Chemoprevention of head and neck cancer by the biodegradable microspheres containing all-trans-retinoic acid

최용두 Kwangju Institute of Science & Technology 2003 국내박사

CT-reconstructed three-dimensional radiotherapy planning in head and neck cancer

Samuel Ryu Kyungpook National Univ. 1988 국내석사

한국인 두경부암종 환자에서 Cytochrome P450 1A1, 2E1 및 N-acetyltransferase 2 효소의 다형성 분석에 따른 유전적 감수성에 대한 연구

김태균 한양대학교 2000 국내박사

두경부암에서 MAGE 1-6 mRNA를 검출하는 새로운 MAGE common primer의 의의

이정삼 仁濟大學校 2001 국내박사

Benefits of statin exposure in patients with head and neck cancer : a systematic review and meta-analysis

천현지 Graduate School, Yonsei University 2022 국내석사

I. 연구 배경 스타틴이 다양한 종류의 암 환자에서 사용 시 생존을 향상시킬 수 있다는 메타 분석 연구가 진행되어 왔으나, 두경부암(head and neck cancer) 환자에서 스타틴 사용 시 생존에 영향을 미치는지에 대한 여부는 완전히 입증되지 않았다. 따라서 본 연구에서는 두경부암 환자에서 스타틴을 사용했을 때 생존에 유의미한 이점이 나타나는지, 그리고 그 외에 추가적인 이점이 있는지 평가하기 위해 메타 분석 연구를 진행해 보았다. II. 연구 내용 및 방법 2020년 7월에 PubMed, EMBASE, CINAHL, 그리고 Cochrane Library를 사용하여 randomized clinical trials, observational studies, 그리고 출판된 conference abstracts를 대상으로 검색이 수행되었다. 검색은 ‘statin’ AND ‘head and neck cancer’와 관련된 Medical Subject Headings와 동의어를 포함하여 진행되었다. 분석에는 두경부암 환자를 대상으로 한 연구가 포함되었으며, 중재는 스타틴 사용이었고, 결과는 두경부암 환자에 대한 이점이었다. 주요 결과인 사망률과 뇌졸중의 발병률은 odds ratio와 95% 신뢰구간으로 추정하여 나타냈다. 연구의 이질성을 평가하기 위해 I2 statistic이 사용되었고, I2 값이 50% 이상인 연구는 유의미하게 이질적인 것으로 평가하였다. 데이터가 유의미한 이질성을 나타낼 경우 random-effects model을 사용하여 pooled odds ratio를 나타냈다. III. 연구 결과 사망률과 뇌졸중의 발병률을 측정하기 위한 분석에는 각각 3,929명과 3,157명의 환자가 포함되었다. 스타틴을 사용하지 않은 환자군과 비교했을 때, 스타틴을 사용한 환자군은 모든 원인(odds ratio, 0.77; 95% confidence interval, 0.61 to 0.96) 및 암(odds ratio, 0.70; 95% confidence interval, 0.51 to 0.94)에 의한 사망률의 감소와 유의미하게 연관되었다. 그러나 두경부암 환자에서 스타틴 사용은 뇌졸중의 발병률의 감소와 유의미한 연관성이 발견되지 않았다(odds ratio, 0.89; 95% confidence interval, 0.33 to 2.41). IV. 결론 두경부암 환자에서 스타틴 사용은 모든 원인 및 암에 의한 사망률의 개선과 유의미하게 연관되었다. 체계적인 검토는 섬유증과 간질에 대한 스타틴의 잠재적인 이익을 보여주었다. 두경부암 환자에서 스타틴 사용 시의 이익을 확립하기 위해서는 더 많은 인구를 대상으로 한 추가적인 연구가 필요하다. Introduction Statin exposure is associated with enhanced survival outcomes in various types of cancers. However, whether statin exposure affects survival in patients with head and neck cancer has not been fully established. The purpose of this study is to evaluate whether statins provide a significant benefit to survival in patients with head and neck cancer. Methods In July 2020, a comprehensive search was conducted using PubMed, EMBASE, CINAHL, and Cochrane Library for randomized clinical trials, observational studies, and published conference abstracts. The search was performed with both MEdical Subject Headings and synonyms related to ‘statins’ AND ‘head and neck cancer’. The studies included targeted patients with head and neck cancer, the intervention was statin use, and the outcomes were benefits for patients with head and neck cancer. After full-text screening, a total of nine studies were eligible for the systematic review. Odds ratios and 95% confidence intervals were pooled to estimate the mortality and incidence of stroke. The I2 statistic was used to evaluate heterogeneity between studies, with studies with I2 values above 50% considered significantly heterogeneous. If the data indicated significant heterogeneity, a random-effects model was used to analyze the pooled odds ratios. Results The measurements of mortality and stroke incidence included 3,929 and 3,157 patients, respectively. Compared to statin non-users, the statin user group was significantly associated with decreased all-cause (odds ratio, 0.77; 95% confidence interval, 0.61 to 0.96) and cancer-specific (odds ratio, 0.70; 95% confidence interval, 0.51 to 0.94) mortality. However, statin exposure was not significantly associated with stroke incidence in patients with head and neck cancer (odds ratio, 0.89; 95% confidence interval, 0.33 to 2.41). Conclusions Statin exposure in patients with head and neck cancer was significantly associated with improved all-cause and cancer-specific mortalities. Our systematic review showed the potential beneficial effects of statins on fibrosis and epilepsy. Additional studies with larger populations are needed to establish the therapeutic role of statins in patients with head and neck cancer.

The effect of YAP inhibition on radiation resistance in head and neck cancer

Kim, Jina 연세대학교 일반대학원 2025 국내박사

목적: 두경부암의 치료는 수술, 방사선치료, 항암화학요법을 포함하는 다학제적인 접근을 필요로 한다. 그러나 이러한 다학제적인 치료에도 불구하고 국소 재발율이 여전히 높아 효과적인 구제적 치료가 필요한 실정이다. 재발한 종양은 종종 항암화학요법이나 방사선치료에 저항성을 보이기에 임상적 접근이 어렵다. Hippo 신호전달경로는 여러 암종에서 주요한 종양 억제 체계로 알려져 있으며, 그 하위 시그널 분자인 Yes-associated protein (YAP)은 세포 증식, 세포 생존 및 치료 저항성 등 다양한 과정에 관여하는 것으로 여겨진다. 이전 연구들에서 YAP이 두경부암에서 종종 증폭되어 있으며, YAP이 과발현된 경우 두경부암의 예후가 좋지 않음을 밝혀낸 바 있다. 본 연구는 두경부암 세포주에서 YAP이 방사선 저항성에 미치는 역할을 평가하고자 하였다. 대상 및 방법: 두경부암 세포주를 스크리닝하여 상대적으로 YAP 발현 정도가 높고 방사선 저항성을 띄는 HEP-2 세포주를 선택하였다. YAP을 타겟으로 한 short hairpin RNA (shRNA) 및 small interfering RNA (siRNA)를 사용하여 YAP을 억제한 후 세포 특성의 변화를 살펴보았다. YAP의 약리학적 억제를 위해서는 Verteporfin 및 CA3를 사용하였다. Nude mouse 모델에서 YAP이 억제된 세포의 생체내 (in vivo) 종양 형성 능력을 평가하였으며, 세포 증식, 집락 형성 및 세포 사멸 분석을 통해서는 YAP의 억제와 방사선 조사의 병용 투여가 시너지 효과를 나타내는지를 확인하였다. 또한, YAP 억제 및 방사선 조사 후 Cyclin D1 과 γH2AX foci의 발현 변화를 확인하였다. 결과: YAP의 억제는 세포 증식의 감소, 세포 이동성의 감소, 방사선 감수성 증가 및 세포 사멸 촉진을 초래하였다. 또한, YAP 억제 시 in vivo에서의 종양 형성 또한 유의하게 감소함을 확인하였다. YAP 억제와 방사선 조사의 병용 투여는 세포 증식 및 세포 사멸 측면에서 YAP 억제 또는 방사선 조사 단독 보다 시너지 효과를 나타내었다. 또한, YAP의 억제는 G0/G1 세포 주기 정지를 유도하였다. 더 나아가 YAP의 발현 정도는 Cyclin D1의 발현과 상관관계를 보였으며, YAP의 억제와 방사선치료의 병용 투여는 Cyclin D1 발현 정도의 감소를 유발하였고, 이는 DNA 손상의 증가로 이어졌다. 결론: YAP은 두경부암 세포에서 세포 증식, 이동 및 세포 사멸에 관여하며, YAP 억제 시 방사선 감수성이 향상되었다. 또한 YAP은 Cyclin D1의 조절을 통해 방사선 조사 후 DNA 손상 반응에 관여하는 것으로 생각된다. YAP을 표적으로 하는 치료는 두경부암에서 방사선 저항성을 극복할 수 있는 잠재적인 치료 전략이 될 것이다. Purpose: The treatment of head and neck cancer requires a multidisciplinary approach involving surgery, radiotherapy, and chemotherapy. However, despite these multimodal treatments, the local recurrence rate remains high, and effective salvage therapies are urgently needed. Recurrent tumors are often resistant to chemotherapy or radiotherapy, presenting a significant clinical challenge. The Hippo pathway is a major tumor suppressor pathway in many cancers, and its downstream effector molecule Yes-associated protein (YAP) is thought to play a role in various processes, including cell proliferation, cell survival, and treatment resistance. YAP is frequently amplified in head and neck cancer, and previous studies have identified its amplification as a poor prognostic factor for head and neck cancer. This study aims to assess the role of YAP in radiation resistance in head and neck cancer cell lines. Materials and Methods: After screening 20 head and neck cancer cell lines, we identified HEP-2 as a cell line with relatively high YAP expression and radioresistance. Using short hairpin RNA (shRNA) and small interfering RNA (siRNA) targeting YAP, we investigated the changes in cellular characteristics following YAP knockdown. For pharmacological inhibition of YAP, we used Verteporfin and CA3. In vivo tumorigenicity of YAP knockdown cells was assessed in nude mice. Cell proliferation, clonogenic, and apoptosis assays were performed to assess whether combining YAP inhibition with irradiation induced any synergistic effects. The change in the expression level of Cyclin D1 and γH2AX foci were investigated upon YAP inhibition and irradiation. Results: YAP knockdown led to reduced cellular proliferation, diminished migration, enhanced radiosensitivity, and increased apoptosis compared with control cells. In vivo tumorigenicity results also confirmed that inhibition of YAP resulted in significantly decreased tumor volume. The combination of YAP knockdown and irradiation resulted in a synergistic effect compared to YAP knockdown or irradiation alone in terms of cell proliferation and apoptosis. In addition, YAP knockdown resulted in G0/G1 cell cycle arrest. Furthermore, YAP expression level was found to correlate with Cyclin D1 expression, and treatment with both pharmacologic YAP inhibition and irradiation resulted in decreased Cyclin D1 levels, which subsequently led to increased DNA damage. Conclusion: YAP is associated with cell proliferation, migration, and apoptosis in head and neck cancer cells. Additionally, YAP, through its regulation of Cyclin D1, is involved in cellular DNA damage response following irradiation. Targeting YAP may provide a potential strategy to overcome radioresistance in head and neck cancer.

The role of cancer stem cell in acquiring radioresistance of head and neck cancer

Park, Young Min 연세대학교 일반대학원 2015 국내박사

본 연구는 방사선 내성 두경부 암 세포주를 만들고 이로부터 종양줄기세포를 분리하여 방사선 내성 발현에 있어서 종양줄기세포의 역할을 규명하고자 한 연구이다. 실제 임상과 유사한 상황에서 방사선을 조사하여 방사선 내성 두경부 암 세포주 (SCC15, SCC25, QLL1)를 만들었고 MTT assay를 시행하여 이들 세포주들이 방사선 내성을 획득하였음을 확인하였다. 이들 세포주로부터 종양줄기세포를 분리하여 줄기세포인자 (CD44, Oct-4, Nanog, Sox-2, CD-133)의 발현을 western blot을 통하여 확인하였다. Monolayer cell들에 비하여 spheroid cell들이 두경부 암에서 관찰되는 방사선 내성의 발현에 중요한 역할을 맡고 있음을 colony-forming assay를 통하여 확인하였고, Src을 inhibition함으로써 이들에서 관찰되던 방사선 내성의 정도가 감소함을 확인하였으며 in vivo study를 통하여 Src의 억제가 방사선 내성 두경부 암 세포주의 방사선 내성을 감소시킬 수 있음을 확인하였다. 본 연구의 결과를 바탕으로 두경부 암에서 관찰되는 방사선 내성의 발현에 종양줄기세포가 중요한 역할을 맡고 있으며, 특히 Src이 이러한 방사선 내성을 유지 및 발현하는데 필수적임을 확인하였다. 향후 targeted therapy의 대상으로 추가적인 연구가 필요할 것으로 보인다. Purpose: Radioresistance is one of the main determinants of the treatment outcome in head and neck cancer. The aim of this study was to establish radioresistant head and neck cancer cell lines and separate cancer stem cells from them to investigate the role of cancer stem cells in radioresistant head and neck cancer. Methods: To induce radioresistant cell lines, irradiation was delivered to SCC15, SCC25, and QLL1 cells with an accumulated dosage of 60 Gy over 30 cycles of irradiation. Radioresistance of irradiated cancer cells were verified by MTT assay. Radioresistant cells were cultured in serum-free media in ultra-low?attachment culture flasks to induce sphere-forming cells. Cancer stem cell characteristics of sphere-forming cells were verified by western blot for CD-44, Oct-4, Nanog, Sox-2, and CD-133. Results: The MTT assay of cell viability showed more radioresistance in the irradiated cancer cell lines than in the non-irradiated cancer cell lines. Sphere-forming cells were identified in all three cancer cell lines 3 to 5 days after serum deprivation. All sphere-forming cells from the three different cancer cell lines expressed stem cell markers; however, they showed different levels of expression. Sphere-forming cells showed more radioresistance than monolayer cells after irradiation by colony forming assay. Inhibition of Src in sphere-forming cells showed reduced radioresistance, low expression of cancer stem cell markers, and less invasion and migration in radioresistant head and neck cancer. Conclusion: Cancer stem cells seem to be the cause of the radioresistant properties of radioresistant head and neck cancer. Src may also play a key role in maintaining radioresistance, and it may be used in target therapy for radioresistant head and neck cancer.

두경부 암세포에서 Carboplatin과 Thioridazine의 병합 처리에 의한 항암 효과

조혁기 계명대학교 대학원 2016 국내박사

두경부 암은 세계적으로 6번째 빈도로 발생되는 암종으로 수술적 제거와 방사선치료가 주요 치료방법으로 알려져 왔다. 그러나 두경부 영역의 암은 수술 후 기능적인 면에서 많은 후유증을 유발하고, 일부 전이가 된 진행된 병기의 암종인 경우 수술로 완전한 제거가 불가능하다는 단점이 있다. 이에 비해 항암치료는 장기의 고유 기능 유지가 가능하고 원격 전이된 암종의 치료에도 적용가능한 장점이 있다. 본 연구에서는 그동안 다양한 암종에서 항암제로 쓰였던 carboplatin과 최근 연구에서 항암효과를 보이는 것으로 보고된 항정신성 약물인 thioridazine을 저 농도로 병합 처리하여 두경부 암세포에서의 세포 사멸 여부 및 그 기전을 알아보고자 하였다. 이번 연구를 통해서 두 약물의 병합처리 시 두경부 암세포의 세포사멸이 농도와 시간에 의존적으로 증가하는 것을 확인하였다. 또한 caspase 억제제를 통한 실험에서 세포 사멸이 억제 되는 것을 확인함으로써 두 약물의 병합 처리에 의한 세포 사멸이 caspase 기전에 의해 일어난다는 것을 알 수 있었다. 이러한 세포사멸은 다른 암세포인 human breast cancer cell과 glioma cell에서도 확인되었지만, 정상 세포군에서는 세포사멸을 유도하지 않는다는 것을 확인할 수 있었다. 두 약물의 병합 처리에 의한 두경부 암세포의 세포 사멸에 관여하는 단백질을 실험한 결과 세포 사멸 억제 단백질인 c-FLIP과 Mcl-1 단백질의 저하를 관찰하였고, mRNA 변화 양상을 통해 전사 이후 단백질의 변형이 일어나는 것을 확인하였다. Sub-lethal dose의 carboplatin과 thioridazine의 병합 처리 시 proteasome의 일종인 PSMA5의 발현 증가를 통해 proteasome 활성도가 증가되어 c-FLIP과 Mcl-1단백질의 발현이 감소하는 것도 확인할 수 있었다. 이러한 이번 연구의 결과는 향후 carboplatin과 thioridazine의 병합 요법이 두경부 암종에서 새로운 항암치료제 개발에 있어 이용 가능성을 보여 주었다. Head and neck cancer is the 6th leading cancer by incidence worldwde. surgery and radiotherapy have been the major treatment for patients with head and neck cancer, while chemotherapy has become an important treatment option for locally advanced head and neck cancer. However, patient survival has been reported to be poor. therefore, the aim of this study is to evaluate the effect of carboplatin and thioridazine to improve outcome in head and neck cancer. Combined treatment with carboplatin and thioridazine markedly induced apoptosis in AMC-HN4 cells. Co-treatment with carboplatin and thioridazine led to activation of caspase-3, and caspase inhibitor markedly blocked apoptosis. carboplatin plus thioridazine induced down-regulation of Mcl-1 and c-FLIP protein expression, but not mRNA expression via up-regulation of proteasome activity. Combined treatment with carboplatin and thioridazine induced up-regulation of PSMA5 (20S proteasome subunit alpha) expression, which has a critical role on proteasome activity. Moreover, ectopic expression of Mcl-1 and c-FLIP completely inhibited carboplatin plus thioridazine induced apoptosis. In contrast, combined treatment with carboplatin and thioridazine induced proteasomal activity via up-regulation of PSMA5 expression. Furthermore, combined treatment with carboplatin and thioridazine induced down-regulation of c-FLIP and Mcl-1 via up-regulation of proteasomal activity. Therefore, combined therapy of carboplatin and thioridazine may be effective and safe anti-cancer therapeutic strategy.

Clinical factors related to second primary lung cancer development in patients with head and neck cancer

김의배 고려대학교 대학원 2008 국내석사

Background: Head and neck cancers (HNC) represent about six percent of all cancers and are associated with tobacco and alcohol use. In addition, patients with HNC are at risk for developing second primary malignancies, at rate of 4% to 7% per year. Smoking is the most important risk factor for both HNC and lung cancer, so the rate of second primary lung cancer development in patients with HNC has been noted. It is also known that second primary lung cancer in the presence of HNC indicates poor survival because of the advanced stage of lung cancer at diagnosis. Hence, early detection of second primary lung cancer might be a crucial factor for prolonging survival. The question of whether to use chest x-rays or chest computed tomography (CT) scans for early detection of primary lung cancer in patients with HNC has not yet been resolved. The aim of our study was to evaluate the incidence and clinical features of second primary lung cancer development in patients with primary HNC. Methods: We conducted a retrospective study of 469 patients newly diagnosed with HNC at Korea University Medical Center between January 2000 and December 2006. Patients were included in the study if they had primary tumors originating from the oral cavity, nasal cavity, paranasal sinus, nasopharynx, oro-hypopharynx, larynx, and salivary gland. They were excluded if they had primary tumors originating from the skin, or if the cell type was lymphoma. The patient medical records were reviewed for the following parameters: age, sex, alcohol and tobacco use, site of tumor origin, TNM stage, histology, treatment of primary or second primary cancers, survival rate, synchronicity, and initial chest x-ray findings. Results: A total of 469 patients were included in this study (389 men and 80 women). The median age of patients was 66.0 years. Eighteen patients (3.8%) were found to have second primary lung cancers. The statistically significant clinical variables for lung cancer development were the origin site of primary HNC (oro-hypopharynx and larynx) (p=0.048), abnormal chest x-ray findings (p=0.027), and histologic type of HNC (squamous cell carcinoma) (p=0.032). Among the 18 patients who developed second primary lung cancer, 13 already had abnormal chest x-ray findings at the time of diagnosis of HNC. The lung cancer cell types were confirmed to be squamous cell carcinoma in 11 patients, SCLC in 3 patients, and undifferentiated NSCLC in 4 patients. Only 3 second primary lung cancers were detected synchronously with HNC. The other 15 second primary lung cancers were detected more than 6 months after HNC was diagnosed. Because of the advanced stages of second primary lung cancers at diagnosis, 13 patients received only palliative treatments, such as chemotherapy and radiotherapy, for the lung lesions. The median overall survival time in second primary lung cancer patients with HNC was 72 months. However, when second primary lung cancers were combined in patients with HNC, the overall median survival time decreased to 16 months (p<0.001). Conclusion: In this retrospective analysis, the rate of second primary lung cancer detection in patients with HNC was 3.8%. Statistically significant clinical risk factors for development of second primary lung cancer in patients with HNC include oro-hypopharynx and larynx primary sites, squamous cell carcinoma, and abnormal findings on chest x-ray at initial diagnosis. Considering the relatively high rate of second primary lung cancer development in patients with HNC, new strategies should be developed for the detection and follow up for lung lesions in this patient group.

Aripiprazole sensitizes head and neck cancer cells to ionizing radiation by enhancing the production of reactive oxygen species

Jeong, Hyeon Jeong 고려대학교 대학원 2022 국내석사

Drug repositioning is an alternative process for drug development in cancer. Specifically, it is a strategy for the discovery of new antitumor drugs by screening previously approved clinical drugs. On the basis of this strategy, Aripiprazole, an antipsychotic drug, was found to have anticancer activity. In this study, we investigated the radiosensitizing effects of Aripiprazole on head and neck cancer cells at sublethal doses of ionizing radiation (IR) in vitro and in vivo. Treatment with Aripiprazole suppressed the growth of head and neck cancer cells in a concentration-dependent manner, as evidenced by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Intriguingly, Aripiprazole significantly enhanced the sensitivity of these cells to the IC50 dose of IR. The combination of Aripiprazole with IR synergistically increased annexin and propidium iodide double-positive and terminal deoxynucleotidyl transferase dUTP nick-end labeling-positive cell populations, and induced cleaved poly (ADP-ribose) polymerase and caspase-3 expression, indicating the induction of apoptosis in these cells. Aripiprazole and IR-induced apoptosis was accompanied by an increase in reactive oxygen species and was almost completely suppressed by addition of the antioxidant, N-acetylcysteine. Finally, Aripiprazole greatly sensitized xenograft tumors to IR at doses that did not affect tumor growth. Taken together, these results suggest that Aripiprazole could be considered a potent radiosensitizer for head and neck cancer.