• Korean Journal of Head & Neck Oncology
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• v.16 no.2
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• pp.172-176
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• 2000

Objectives: To improve local control and reduce toxicity, 3-D conformal radiotherapy was used as a boost the primary tumor site following fractionated radiotherapy in patients with nasopharyngeal carcinoma. Materials and Methods: Eight patients with previously untreated nasopharyngeal carcinomas were treated with 3-D conformal radiotherapy following fractionated radiotherapy from September 1998 to April 2000. All patients had biopsy confirmation of disease before radiation therapy. Stages were II in 1, III in 5, and IV in 2. Two patients received cisplatin based chemotherapy in addition to radiation therapy; induction chemotherapy in 1, concurrent chemoradiation in 1. 3-D conformal radiotherapy delivered using 6MV Linac as a boost(range 25.2-28.8Gy, median 25.7Gy) following conventionally fractionated radiotherapy(range 50.4Gy). Average total dose ranged from 75.6-79.2Gy(median 76Gy). Follow-up time was 4-21 months(median 9.6 months). Results: Seven of 8 patients were evaluated radiologically within 3 months after completion of radiation therapy. All 7 patients were seen complete remission. One of 7 patients had distant metastasis after 5 months and local failure after 7 months. The tree interval of local recurrence was ranged from 4 - 21 months(median 10.2 months). One patient without radiological evaluation got complete remission clinically. Treatment related toxicity was grade 1-3 xerostomia, dysphagia, and mucositis. During 3-D conformal radiotherapy, there was no aggravation of any toxicity. Conclusion: Although the number of patients was small and follow-up period was short, 3-D conformal radiotherapy following conventional radiotherapy improved tumor control and dose escalation without increased toxicity. Survival and late toxicity should be evaluated through long term follow-up. In addition, it is necessary to confirm the benefits of 3-D conformal radiotherapy in nasopharyngeal carcinoma with randomized trial.

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.7
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• pp.2707-2712
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• 2015

Background: The human homologue of the mouse double minute 2 (MDM2) gene is a negative regulator of Tp53. MDM2-309T>G a functional promoter polymorphism was found to be associated with overexpression thereby attenuation of Tp53 stress response and increased cancer susceptibility. We have planned to evaluate the possible role of MDM2-309T>G polymorphism with risk and response to chemotherapy in AML. Materials and Methods: A total of 223 de novo AML cases and 304 age and sex matched healthy controls were genotyped for the MDM2-309T>G polymorphism through the tetra-primer amplification refractory mutation system (ARMS)-PCR method. In order to assess the functional relationship of -309T>G SNP with MDM2 expression level, we quantified MDM2 mRNA in 30 primary AML blood samples through quantitative RT-PCR. Both the (-309T>G) genotypes and the MDM2 expression were correlated with disease free survival (DFS) rates among patients who have achieved complete remission (CR) after first induction chemotherapy. Results: MDM2-309T>G polymorphism was significantly associated with AML development (p<0.0001). The presence of either GG genotype or G allele at MDM2-309 confered 1.79 (95% CI: 1.12-2.86; p<0.001) and 1.46 fold (95%CI: 1.14-1.86; p= 0.003) increased AML risk. Survival analysis revealed that CR+ve cases with GG genotype had significantly increased DFS rates (16months, p=0.05) compared to CR+ve TT (11 months) and TG (9 months) genotype groups. Further, MDM2 expression was also found to be significantly elevated in GG genotype patients (p=0.0039) and among CR+ve cases (p=0.0036). Conclusions: The MDM2-309T>G polymorphism might be involved in AML development and also serve as a good prognostic indicator.

• Asian Pacific Journal of Cancer Prevention
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• v.14 no.10
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• pp.5989-5993
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• 2013

Background: Radiation therapy is the mainstay of treatment for nasopharyngeal carcinoma. Importance of tumor coverage and challenges posed by its unique and critical location are well evident. Therefore we aimed to evaluate our radiation treatment plan through dose volume histograms (DVHs) to find planning target volume (PTV) dose coverage and factors affecting it. Materials and Methods: This retrospective study covered 45 histologically proven nasopharyngeal cancer patients who were treated with definitive 3D-CRT and chemotherapy between Feb 2006 to March 2013 at the Department of Oncology, Section Radiation Oncology, Aga Khan University Hospital, Karachi, Pakistan. DVH was evaluated to find numbers of shrinking field (phases), PTV volume in different phases and its coverage by the 95% isodose lines, along with influencing factors. Results: There were 36 males (80%) and 9 females (20%) in the age range of 12-84 years. Stage IVA (46.7%) was the most common stage followed by stage III (31.1). Eighty six point six-percent received induction, 95.5% received concurrent and 22.2% received adjuvant chemotherapy. The prescribed median radiation dose was 70Gy to primary, 60Gy to clinically positive neck nodes and 50Gy to clinically negative neck regions. Mean dose to spinal cord was 44.2Gy and to optic chiasma was 52Gy. Thirty seven point eight-percent patients completed their treatment in three phases while 62.2% required four to five phases. Mean volume for PTV3 was $247.8cm^3$ (50-644.3), PTV4 $173.8cm^3$ (26.5-345.1) and PTV5 $119.6cm^3$ (18.9-246.1) and PTV volume coverage by 95% isodose lines were 74.4%, 85.7% and 100% respectively. Advanced T stage, intracranial extension and tumor volume > $200cm^3$ were found to be important factors associated with decreased PTV coverage by 95% isodose line. Conclusions: 3D CRT results in adequate PTV dose coverage by 95% isodose line. However advanced T stage, intracranial extension and large target volume require more advanced techniques like IMRT for appropriate PTV coverage.

• Korean Journal of Head & Neck Oncology
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• v.34 no.2
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• pp.11-15
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• 2018

Background/Objectives: The efficacy of radiotherapy alone versus chemoradiotherapy has been studied in patients with T2N0M0 laryngeal squamous cell carcinoma. Materials & Methods: Thirty nine patients with newly diagnosed T2N0M0 laryngeal squamous cell carcinoma were treated with either radiotherapy(RT group, 66-70Gy) or chemoradiotherapy(CRT group, cisplatin based concurrent chemoradiation with or without 2 cycles induction chemotherapy including cisplatin, $5-FU{\pm}$ docetaxel / radiation therapy same with above mentioned). The mean follow-up was 73.5 months. Results: The overall survival (OS), disease specific survival (DSS), disease free survival (DFS), and larynx preservation survival (LPS) at 5 years were 70%, 79%, 67%, and 71%. The complete response rate was 82.4% in RT group, and was 95.5% in CRT group. OS (57% vs 80%), DSS (69% vs 86%), DFS (52% vs 77%), and LPS (63% vs 77%) at 5 years were higher in CRT group than RT group, but it was not statistically significant. In subsite analysis, CRT group tends to improve DFS, compared to RT group, in glottic cancer (p=0.06). The toxicities were tolerable and no fatal case was observed in both groups. Conclusion: Chemoradiotherapy is effective as primary therapy for T2 laryngeal squamous cell carcinoma and showed manageable treatment induced toxicity.

• Asian Pacific Journal of Cancer Prevention
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• v.13 no.11
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• pp.5339-5343
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• 2012

The induction of apoptosis in target cells is a key mechanism for most anti-tumor therapies. Bufalin is a cardiotonic steroid that has the potential to induce differentiation and apoptosis of tumor cells. Research on bufalin has so far mainly involved leukemia, prostate cancer, gastric cancer and liver cancer, and has been confined to in vitro studies. The bufadienolides bufalin and cinobufagin have been shown to induce apoptosis in a wide spectrum of cancer cell. The present article reviews the anticancer effects of bufalin. It induces apoptosis of lung cancer cells via the PI3K/Akt pathway and also suppressed the proliferation of human non-small cell lung cancer A549 cell line in a time and dose dependent manner. Bufalin, bufotalin and gamabufotalin, key bufadienolides, significantly sensitize human breast cancer cells with differing ER-alpha status to apoptosis induction by the TNF-related apoptosis-inducing ligand (TRAIL). In addition, bufadienolides induce prostate cancer cell apoptosis more significantly than that in breast epithelial cell lines. Similar effects have been observed with hepatocellular carcinoma (HCC) but the detailed molecular mechanisms of inducing apoptosis in this case are still unclear. Bufalin exerts profound effects on leukemia therapy in vitro. Results of multiple studies indicate that bufalin has marked anti-tumor activities through its ability to induce apoptosis. Large-scale randomized, double-blind, placebo or positive drug parallel controlled studies are now required to confirm the efficacy and apoptosis-inducing potential of bufalin in various cancers in the cliniucal setting.

• Journal of Life Science
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• v.30 no.5
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• pp.460-467
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• 2020

Hepatocellular carcinoma (HCC) is one of the most commonly diagnosed cancers in the word. Although radiation and chemotherapy are generally effective, there are various side effects that greatly limit the effectiveness of these treatments. Therefore, traditional herbs may have potential as important resources for the discovery of liver cancer therapeutics. In this study, we selected three Korean herbal medicine formulas from the Donguibogam, namely Bigihwan (BGH), Daechilgithang (DCGT), and Mokwhyangbinranghwan (MHBRH), and evaluated their anti-cancer effects on HCC cells. According to our results of three ethanol extracts, BGH was more effective at suppressing HCC growth than DCGT or MHBRH. Furthermore, flow cytometry analysis showed that inhibition of HCC proliferation by the three extracts was associated with the induction of apoptosis and autophagy. In particular, BGH significantly increased mitochondrial impairment and showed the possibility of inducing mitophagy in comparison with the other two extracts. BGH prominently upregulated the levels of microtubule-associated protein light chain-3 which was accompanied by a decrease in the expression of anti-apoptotic Bcl-2 without altering the expression of pro-apoptotic Bax. In addition, the levels of PTEN-induced kinase 1 were also markedly increased in BGH-treated HCC cells. Moreover, autophagy blocking improved cell viability and reduced apoptosis after the three treatments, indicating that autophagy by these extracts enhances HCC cells against cytotoxicity. In conclusion, our findings show that BGH demonstrates the highest anti-cancer activity among the three formulas and inhibits the proliferation of HCC cells through autophagy induction.

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.15
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• pp.6463-6468
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• 2015

Background: Chemotherapy is one of the common approaches in treatment of cancers, especially leukemia. However, drug resistance phenomena reduce the likelihood of treatment success. Resveratrol is a herbal compound which through complicated processes makes some selected cells sensitive to treatment and induction of apoptosis. In the present study, the effects of resveratrol on the expression of miR 15a and miR16-1 and apoptosis in the CCRF-CEM cell line were investigated. Materials and Methods: The CCRF-CEM cell line was cultured under standard conditions and changes in miR 15a and miR 16-1 expression were analyzed by real time-PCR technique, with attention to reveratrol dose and time dependence. Also, apoptosis is evaluated by flow cytometry using annexin V and PI. Results: CCRF-CEM cells underwent dose-dependent apoptotic cell death in response to resveratrol. MiR 15a and miR 16-1 expression was up-regulated after 24 and 48 hours resveratrol treatment (p<0.05). Conclusions: The results of our study indicate that resveratrol induces apoptosis in a time and dose-dependent manner in CCRF-CEM cells. Also, increased expression level of miR 16-1 and miR 15a by means of resveratrol in CCRF-CEM cells might have a role in apoptosis induction and predisposition. According to our results resveratrol can be regarded as a dietary supplement to improve efficacy of anti-leukemia therapies.

• Asian Pacific Journal of Cancer Prevention
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• v.13 no.7
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• pp.3519-3528
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• 2012

Inhibitory effects of Maclura amboinenesis Bl, one plant used traditionally for the treatment of cancers, on metastatic potential of highly metastatic B16F10 melanoma cells were investigated in vitro. Cell proliferation was assessed using the MTT colorimetric assay. Details of metastatic capabilities including invasion, migration and adhesion of B16F10 melanoma cells were examined by Boyden Chamber invasion and migration, scratch motility and cell attachment assays, respectively. The results demonstrated that n-hexane and chloroform extracts exhibited potent anti-proliferative effects (p<0.01), whereas the methanol and aqueous extracts had less pronounced effects after 24 h exposure. Bioactivity-guided chromatographic fractionation of both active n-hexane and chloroform extracts led to the isolation of two main prenylated xanthones and characterization as macluraxanthone and gerontoxanthone-I, respectively, their structures being identified by comparison with the spectral data. Interestingly, both exhibited potent effective effects. At non-toxic effective doses, n-hexane and chloroform extracts (10 and $30{\mu}g/ml$) as well as macluraxanthone and gerontoxanthone-I (3 and $10{\mu}M$) significantly inhibited B16F10 cell invasion, to a greater extent than $10{\mu}m$ doxorubicin, while reducing migration of cancer cells without cellular cytotoxicity. Moreover, exposure of B16F10 melanoma cells to high concentrations of chloroform ($30{\mu}g/ml$) and geratoxanthone-I ($20{\mu}M$) for 24 h resulted in delayed adhesion and retarded colonization. As insights into mechanisms of action, typical morphological changes of apoptotic cells e.g. membrane blebbing, chromatin condensation, nuclear fragmentation, apoptotic bodies and loss of adhesion as well as cell cycle arrest in the G1 phase with increase of sub-G1 cell proportions, detected by Hoechst 33342 staining and flow cytometry were observed, suggesting DNA damage and subsequent apoptotic cell death. Taken together, our findings indicate for the first time that active n-hexane and chloroform extracts as well as macluraxanthone and gerontoxanthone-I isolated from Maclura amboinensis Bl. roots affect multistep of cancer metastasis processes including proliferation, adhesion, invasion and migration, possibly through induction of apoptosis of highly metastatic B16F10 melanoma cells. Based on these data, M. amboinensis Bl. represents a potential candidate novel chemopreventive and/or chemotherapeutic agent. Additionally, they also support its ethno-medicinal usage for cancer prevention and/or chemotherapy.

• Journal of Life Science
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• v.17 no.7 s.87
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• pp.896-904
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• 2007

Regulation mechanism of apoptosis has been known to be important for understanding the pathogenesis of a number of human diseases including cancers. The effects of $RRR-{\alpha}-tocopheryl$ succinate(vitamin E succinate, VES) on the cell viability, generation of ROS, expression of proteins involved in apoptosis, and growth of human chronic myelogenous leukemia K562 cells were analyzed in this study. VES treatment not only induced the generation of the ROS but also increased the levels of $NF-{\kappa}B$, COX-2, and $p21^{WAF1/CIP1}$ in K562 cells. It modulates the levels of pro-apoptotic proteins such as Bax provoking the apoptosis in K562 cells. The cleavage of PARP into 89 kDa was also increased upon VES treatment in a dosage-dependent manner. Induction of an apoptosis was evident by the increase of sub-Gl peak and cell shrinkage condensed chromatin in K562 cells treated with VES. It also resulted in an inhibition of tumor growth by 50% and prolonged survival of the Iymphoma-induced mice. This potentiation of VES obtained in vitro and in vivo may indicate the feasibility of more effective chemotherapy in chronic myelogenous leukemia.

• Journal of the Korean Association of Oral and Maxillofacial Surgeons
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• v.31 no.4
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• pp.306-311
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• 2005

Despite advances in surgery, radiotherapy, and chemotherapy, the survival of patients with oral squamous cell carcinoma has not significantly improved over the past several decades. Gene therapy is currently under investigation and shows us new possibility of cancer curing method. This experiment was undergone to find out the cell growth inhibition effect and evidence of apoptosis by HCCS-1(human cervical cancer suppressor-1), one of the candidates of tumor suppressor gene, transducted to human oral cancer cell line. To determine the efficiency of the adenovirus as a gene delivery vector cell line was transducted with LacZ gene and analysed with X-gal staining. Northern blot was performed to confirm the transfection with HSCC-1 gene and cell viability was assessed by cell cytotoxicity assay using cell count kit(CCK). To show the evidence of apoptosis, DNA fragmentation assay and flow cytometry(FACS) were performed. We had successfully construct the recombinant HSCC-1 adenovirus(Ad5CMV-HCCS-1), and importation efficiency was 20% at 2 MOI(multiplicity of infection), 80% at 20 MOI. Northern blot analysis showed that a single 0.6kb mRNA transcript was expressed in Ad5CMV-HCCS-1 transducted cell lines. As a result of CCK, when comparing to control subjects, transducted group showed 50% growth inhibition. In DNA fragmentation assay, according to increasing of MOI, DNA volume was diminished. In FACS analysis, DNA distribution showed fragmentation. This results imply that HCCS-1gene has growth inhibition effect in human oral cancer cell lines through apoptosis induction.