• Oncology Letters
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• v.42 no.5
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• pp.2149-2158
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• 2019

Primary refractory acute myeloid leukemia (AML) and early recurrence of leukemic cells are among the most difficult hurdles to overcome in the treatment of AML. Moreover, uncertainties surrounding the molecular mechanism underlying refractory AML pose a challenge when it comes to developing novel therapeutic drugs. However, accumulating evidence suggests a contribution of phosphatase and tensin homolog (PTEN)/protein kinase B (AKT) signaling to the development of refractory AML. To assess PTEN/AKT signaling in AML, two types of AML cell lines were evaluated, namely control HL60 cells and KG1α cells, a refractory AML cell line that is resistant to idarubicin and cytarabine (AraC) treatment. Changes in the expression level of glycolysis- and mitochondrial oxidative phosphorylation-related genes and proteins were evaluated by reverse transcription-quantitative polymerase chain reaction and western blot analyses, respectively. The mitochondrial oxygen consumption and extracellular acidification rates were measured using an XF24 analyzer. CCK8 assay and Annexin V/PI staining were used to analyze cell viability and cellular apoptosis, respectively. The PTEN protein was found to be depleted, whereas AKT phosphorylation levels were elevated in KG1α cells compared with HL60 cells. These changes were associated with increased expression of glucose transporter 1 and hexokinase 2, and increased lactate production. AKT inhibition decreased the proliferation of KG1α cells and decreased extracellular acidification without affecting HL60 cells. Notably, AKT inhibition increased the susceptibility of KG1α cells to chemotherapy with idarubicin and AraC. Taken together, the findings of the present study indicate that activation of AKT by PTEN deficiency sustains the refractory AML status through enhancement of glycolysis and mitochondrial respiration, effects that may be rescued by inhibiting AKT activity.

• Journal of Life Science
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• v.34 no.9
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• pp.620-631
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• 2024

Bone marrow toxicity is a side effect of chemotherapy with anticancer drugs or the exposure to chemicals, such as benzene. When myelotoxicity occurs, the number of white blood cells decreases, which reduces immune functioning and increases the risk of infection or the development of tumors. Angelica gigas Nakai extract (AGNEX) and green coffee bean extract (GCBE) have many effects, such as anti-cancer and antioxidant effects, as well as effects on the immune functioning. In this experiment, the preventive effect of AGNEX and GCBE against benzene-induced bone marrow toxicity was confirmed in Sprague Dawley rats (SD rats) in vivo. Benzene (1 ml/kg mixed with corn oil 1:1) was intraperitoneally administered to SD rats (six weeks, N = 9/group) once a day, and AGNEX (12 mg/kg) and GCBE (6, 12, and 24 mg/kg) were administered orally daily for five weeks. To determine the preventive effect, AGNEX (12 mg/kg) and GCBE (6, 12, and 24 mg/kg) were administered orally before the administration of benzene. Consequently, AGNEX 12 mg/kg and GCBE 12 mg/kg were effective at reducing leukocytes and lymphocytes, specifically granulocyte. Additionally, the treatment also showed protective effects specifically on spleen and liver weight changes and spleen damage. Through this protective effect, AGNEX and GCBE were confirmed to prevent bone marrow toxicity by enhancing the functioning of the immune system.

• Radiation Oncology Journal
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• v.10 no.2
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• pp.247-253
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• 1992

Between August 1987 and July 1991, 22 patients with acute nonlymphocytic leukemia have received allogeneic bone marrow transplantation (BMT) with non-T-lymphocyte-depleted marrow obtained from matched sibling donors. Of these patients, 12 patients were in first complete remission (CR) and 10 patients in second CR or greater or in relapse. All patients were treated with a preparative regimen consisting of cyclophosphamide (CTX, 60 mg/kg) or combined drugs, and 850 cGy single-dose or $150\~200$ cGy fractionated total body irradiation (TBI) administered twice daily for a total dose of $1200\~1320$ cGy. Survivors have been followed from 8 to 64.5 months (median, 24 months). The overall 2 year survival rate, relapse rate and incidence of radiation pneumonitis and graft versus host disease (GVHD) have been evaluated by age, phase of disease, initial WBC count, modality of TBI or conditioning chemotherapy. Overall 2 year survival was $58{\%}$. The median survival was 31 months and mean survival was 23.2 months. Overall survival have significant impact in patients of age >19 years old (p=0.008), patients in first CR (p=0.09). Two year survival rate is significantly correlated with age ( >19 vs $\leqq$19, $79.4\%$ vs $14.3\%$, p=0.0008), regimen of chemotherapy (CTX vs combined drug, $76.9\%\;vs\;33.3\%$, p=0.04), phase of disease (1st CR vs \geqq2nd$ CR or relapse, $83.3\%\;vs\;30\%$, p=0.01) and method of TBI (fractionated vs single dose, $70.7\%\;vs\;37.5\%$, p=0.05). The influence of French-American-British (FAB) subtypes on relapse rate is not significant, but initial WBC count > 20000/$mm^3$ is associated with increased relapse rate. There is difference in the rate of radiation pneumonitis ($14.3\%\;vs\;25\%$), GVHD ($14.3\%\;vs\;50\%$) and relapse ($21.4\%\;vs\;50\%$) according to fractionated versus single-dose TBI. As mentioned above, fractionated TBI is compatible for the preparative regimen combined with chemotherapy En allogeneic BMT of first CR patients under 41 years of age with suitable donor. Those results from a retrospective, non-randomized study clearly need additional clinical data, ideally from a randomized study.

• Journal of Chest Surgery
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• v.36 no.10
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• pp.711-720
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• 2003

Bakground : Complete resection by the surgery has been selected as the treatment of choice in lung cancer patients, but in cases of recurrence after excision or inoperable cases, the importance of anticancer chemotherapy has been emphasized. If one can select a set of the sensitive chemotherapeutic agents before anticancer chemotherapy, it will give more favourable results. Subrenal capsular assay has been recognized as a useful in-vivo chemosensitivity test of thoracic and abdominal tumors and it can be done in a short time for a rapid interpretation of tumor responsiveness to anticancer chemotherapeutic drugs. It has been reported that various kinds of cancer cells can be implantable to the kidney, but so far there is no comparative study of xenogeneic cell implantation on liver, spleen and kidney. The author implanted the human lung cancer cells under the capsule of S.D rat's liver, spleen and kidney respectively and compared the pattern of growth and histology. Material and Method: After incubation of human lung cancer cell line (SW-900 G IV) in RPMI 1640 (Leibovitz L-15 medium) culture media, 3${\times}$3${\times}$3 mm size fibrin clots which contain 108 cancer cells were made. Thereafter the fibrin clots were implanted at subcapsule area of liver, spleen and kidney of S.D. female rat. For immune suppression, cyclosporin-A (80 mg/Kg) was injected subcutaneously daily from post-implantation first day to sixth day. The body weight was measured at pre and post implantation periods. The growth pattern and the size of tumor mass were observed and the pathologic examination and serum tumor marker tests were performed. Result: Body weight increased in both of control and experimental groups. Serum Cyfra 21-1 was not detected. Serum levels of CEA and NSE revealed no significant change. The SCC-Ag increased significantly in implanted group. The growth rate of human lung cancer cells which was implanted on spleen was higher than on liver or kidney. The surface area, thickness, and volume of tumor mass were predominant at spleen. The success rates of implantation were 80% on kidney, 76.7% on spleen and 43.3% on liver. Pathologic examination of implanted tumors showed characteristic findings according to different organs. Tumors that were implanted on kidney grew in a round shape, small and regular pattern. In the spleen, tumors grew well and microscopic neovascularization and tumor thrombi were also found, but the growth pattern was irregular representing frequent daughter mass. Human lung cancer cells that were implanted in the liver, invaded to the liver parenchyme, and had low success rate of implantation. Microscopically, coagulation necrosis and myxoid fibrous lesion were observed. Conclusion: The success rate of implantation was highest in the kidney. And the mass revealed regular growth that could be measured easily. The SCC-Ag was presented earlier than CEA or Cyfra21-1. The Cyfra21-1 was not detected at early time after implantation. The best model for tumor implantation experiment for chemosensitivity test was subrenal capsular analysis than liver and spleen and the useful serum tumor marker in early period of implantation was the SCC-Ag.

• Tuberculosis and Respiratory Diseases
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• v.59 no.6
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• pp.613-618
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• 2005

Background : Recently, medical treatment of multi-drug resistant pulmonary tuberculosis has been unsuccessful. Through analyzing the cases with surgical treatment, we hope to provide some help in treating multi-drug resistant pulmonary tuberculosis in the future. Material and Method : A retrospective review was performed with 138cases of surgical treatment of multi-drug resistant tuberculosis during 10years from January 1994 to December 2003 at National Masan Hospital. Results : The ratio of men to women, 5.1:1 indicates that there were more incidences in men. The number of the resistant drugs was 5.3 with a mean age of 42.6 years. Cavitary lesions on the plain chest X-rays were seen in 94cases (68.1%). 128cases had positive sputum culture preoperatively. Types of operations were 24 pnemonectomies, 83 lobectomies, 10 bilobectomies, 19 lobectomies with segmentectomies or wedge resections, 1 wedge resection, and 1 carvenoplasty. There was no death after operation. There were 6cases of air leakage over a week, 6cases of postoperative bleeding, 8cases of bronchopleural fistula and empyema, 16cases of dead space, 1case of atelectasis, 1case of wound infection, 1case of cyst as postoperative complication. Postoperative complication showed higher long-term negative conversion rate of 92.8%. Conclusion : There has been many discussions about operative indications, postoperative drug regimens, length of postoperative chemotherapy. In our study, we showed higher long-term success rate of postoperative chemotherapy with pulmonary resection on multi-drug resistant pulmonary tuberculosis.

• The Korean Journal of Nuclear Medicine
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• v.38 no.2
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• pp.180-189
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• 2004

Although the outcome of cancer patients after cytotoxic chemotherapy is related diverse mechanisms, multidrug resistance (MDR) for chemotherapeutic drugs due to cellular P-glycoprotein (Pgp) or multidrug-resistance associated protein (MRP) is most important factor in the chemotherapy failure to cancer. A large number of pharmacologic compounds, including verapamil, quinidine, tamoxifen, cyclosporin A and quinolone derivatives have been reported to overcome MDR. Single photon emission computed tomography (SPECT) and positron emission tomography (PET) are available for the detection of Pgp and MRP-mediated transporter. $^{99m}Tc$-MIBI and other $^{99m}Tc$-radiopharmaceuticals are substrates for Pgp and MRP, and have been used in clinical studies for tumor imaging, and to visualize blockade of PgP-mediated transport after modulation of Pgp pump. Colchicine, verapamil and daunorubicin labeled with $^{11}C$ have been evaluated for the quantification of Pgp-mediated transport with PET in vivo and reported to be feasible substrates with which to image Pgp function in tumors. Leukotrienes are specific substrates for MRP and $N-[^{11}C]acetyl-leukotriene$ E4 provides an opportunity to study MRP function non-invasively in vivo. SPECT and PET pharmaceuticals have successfully used to evaluate pharmacologic effects of MDR modulators. Imaging of MDR and reversal of MDR with bioluminescence in a living animal is also evaluated for future clinical trial. We have described recent advances in molecular imaging of MDR and reviewed recent publications regarding feasibility of SPECT and PET imaging to study the functionality of MDR transporters in vivo.

• Journal of Chest Surgery
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• v.35 no.11
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• pp.799-806
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• 2002

In spite of the establishment of chemotherapy and the gradual decrease in prevalence, pulmonary tuberculosis is still mainly treated with an operation. Through analyzing and examining some cases of surgical treatment, we hope to provide some help in treating of pulmonary tuberculosis in the future. Material and Method: By comparing four journals previously published in our department with 144 cases of lung surgery during ten years from January of 1991 to December of 2000 performed by the department of thoracic and cardiovascular surgery of the National Medical Center, we analyzed and reviewed the most recent trends and the results of the surgical treatment. Annual frequency of the operation, distribution of age, examination of sputum, adaptability and types of techniques, complications, and results of the postoperative follow-up were used as methods. Result: It was found that the annual frequency of operations had decreased. The ratio of men to women, 2:1 indicates that there are more incidences in men. Aging of patients could be speculated by the .results that the decrease in the incidence rate in the 20s age range and increase rate in the 50s age range. The range of preoperative lesions belonged mostly to far advanced and moderately advanced tuberculosis. By monitoring the period of use in preoperative antituberculosis drugs, cases for more than 3 years remarkably increased from 16.0 % to 55.6 %. The positive reactive rate for preoperative sputum examinations were drastically decreased from 91 % to 27 %. Total pulmonary destruction and partial destruction were the most common cases in terms of adaptability to the operations and there were significant increases in forming empyema accompanied by parenchymal lesions from 4.0 % to 20.1 %. Pneumonectomy and pulmonary lobectomy were the major type of operations. Especially, there were increases in the incident rate of empyema and recurrence of tuberculosis resulted. Post operative follow-up indicates that the rate of complete recovery was more than 70 % and the rate of gradual increase in treating with persistent antituberculosis drug was from 5.8 % to 18.0 %. Conclusion: In recent cases, there is an increasing number of patients showing tolerance to chemotherapy. Patients with pleural tuberculosis and severe lesions were typically increased. It is important to accurately analyze those complaints accurately that are mostly difficult to be treated medically. Surgical treatment is strongly recommended Before multiple drug resistance occurs.

• Journal of Life Science
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• v.21 no.7
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• pp.953-960
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• 2011

Necrosis is characterized by the cell membrane rupture and release of the cellular contents, including high-mobility group box 1 protein (HMGB1), into the extracellular microenvironment. HMGB1 acts as a transcriptional regulator in nuclei, but exerts a pro-inflammatory and tumor-promoting cytokine activity when released into the extracellular space. Its overexpression is associated with tumor progression and chemoresistance. Thus, HMGB1 acts as a clinically important molecule in tumor biology. In this study, we examined whether HMGB1 affects cell death induced by anti-cancer drugs. Here we show that HMGB1 prevented cisplatin (alkylating agent)-induced apoptosis and switched the cell fate to necrosis in MCF-7, MDA-MB231, and MDA-MB361 cells. Similar apoptosis-to-necrosis switch effects of HMGB1 were observed in cells treated with 4-HC, another alkylating agent. In contrast, HMGB1 did not exert any significant effects on docetaxel (DOC)-induced apoptosis in MCF-7 cells. We also show that cisplatin-induced apoptosis was switched to necrosis in MCF-7 multicellular tumor spheroids (MTS) that were cultured for 8 days and had necrotic cores, but DOC-induced apoptosis was prevented without the apoptosis-to-necrosis switch. Finally, the levels of RAGE, a receptor of HMGB1, were increased with extended culture of MTS. These findings demonstrate that HMGB1 switches alkylating agent-induced apoptosis to necrosis, suggesting that the strategy to prevent necrosis occurring as an undesirable action of alkylating agent-based chemotherapy should be delineated to improve the efficacy of chemotherapy for cancer.

• Tuberculosis and Respiratory Diseases
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• v.42 no.1
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• pp.19-24
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• 1995

Background: Although pulmonary tuberculosis is effectively controlled with 6 months or 9 months short course standard regimens, comparable numbers of treatment failures ensued because of inadequate treatment mainly due to patient's poor compliance. Indequate treatment with standard regimens during initial treatment may cause emergence of drug resistance and prolong the duration of chemotherapy. Also it may make the patient lesser compliant and finally increase the morbidity and the mortality. Methods: A clinical study was done to evaluate clinical and bacteriological characteristics of 94 patients who were retreated for pulmonary tuberculosis. Results: 1) 62 of the 94 patients were male and 32 patients were female. Mean age is 51 years old in male and 45 years old in female. 2) The extent of the disease on the chest radiograph was minimal in 10(11.1%) patients, moderate in 31(33.3%) patients, and far advanced in 52(55.6%) patients. 3) On sputum bacteriologic examination, 73(77.7%) patients were positive in sputum AFB smear and/or culture for Mycobacterium tuberculosis. 4) Results of drug sensitivity test performed in 42 patients showed that the resistance to one drug is in 9(20.5%) patients, two drugs in 18(40.8%) patients, and more than three drugs in 14(31.8%) patients. 5) Poor patient's compliance was the leading cause of the retreatment of pulmonary tuberculosis(43.6%) 6) Only 24(25.5%) patients of the 94 retreatment patients were successfully treated and 39(41.6%) patients were dropped out during follow-up. Conclusion: We concluded that poor patient's compliance was the most important cause of treatment failure not only in primary treatment patients but also in retreatment patients. Primary treatment of pulmonary tuberculosis should be completed under strict monitoring of the patient because significant number of retreatment patients had multiple drug resistance and poor outcome.

• Journal of Life Science
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• v.22 no.9
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• pp.1224-1230
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• 2012

Cancer chemotherapy drugs command a large share of the market, and the development of new therapeutics with high efficacy and specificity is an active area of study. Recently, the development of cancer therapeutics from natural products targeting angiogenesis has drawn attention due to conventional chemotherapeutics showing serious side effects and resistance in cancer cells. In this study, we investigated the pharmacological efficacy of Gomisin A, an active ingredient of Schizandra chinensis baillon, on tumor growth and metastasis. Administration of Gomisin A at 10 and 100 ${\mu}g/ml$ reduced tumor growth in vivo by $80.5{\pm}8.1%$ and $96.2{\pm}2%$, respectively, compared with positive tumor controls. Treatment of Gomisin A in normal and various tumor cell lines did not exert significant toxicity. Mice treated with Gomisin A at a concentration of 10 and 100 ${\mu}g$/head showed a significant reduction in tumor-induced angiogenesis of $151{\pm}16.9%$ and $98.5{\pm}29.5%$, respectively. Furthermore, tumor metastasis analysis revealed that the administration of Gomisin A at a concentration of 10 and 100 ${\mu}g$/head inhibited tumor metastasis by $13.5{\pm}8.56%$ and $58.3{\pm}9.12%$, respectively. In addition, Gomisin A significantly decreased cell adhesion of the B16BL6 cells to the extracellular matrix. These results demonstrate that Gomisin A inhibits tumor growth via suppression of angiogenesis and tumor metastasis inhibition, without cellular toxicity. The pharmacological efficacy of Gomisin A suggests that it may be a potential candidate for the development of cancer drugs.