotide pretreatment.
BACKGROUND
Ionizing radiation (IR) is a widely used approach to cancer therapy, ranking second only to surgery in rate of utilization. Responses of cancer patients to radiotherapy depend in part on the intrinsic radiosensitivity of the tumor cells. Thus, promoting tumor cell sensitivity to IR could significantly enhance the treatment outcome and quality of life for patients.


METHODS
Mammary tumor cells were treated by a 16-base phosphodiester-linked oligonucleotide homologous to the telomere G-rich sequence TTAGGG (T-oligo: GGTTAGGTGTAGGTTT) or a control-oligo (the partial complement, TAACCCTAACCCTAAC) followed by IR. The inhibition of tumor cell growth in vitro was assessed by cell counting and clonogenic cell survival assay. The tumorigenesis of tumor cells after various treatments was measured by tumor growth in mice. The mechanism underlying the radiosensitization by T-oligo was explored by immunouorescent determination of phosphorylated histone H2AX (γH2AX) foci, β-galactosidase staining, comet and Terminal deoxynucleotidyl transferase dUTP Nick End Labeling (TUNEL) assays. The efficacy of the combined treatment was assessed in a spontaneous murine mammary tumor model.


RESULTS
Pretreatment of tumor cells with T-oligo for 24 hours in vitro enhanced both senescence and apoptosis of irradiated tumor cells and reduced clonogenic potential. Radiosensitization by T-oligo was associated with increased formation and/or delayed resolution of γH2AX DNA damage foci and fragmented DNA. T-oligo also caused radiosensitization in two in vivo mammary tumor models. Indeed, combined T-oligo and IR-treatment in vivo led to a substantial reduction in tumor growth. Of further significance, treatment with T-oligo and IR led to synergistic inhibition of the growth of spontaneous mammary carcinomas. Despite these profound antitumor properties, T-oligo and IR caused no detectable side effects under our experimental conditions.


CONCLUSIONS
Pretreatment with T-oligo sensitizes mammary tumor cells to radiation in both in vitro and in vivo settings with minimal or no normal tissue side effects.
Weng
Desheng
D
Department of Medicine, Boston University School of Medicine, MA 02118, USA.
Cunin
Monique C
MC
Song
Baizheng
B
Price
Brendan D
BD
Eller
Mark S
MS
Gilchrest
Barbara A
BA
Calderwood
Stuart K
SK
Gong
Jianlin
J
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D016922:Cellular Senescence / Q000187:drug effects / Q000528:radiation effects; D003131:Combined Modality Therapy; D020552:Comet Assay; D004249:DNA Damage / Q000187:drug effects / Q000528:radiation effects; D005260:Female; D005697:Galactosides / Q000032:analysis; D006657:Histones / Q000378:metabolism; D020287:In Situ Nick-End Labeling; D015674:Mammary Neoplasms, Animal / Q000532:radiotherapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D009841:Oligonucleotides / Q000494:pharmacology*; D010766:Phosphorylation / Q000528:radiation effects; D011836:Radiation Tolerance / Q000187:drug effects*; D011839:Radiation, Ionizing; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology* / Q000627:therapeutic use; D016615:Telomere / Q000235:genetics
D005697:Galactosides; D006657:Histones; D009841:Oligonucleotides; D011838:Radiation-Sensitizing Agents; C007816:beta-galactoside; C475961:gamma-H2AX protein, mouse