• Radiation Oncology Journal
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• v.31 no.2
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• pp.57-65
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• 2013

Beta-lapachone (${\beta}$-Lap; 3,4-dihydro-2, 2-dimethyl-2H-naphthol[1, 2-b]pyran-5,6-dione) is a novel anti-cancer drug under phase I/II clinical trials. ${\beta}$-Lap has been demonstrated to cause apoptotic and necrotic death in a variety of human cancer cells in vitro and in vivo. The mechanisms underlying the ${\beta}$-Lap toxicity against cancer cells has been controversial. The most recent view is that ${\beta}$-Lap, which is a quinone compound, undergoes two-electron reduction to hydroquinone form utilizing NAD(P)H or NADH as electron source. This two-electron reduction of ${\beta}$-Lap is mediated by NAD(P)H:quinone oxidoreductase (NQO1), which is known to mediate the reduction of many quinone compounds. The hydroquinone forms of ${\beta}$-Lap then spontaneously oxidizes back to the original oxidized ${\beta}$-Lap, creating futile cycling between the oxidized and reduced forms of ${\beta}$-Lap. It is proposed that the futile recycling between oxidized and reduced forms of ${\beta}$-Lap leads to two distinct cell death pathways. First one is that the two-electron reduced ${\beta}$-Lap is converted first to one-electron reduced ${\beta}$-Lap, i.e., semiquinone ${\beta}$-Lap $(SQ)^{{\cdot}-}$ causing production of reactive oxygen species (ROS), which then causes apoptotic cell death. The second mechanism is that severe depletion of NAD(P)H and NADH as a result of futile cycling between the quinone and hydroquinone forms of ${\beta}$-Lap causes severe disturbance in cellular metabolism leading to apoptosis and necrosis. The relative importance of the aforementioned two mechanisms, i.e., generation of ROS or depletion of NAD(P)H/NADH, may vary depending on cell type and environment. Importantly, the NQO1 level in cancer cells has been found to be higher than that in normal cells indicating that ${\beta}$-Lap may be preferentially toxic to cancer cells relative to non-cancer cells. The cellular level of NQO1 has been found to be significantly increased by divergent physical and chemical stresses including ionizing radiation. Recent reports clearly demonstrated that ${\beta}$-Lap and ionizing radiation kill cancer cells in a synergistic manner. Indications are that irradiation of cancer cells causes long-lasting elevation of NQO1, thereby sensitizing the cells to ${\beta}$-Lap. In addition, ${\beta}$-Lap has been shown to inhibit the repair of sublethal radiation damage. Treating experimental tumors growing in the legs of mice with irradiation and intraperitoneal injection of ${\beta}$-Lap suppressed the growth of the tumors in a manner more than additive. Collectively, ${\beta}$-Lap is a potentially useful anti-cancer drug, particularly in combination with radiotherapy.

• Radiation Oncology Journal
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• v.35 no.4
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• pp.340-348
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• 2017

Purpose: To evaluate the diagnostic accuracy of computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography/computed tomography (PET/CT) in predicting pelvic lymph node (LN) metastases in patients with cervical cancer. Materials and Methods: From January 2009 to March 2015, 114 patients with FIGO stage IA1-IIB uterine cervical cancer who underwent hysterectomy with pelvic lymphadenectomy and took CT, MRI, and PET/CT before surgery were enrolled in this study. The criteria for LN metastases were a LN diameter ${\geq}1.0cm$ and/or the presence of central necrosis on CT, a LN diameter ${\geq}1.0cm$ on MRI, and a focally increased FDG uptake on PET/CT. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy for pelvic LN metastases were estimated. Results: The sensitivity, specificity, PPV, NPV, and accuracy for detection of pelvic LN metastases were 51.4%, 85.9%, 41.3%, 90.1%, and 80.3% for CT; 24.3%, 96.3%, 56.3%, 86.8%, and 84.6% for MRI; and 48.6%, 89.5%, 47.4%, 90.0%, and 82.9% for PET/CT, respectively. The sensitivity of PET/CT and CT was higher than that of MRI (p=0.004 and p= 0.013, respectively). The specificity of MRI was higher than those of PET/CT and CT (p=0.002 and p=0.001, respectively). The difference of specificity between PET/CT and CT was not statistically significant (p=0.167). Conclusion: These results indicate that preoperative CT, MRI, and PET/CT showed low to moderate sensitivity and PPV, and moderate to high specificity, NPV, and accuracy. More efforts are necessary to improve sensitivity of imaging modalities in order to predict pelvic LN metastases.

• Journal of Korean Neurosurgical Society
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• v.42 no.3
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• pp.200-204
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• 2007

Objective : Radiation therapy is an important treatment for brain tumor. However, serious complications such as radiation necrosis can occur and it may be secondary to the expression of acute phase genes, like cytokines. In particular, inflammatory cytokines (IL-$1{\beta}$, TNF-${\alpha}$) and other immunomodulatory cytokines (TNF-${\alpha}$, TGF-${\beta}1$) might be changed after irradiation (high single dose irradiation). Although it has been reported that IL-1 level is remarkably elevated within 8 week after the irradiation to the rat brain. the change of cytokines levels at acute phase (within 24 hours) has not been reported. In the present study, we examined TNF-${\alpha}$, TGF-${\beta}1$, and IL-$1{\beta}$ levels in acute phase to clarify the early effect of cytokines on the radiation-induced brain damage. Methods : Fifty Sprague-Dawley rats were used and these were divided into irradiation group and control group. After a burr-hole trephination on the right parietal area using a drill, a single 10Gy was irradiated at the trephined site. Their forebrains were extirpated at 30 min, 2 hr, 8 hr, 12 hr and 24 hr, respectively and examined for the expression of TNF-${\alpha}$, TGF-${\beta}1$, and IL-$1{\beta}$. Results : The expression of TNF-${\alpha}$ and TGF-${\beta}1$ were decreased until 12 hr after irradiation but elevated thereafter. The expression of IL-1 was peak at 8 hr and then decreased until 12 hr but elevated after this time window. The present study indicated that expression of cytokines (TNF-${\alpha}$, TGF-${\beta}1$ and IL-$1{\beta}$) were increased at 24 hr after the irradiation to the rat brain. IL-$1{\beta}$ level, on the other hand. reached peak at 8 hr after radiation injury. Conclusion : These findings indicate that IL-1, among various cytokines, may have a more important role in the inflammatory reaction by radiation injury at acute phase and provide some clues for better understanding of the pathogenesis of radiation injury.

• Radiation Oncology Journal
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• v.34 no.3
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• pp.223-229
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• 2016

Purpose: This study is to investigate the effect of captopril when combined with irradiation. Materials and Methods: 4T1 (mouse mammary carcinoma) cells were injected in the right hind leg of Balb/c mice. Mice were randomized to four groups; control (group 1), captopril-treated (group 2), irradiated (group 3), irradiated and captopril-treated concurrently (group 4). Captopril was administered by intraperitoneal injection (10 mg/kg) daily and irradiation was delivered on the tumor-bearing leg for 15 Gy in 3 fractions. Surface markers of splenic neutrophils (G-MDSCs) and intratumoral neutrophils (tumor-associated neutrophils [TANs]) were assessed using flow cytometry and expression of vascular endothelial growth factor (VEGF) and hypoxia-inducible factor 1 alpha ($HIF-1{\alpha}$) of tumor was evaluated by immunohistochemical (IHC) staining. Results: The mean tumor volumes (${\pm}$standard error) at the 15th day after randomization were $1,382.0({\pm}201.2)mm^3$ (group 1), $559.9({\pm}67.8)mm^3$ (group 3), and $370.5({\pm}48.1)mm^3$ (group 4), respectively. For G-MDSCs, irradiation reversed decreased expression of CD101 from tumor-bearing mice, and additional increase of CD101 expression was induced by captopril administration. Similar tendency was observed in TANs. The expression of tumor-necrosis factor-associated molecules, CD120 and CD137, are increased by irradiation in both G-MDSCs and TANs. Further increment was observed by captopril except CD120 in TANs. For IHC staining, VEGF and $HIF-1{\alpha}$ positivity in tumor cells were decreased when treated with captopril. Conclusion: Captopril is suggested to have additional effect when combined to irradiation in a murine tumor model by modulation of MDSCs and angiogenesis.

• Journal of Korean Academy of Oral and Maxillofacial Radiology
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• v.13 no.1
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• pp.17-27
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• 1983

The author observed the effects of /sup 60/Co irradiation on the development and subcellular structure of tongue tissue of the fetal rats. The lower left abdomen of mothers were exposed to radiation on 15½th day of gestation with 300R. The fetuses were removed on the 6hr, 14hr, 24hr, 48hr and 72hr after irradiation and the light microscopic and electron microscopic observations of the lingual epithelium, lamina propria and muscle layer were carried out. The results were as follows: 1. The irradiated fetuses showed the retardation of filiform papillae formation. 2. Epithelial cells revealed fusion and myelination of mitochondria, large autolysosomes, increased lipid droplets, retardation of tonofilaments and desmosome formation. 3. In the lamina propria, undifferentiated cells showed bleb formation of nuclear membrane, pyknosis and fragmentation of nucleus, edema of cytoplasm I and nucleus, increased auto-lysosomes, dilatation of cell membrane and cell necrosis. Also, collagenous fibril formation was inhibited by irradiation. 4. In the muscle layer, growth of myotubes was inhibited. Myotubes showed swelling of mitochondria, loss of mitochondrial cristae, autolysosomes, retardation of myofibril formation, and large vacuoles. Undifferentiated cells adjacent myotube contained pyknotic nucleus and autolysosomes. 5. Among the various tissues of tongue, it seems that mesenchymal cells were most radiosensitive.

• Maxillofacial Plastic and Reconstructive Surgery
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• v.42
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• pp.29.1-29.7
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• 2020

Background: Microvascular reconstruction is the treatment of choice after oral cancer ablation surgery. There are few published studies of free flap survival among Korean populations. This study aimed to determine the survival rate after 121 consecutive cases of maxillofacial microvascular reconstruction and to analyze the complications associated with microsurgery. Methods: This study included consecutive patients who underwent microsurgical reconstruction with free flaps, from January 2006 through September 2019, performed by a single surgeon at the oral and maxillofacial surgery department of a tertiary medical center. A total of 121 cases were reviewed retrospectively. The flap survival rate, flap type, radiotherapy history, complications, and treatment results were analyzed. Results: Four different flap types were used for microvascular reconstruction: radial forearm (n = 65), fibula (n = 34), latissimus dorsi (n = 21), and serratus anterior muscle with rib bone free flap (n = 1). Total necrosis of the flap was found in four cases (two latissimus dorsi flaps and two fibular flaps). The free flap survival rate was 97.5%. Nineteen patients received radiotherapy before surgery, and none of them experienced flap failure. The mean operation time was 334 ± 83.1 min, and the mean ischemic time was 48.9 ± 12.7 min. Conclusions: The success rate was reliable and comparable with previous studies. The success rate was not affected by radiation therapy. Free flaps can be safely used even after radiation treatment.

• Journal of Radiation Industry
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• v.18 no.1
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• pp.63-70
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• 2024

Phlorocyclin (PC) and isophorocyclin (IPC) are rare benzofuran derivaitves obtained from the representive dihydrochalcone glucoside, phloridzin (PZ) and are a type of neolignan backbone with a potential anti-glycative agents. However, research related to the enhancement of biological functionallites to inflammation of the newly converted products is very limited. This research was directed with the purpose of discovery more effective anti-inflammatory agents in macrophages of newly radiolysis products PC and IPC. The anti-inflammatory capacities of the characterized products in RAW 264.7 and DH82 macrophages treated with lipopolysaccharide (LPS) to stimulate an inflammation response were examined. The pro-inflammatory factors such as prostaglandin E2 (PGE2), tumor necrosis factor-α (TNF-α), nitric oxide (NO), interleukin-6 (IL-6), and IL-10, without cytotoxicity in LPS-stimulated macrophages, were significantly inhibited after treatment with PC and IPC, when compared to PZ. Moreover, PC and IPC decreased the appearance of cyclooxygenase-2 (COX-2) and inducible NO synthase (iNOS) proteins in macrophages. The cyclization products modified by radiolysis showed the greatest anti-inflammatory effects in macrophage cells, indicating PC and IPC are a potential candidate for use in anti-inflammatory agents.

• Journal of Radiation Protection and Research
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• v.35 no.2
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• pp.49-56
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• 2010

Developments of radioprotective agents are important issues for minimizing the troubles and the effective treatments in radiotherapy. But few agents are useful in clinical and practical fields. It was shown that trace elements in alcohol beverages might have radioprotective effect. In this study, the types of cell death of lymphocytes according to the commercial alcohol beverage was investigated. Normal healthy volunteers ingested distilled water, beer or soju containing $81.5mg{\cdot}dl^{-1}$ ethyl ahcohol, respectively. After 2 hours, their blood were sampled with their consents. Fraction of lymphocytes was isolated by density gradient method with Histopaque-1077 (Sigma) and irradiated with dose from 0.5 to 5 Gy. After 60 hour incubation, the cells were harvested and analysed by flow cytometry. Cell viability was decreased by dose dependent manner. Cell viability of beer group was reduced about 15% compared with control group. Apoptosis in soju group was reduced about 20% compared with control group. Apoptosis of beer and control groups are similar. Necrosis of soju group significantly increased about 35% compared with control group. Early apoptosis of beer group was increased compared with control group. Early apoptosis of soju group was decreased about 25% compared with control group. Late apoptosis of beer and control group was increased by dose dependent manner. Late apoptosis of soju group was increased about 20-30% compared with control group. Late apoptosis of soju was increased and the radioprotective effect of soju was minimal because late apoptosis induced the cell necrosis. In case of soju trace elements, total cell apoptosis was decreased about 20% and early cell apoptosis was remarkably low. In this case, mitotic cells death may be dominant mechanism. Therefore, trace elements in soju may not be effective radioprotective agents.

• Radiation Oncology Journal
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• v.19 no.3
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• pp.230-236
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• 2001

Purpose : To evaluate treatment results in terms of local control, complications and survival after reirraidiation in recurrent cervical cancer following definite radiation therapy. Material and methods : From November 1987 through March 1998, eighteen patients with recurrent cervical cancer following definite radiation therapy were subsequently treated with reirradiation at Keimyung University Dongsan Medical Center. In regard to the initial FIGO stage, one patient was stage la, five were stage IIa, three were IIb, two were IIb and two were IVa. The age range was 37 to 79 years old with median age of 57. The time interval from initial definite radiation therapy to recurrence ranged from 6 to 122 months with a median of 58 months. The recurrent sites were the uterine cervix in seven patients, vagina in ten and pelvic lymph node in one. Reirradiation was peformed with external radiation and intracavitary radiation in twelve patients, external radiation and implantation in four and external radiation alone in two. The range of external radiation dose was $2,100\~5,400\;cGy$ and the range of the total radiation dose was $3,780\~8,550\;cGy$. The follow-up periods ranged from 8 to 20 months with median of 25 following reirradiation. Results : Fourteen of eighteen patients $(78\%)$ had local control just after reirradiation. The two year disease free survival (2YDFS) rate was $53.6\%$. There were statistically significant differences in the 2YDFS according to both recurrent site (2YDFS $28.5\%$ in uterine cervix, $71.4\%$ in vagina, (p=0.03)) and the total dose (2YDFS $71.8\%$ in >6,000 cGy , $25\%$ in $\leq6,000$ cGy, p=0.007). Seven of ten patients who were followed for more than 20 months remain alive and disease free (7/18, $39\%$). Patients treated with external radiation and intracavitary radiation had a higher rate of 2YDFS. Seven patients including 4 patients with no local control experienced local failure in the uterus or vagina and two patients died with distant metastasis. Complications included rectal bleeding in 3 patients, bowel obstruction treated with surgery in two, hematuria in one, radiation cystitis in two, soft tissue swelling in two and vaginal necrosis spontaneously healed in one. There was no statistical difference in complications according to the total dose or the time to recurrence from initial radiation. Conclusion : In patients with recurrence following definite radiation therapy in the uterine cervical cancer, reirradiation may be effective but requires an effort to reduce radiation induced severe complications.

• Maxillofacial Plastic and Reconstructive Surgery
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• v.38
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• pp.46.1-46.7
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• 2016

Background: Osteoradionecrosis is the most dreadful complication after head and neck irradiation. Orocutaneous fistula makes patients difficult to eat food. Fibular free flap is the choice of the flap for mandibular reconstruction. Osteocutaneous flap can reconstruct both hard and soft tissues simultaneously. This study was to investigate the success rate and results of the free fibular flap for osteoradionecrosis of the mandible and which side of the flap should be harvested for better reconstruction. Methods: A total of eight consecutive patients who underwent fibula reconstruction due to jaw necrosis from March 2008 to December 2015 were included in this study. Patients were classified according to stages, primary sites, radiation dose, survival, and quality of life. Results: Five male and three female patients underwent operation. The mean age of the patients was 60.1 years old. Two male patients died of recurred disease of oral squamous cell carcinoma. The mean dose of radiation was 70.5 Gy. All fibular free flaps were survived. Five patients could eat normal diet after operation; however, three patients could eat only soft diet due to loss of teeth. Five patients reported no change of speech after operation, two reported worse speech ability, and one patient reported improved speech after operation. The ipsilateral side of the fibular flap was used when intraoral soft tissue defect with proximal side of the vascular pedicle is required. The contralateral side of the fibular flap was used when extraoral skin defect with proximal side of the vascular pedicle is required. Conclusions: Osteonecrosis of the jaw is hard to treat because of poor healing process and lack of vascularity. Free fibular flap is the choice of the surgery for jaw bone reconstruction and soft tissue fistula repair. The design and selection of the right or left fibular is dependent on the available vascular pedicle and soft tissue defect sites.