Abstract
IntroductionIonizing 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.MethodsMammary 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 immunofluorescent 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.ResultsPretreatment 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.ConclusionsPretreatment 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.
Highlights
Ionizing radiation (IR) is a widely used approach to cancer therapy, ranking second only to surgery in rate of utilization
Sensitization of tumor cells to radiation by T-oligo To determine if T-oligo can enhance the inhibition of mammary tumor cell growth due to radiation, tumor cells from MMT mice were cultured with T-oligo at concentrations ranging from 0 to 40 μM for 24 hours and irradiated
Tumor cells cultured in Dulbecco’s Modified Eagle’s Medium (DMEM) medium alone or DMEM containing the same concentration of a control oligo were used as controls
Summary
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. Promoting tumor cell sensitivity to IR could significantly enhance the treatment outcome and quality of life for patients. Usually in combination with surgical excision, have reduced the provide a promising approach to enhancing the effect of radiotherapy and/or reducing its side effects. Telomeres consist of guanine-rich tandem repeats that prevent chromosome ends from being recognized as DNA double-strand breaks. McClintock’s historical observation that loss of telomeric sequences in maize chromosomes renders DNA ends recombinogenic highlighted the importance of telomeres and their associated complexes in chromosomal integrity [1]. More recent work has established that disruption of the T-loop by experimental DNA damage, telomere shortening or expression of a dominant-negative mutant of loop-binding factor leads to cellular apoptosis or senescence [2,3]
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