Cell‐free plasma DNA is elevated in cancer patients and decreases in response to effective treatments. Consequently, these nucleic acids have potential as new tumor markers. In our current study, we ...investigated whether the plasma DNA concentrations in patients with cancer are altered during the course of radiation therapy. To first determine the origin of cell‐free plasma DNA, plasma samples from mice bearing transplanted human tumors were analyzed for human‐specific and mouse‐specific cell‐free DNA. Human‐specific DNA was detectable only in plasma from tumor‐bearing mice. However, mouse‐specific plasma DNA was significantly higher in tumor‐bearing mice than in normal mice, suggesting that cell‐free plasma DNA originated from both tumor and normal cells. We measured the total cell‐free plasma DNA levels by quantitative polymerase chain reaction in 15 cancer patients undergoing radiation therapy and compared these values with healthy control subjects. The cancer patients showed higher pretreatment plasma DNA concentrations than the healthy controls. Eleven of these patients showed a transient increase of up to eightfold in their cell‐free plasma DNA concentrations during the first or second week of radiation therapy, followed by decreasing concentrations toward the end of treatment. In two other cancer patients, the cell‐free plasma DNA concentrations only decreased over the course of the treatment. The total cell‐free plasma DNA levels in cancer patients thus show dynamic changes associated with the progression of radiation therapy. Additional prospective studies will be required to elucidate the potential clinical utility and biological implications of dynamic changes in cell‐free plasma DNA during radiation therapy. (Cancer Sci 2009; 100: 303–309)
Loss of the cell-cycle regulatory protein p53 or overexpression of the antiapoptotic protein Bcl-2 is associated with resistance to radiation in several types of cancer cells. Flavopiridol, a ...synthetic flavone, inhibits the growth of malignant tumors cells in vitro and in vivo through multiple mechanisms. The purpose of the present study is to clarify whether flavopiridol enhances the cytotoxic effects of radiation in tumor cells that contain dysfunction p53 or that overexpress Bcl-2.
A human glioma cell line (A172/mp53) stably transfected with a plasmid containing mutated p53 and a human cervical cancer cell line (HeLa/bcl-2) transfected with a bcl-2 expression plasmid were used. Cells were incubated with flavopiridol for 24 h after radiation, and then cell viability was determined by a colony formation assay. Foci of phosphorylated histone H2AX were also evaluated as a sensitive indicator of DNA double-strand breaks.
Compared with the parental wild-type cells, both transfected cell lines were more resistant to radiation. Post-treatment with flavopiridol increased the cytotoxic effects of radiation in both transfected cell lines, but not in their parental wild-type cell lines. Post-treatment with flavopiridol inhibited sublethal damage repair as well as the repair of DNA double-strand breaks in response to radiation.
Flavopiridol enhanced the cytotoxic effect of radiation in radioresistant tumor cells that harbor p53 dysfunction or Bcl-2 overexpression. A combination treatment of flavopiridol with radiation has the potential to conquer the radioresistance of malignant tumors induced by the genetic alteration of p53 or bcl-2.
Objective
To identify reliable predictors of overall survival (OS), locoregional control (LC), and metastasis-free survival (MFS) after definitive concurrent chemo-radiotherapy (CCRT) for squamous ...cell carcinoma (SCC) of the pharynx (nasopharynx, oropharynx and hypopharynx), we examined 16 potential prognostic factors, including pre-treatment hemoglobin level and pre- and post-treatment
18
Ffluorodeoxyglucose positron emission tomography CT (F-18 FDG-PET/CT) maximum standardized up-take values (SUV
max
) of primary sites and lymph node (LN) regions.
Methods
We retrospectively reviewed records of 70 patients treated with definitive CCRT for pharyngeal cancer in our institution during July 2006–April 2012, with particular regard to 16 prognostic factors: age, sex, T stage, N stage, retropharyngeal LN (RPLN) involvement, existence of multiple primary cancer, treatment interruptions, overall treatment time, chemotherapy type, pre-treatment hemoglobin level, pre-treatment body mass index, enteral feeding period, and pre- and post-treatment F-18 FDG-PET/CT SUV
max
of primary site and LN region. All patients in our cohort underwent pre- and post-treatment F-18 FDG-PET/CT.
Results
Multivariate analysis associated improved OS with pre-treatment hemoglobin level (≥12 g/dL; hazard ratio HR 3.902; 95 % confidence interval CI 1.244–12.236;
P
= 0.020) and post-treatment SUV
max
(primary site) (SUV
max
<5.00; HR 4.237; 95 % CI 1.072–16.747;
P
= 0.039). Improved LC was associated with pre-treatment hemoglobin level (≥12 g/dL; HR 2.983; 95 % CI 1.123–7.920;
P
= 0.028), and post treatment SUV
max
(primary site) (SUV
max
<5.00; HR 5.233; 95 % CI 1.582–17.309;
P
= 0.007). No variable was found to be significant for improved MFS.
Conclusions
Significant predictors for outcome in pharyngeal SCC treated with definitive CCRT were pre-treatment baseline hemoglobin level and post-treatment F-18 FDG-PET/CT SUV
max
for primary site. Patients who have hemoglobin level lower than 12 g/dL may tend to have dismal prognosis. Additional treatment should be considered in those who have higher SUV
max
at primary site in post-treatment F-18 FDG-PET/CT finding.
Primary sebaceous carcinoma of the tongue Oshiro, Hisashi; Iwai, Toshinori; Hirota, Makoto ...
Medical molecular morphology,
12/2010, Volume:
43, Issue:
4
Journal Article
Peer reviewed
Sebaceous carcinoma is the rarest type of oral malignancies. We report a case of primary sebaceous carcinoma of the tongue. Systemic imaging studies revealed that the patient had a T2N2cM0 ...(International Union Against Cancer guidelines) primary lingual tumor. Histopathological examination revealed neoplastic sebocytic and basaloid cells, and Sudan III staining and electron microscopy revealed intracytoplasmic lipid droplets. The neoplastic cells stained positive for adipophilin; epithelial membrane antigen; epithelial antigen; and cytokeratins 7, 8, and 15, but negative for cytokeratins 5/6, 18, 19, and 20; the androgen receptor; and carcinoembryonic antigen. Superselective intraarterial chemotherapy was administered via the superficial temporal artery concurrent with daily radiotherapy. Multiple biopsies confirmed a complete response of the primary lesion. The patient then underwent neck dissection followed by pathological examination, which revealed lymph nodes metastases. After postoperative radiotherapy to the neck, distant metastases were identified in the mediastinal lymph nodes and the lung. The patient died 17 months after completing the initial course of chemoradiotherapy. Our case demonstrates that superselective intraarterial chemotherapy combined with concurrent radiotherapy can be effective in treating the primary lesion of patients with a sebaceous carcinoma of the tongue. However, an effective strategy to eradicate metastases has yet to be established.
Abstract Background and purpose Overexpression of Bcl-2 is frequent in human cancers and has been associated with radioresistance. Here we investigated the potential impact of heavy ions on Bcl-2 ...overexpressing tumors. Materials and methods Bcl-2 cells (Bcl-2 overexpressing HeLa cells) and Neo cells (neomycin resistant gene-expressing HeLa cells) exposed to γ-rays or heavy ions were assessed for the clonogenic survival, apoptosis and cell cycle distribution. Results Whereas Bcl-2 cells were more resistant to γ-rays (0.2 keV/μm) and helium ions (16.2 keV/μm) than Neo cells, heavy ions (76.3-1610 keV/μm) yielded similar survival regardless of Bcl-2 overexpression. Carbon ions (108 keV/μm) decreased the difference in the apoptotic incidence between Bcl-2 and Neo cells, and prolonged G2 /M arrest that occurred more extensively in Bcl-2 cells than in Neo cells. Conclusions High-LET heavy ions overcome tumor radioresistance caused by Bcl-2 overexpression, which may be explained at least in part by the enhanced apoptotic response and prolonged G2 /M arrest. Thus, heavy-ion therapy may be a promising modality for Bcl-2 overexpressing radioresistant tumors.
We experienced two cases of mucosa-associated lymphoid tissue (MALT) lymphoma arising at unusual locations and used F-18 fluorodeoxyglucose (FDG) positron emission tomography/computed tomography ...(PET/CT) to evaluate their response to radiation therapy (RT). A 62-year-old male with proven prostatic MALT lymphoma and a 43-year-old woman with proven duodenal MALT lymphoma had diffuse FDG uptake in the lesion. Both cases were treated with RT; following FDG, PET/CT showed decreased FDG uptake in each lesion. Neither patient had evidence of recurrence at more than 18 months after RT. FDG PET/CT is useful for indicating the treatment site in MALT lymphoma and in evaluation of therapeutic response following RT.
The hypoxic microenvironment is closely associated with the radiation resistance of tumor cells. Hypoxia induces several genes such as hypoxia-inducible factor (HIF-1) and vascular endothelial growth ...factor (VEGF) to promote tumor cell growth and survival. The up-regulated expression levels of HIF-1 and VEGF in tumor cells also correlate with their resistance to radiation, suggesting that these genes are potential therapeutic targets for strategies designed to enhance radiation effects. To further investigate this possibility, we investigated the effects of suppressing these genes upon the radiation sensitivity of cancer cells. We conducted these experiments using multicellular spheroids as a three-dimensional in vitro tumor model and RNA interference as the method of gene suppression.
SQ5 human lung carcinoma cells were treated with HIF-1/VEGF siRNA and/or radiation. Reversed transfection methods were employed for the spheroids. Gene expression was analyzed using quantitative RT-PCR and western blotting. Cell toxicity was qualified by colony formation assay.
Compared with monolayer cells, spheroids showed up-regulated expression of HIF-1 and increased radiation resistance. Hypoxic conditions elevated the expression of HIF-1 and VEGF and enhanced the surviving fraction of spheroids after exposure to radiation. However, when the expression of HIF-1 and VEGF was down-regulated by transfection of targeting siRNA, this did not influence the cytotoxic effects of the radiation under either normoxic or hypoxic conditions.
We have established a method to transfect siRNA into spheroid cells. Our current data indicate that the functions of HIF-1 or VEGF are independent of radiation sensitivity in spheroids under either normoxic or hypoxic conditions.
Bcl-2, an inhibitor of apoptosis frequently shows elevated expression in human tumors, thus resulting in resistance to radiation therapy. Therefore, inhibiting Bcl-2 function may enhance the ...radiosensitivity of tumor cells. Tetrocarcin A (TC-A) and bcl-2 antisense oligonucleotides exhibit antitumor activity by inhibiting Bcl-2 function and transcription, respectively. We investigated whether these antitumor agents would enhance the cytotoxic effects of radiation in tumor cells overexpressing Bcl-2.
We used HeLa/bcl-2 cells, a stable Bcl-2-expressing cell line derived from wild-type HeLa (HeLa/wt) cells. Cells were incubated with TC-A and bcl-2 antisense oligonucleotides for 24 h after irradiation, and cell viability was then determined. Apoptotic cells were quantified by flow cytometric assay.
The HeLa/bcl-2 cells were more resistant to radiation than HeLa/wt cells. At concentrations that are not inherently cytotoxic, both TC-A and bcl-2 antisense oligonucleotides increased the cytotoxic effects of radiation in HeLa/bcl-2 cells, but not in HeLa/wt cells. However, in HeLa/bcl-2 cells, additional treatment with TC-A in combination with radiation did not significantly increase apoptosis.
The present results suggest that TC-A and bcl-2 antisense oligonucleotides reduce radioresistance of tumor cells overexpressing Bcl-2. Therefore, a combination of radiotherapy and Bcl-2 inhibitors may prove to be a useful therapeutic approach for treating tumors that overexpress Bcl-2.
Significant evidence indicates that ionizing radiation causes biological effects in nonirradiated bystander cells having received signals from directly irradiated cells. There is little information ...available hitherto as to the bystander effect of energetic heavy ions; however, our previous work has shown that in confluent cultures of normal human fibroblast AG01522 cells, targeted exposure of 0.0003% of cells to microbeams of 18.3 MeV/u 12C (103 keV/μm) and 13.0 MeV/u 20Ne (375 keV/μm) ions can similarly cause almost 10% decreases in the clonogenic survival, and twofold increments in the incidence of apoptosis whose temporal kinetics varies between irradiated and bystander cells. Using this experimental system, here we further report that bystander responses of AG01522 cells to 17.5 MeV/u 20Ne ions (294 keV/μm) are consistent with those to 18.3 MeV/u 12C and 13.0 MeV/u 20Ne ions. We also demonstrate that such bystander-induced reductions in the survival are less pronounced and occur independently of Bcl-2 overexpression in human cervical cancer HeLa cells.
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