Cancer Research and Treatment

Original Articles

Engineering of Anti-CD133 Trispecific Molecule Capable of Inducing NK Expansion and Driving Antibody-Dependent Cell-Mediated Cytotoxicity: Jörg U. Schmohl, Martin Felices, Felix Oh, Alexander J. Lenvik, Aaron M. Lebeau, Jayanth Panyam, Jeffrey S. Miller, Daniel A. Vallera; Cancer Res Treat. 2017;49(4):1140-1152. Published online February 20, 2017; DOI: https://doi.org/10.4143/crt.2016.491

Purpose
The selective elimination of cancer stem cells (CSCs) in tumor patients is a crucial goal because CSCs cause drug refractory relapse. To improve the current conventional bispecific immune-engager platform, a 16133 bispecific natural killer (NK) cell engager (BiKE), consisting of scFvs binding FcγRIII (CD16) on NK cells and CD133 on carcinoma cells, was first synthesized and a modified interleukin (IL)-15 crosslinker capable of stimulating NK effector cells was introduced.
Materials and Methods
DNA shuffling and ligation techniques were used to assemble and synthesize the 1615133 trispecific NK cell engager (TriKE). The construct was tested for its specificity using flow cytometry, cytotoxic determinations using chromium release assays, and lytic degranulation. IL-15–mediated expansion was measured using flow-based proliferation assays. The level of interferon (IFN)-γ release was measured because of its importance in the anti-cancer response.
Results
1615133 TriKE induced NK cell–mediated cytotoxicity and NK expansion far greater than that achieved with BiKE devoid of IL-15. The drug binding and induction of cytotoxic degranulation was CD133⁺ specific and the anti-cancer activity was improved by integrating the IL-15 cross linker. The NK cell–related cytokine release measured by IFN-γ detection was higher than that of BiKE. NK cytokine release studies showed that although the IFN-γ levels were elevated, they did not approach the levels achieved with IL-12/IL-18, indicating that release was not at the supraphysiologic level.
Conclusion
1615133 TriKE enhances the NK cell anti-cancer activity and provides a self-sustaining mechanism via IL-15 signaling. By improving the NK cell performance, the new TriKE represents a highly active drug against drug refractory relapse mediated by CSCs.

Citations

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Anti-cancer Effects of a Novel Quinoline Derivative 83b1 on Human Esophageal Squamous Cell Carcinoma through Down-Regulation of COX-2 mRNA and PGE₂: Ivan Ho Yuen Pun, Dessy Chan, Sau Hing Chan, Po Yee Chung, Yuan Yuan Zhou, Simon Law, Alfred King Yin Lam, Chung Hin Chui, Albert Sun Chi Chan, Kim Hung Lam, Johnny Cheuk On Tang; Cancer Res Treat. 2017;49(1):219-229. Published online July 18, 2016; DOI: https://doi.org/10.4143/crt.2016.190

Abstract PDF Supplementary Material PubReader ePub

Purpose
83b1 is a novel quinoline derivative that has been shown to inhibit cancer growth in human esophageal squamous cell carcinoma (ESCC). This study was conducted to comprehensively evaluate the cytotoxic effects of 83b1 on a series of ESCC cell lines and investigate the mechanisms by which 83b1 suppresses cancer growth based on molecular docking analysis.
Materials and Methods
A series of ESCC and nontumor immortalized cell lines were exposed to 83b1 and cisplatin (CDDP) in a dose-dependent manner, and the cytotoxicity was examined by a MTS assay kit. Prediction of the molecular targets of 83b1 was conducted by molecular docking analysis. Expression of cyclooxygenase 2 (COX-2) mRNA and COX-2–derived prostaglandin E2 (PGE2) were measured by quantitative real-time polymerase chain reaction and enzymelinked immuno-sorbent assay, respectively. In vivo anti-tumor effect was determined using a nude mice xenografted model transplanted with an ESCC cell line, KYSE-450.
Results
83b1 showed the significant anti-cancer effects on all ESCC cell lines compared to CDDP; however, 83b1 revealed much lower toxic effects on non-tumor cell lines than CDDP. The predicted molecular target of 83b1 is peroxisome proliferator-activated receptor delta (PPARδ), which is a widely known oncoprotein. Additionally the expression of COX-2 mRNA and COX-2–derived PGE2 were down-regulated by 83b1 in a dose-dependent manner in ESCC cell lines. Furthermore, 83b1 was shown to significantly reduce the tumor size in nude mice xenograft.
Conclusion
The results of this study suggest that the potential anti-cancer effects of 83b1 on human esophageal cancers occur through the possible oncotarget, PPARδ, and down-regulation of the cancer related genes and molecules.

Citations

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Selective Cytotoxicity of the New Platnum ( 2 ) Complexes on Human Gastric Cancer Cell - lines and Normal Kidney Cells: Jee Chang Jung, Sung Goo Chang, Young Soo Rho; J Korean Cancer Assoc. 1999;31(5):1035-1043.

Abstract PDF: PURPOSE
Platinum coordination complex (cisplatin) has been currently used as one of the most effective compound in the treatment of various solid tumors. However, its use has been limited by severe side effects such as renal toxicity. Our platinum-based drug discovery program has been aimed at developing drugs capable of diminishing toxicity and selective cytotoxicity.
MATERIALS AND METHODS
A new series of highly water soluble platinum (II) complexes Pt (II) [1,3-Bis (phenylthio) propane) (trans-l-1,2-diaminocyclohexane) (PC-1) and Pt (II) [1,3-Bis-(phenylthio) (propane)]-1,2-diaminocyclohexane (PC-2) were synthesized and characterized by their elemental analysis and by various spectroscopic techniques [infrared (.IR), ""C-nuclear magnetic resonance (NMR)]. In vitro antitumor activity and nephrotoxi -cities of new Pt (II) complexes were tested against MKN-45 human gastric cancer cell- lines and normal kidney cells using colorimetric MTT[3-(4,5-dimethyl thiazol-2-yl)-2,5- diphenyl tetrazolium bromide] assay for cell survival and proliferation.
RESULTS
PC-1 showed activity against MKN-45/P and MKN-45/CDDP human gastric adenocarcinoma cells, and the antitumor activity of this compound was comparable or superior to that of PC-2 and cisplatin. The nephrotoxicity of PC-1 and PC-2 were found quite less than that of cisplatin using MTT, [H] thymidine uptake and glucose consumption tests in rabbit proximal tubule cells, human kidney cortical cells and human renal cortical tissues.
CONCLUSION
Based on these results, this novel platinum (II) complex compound (PC-1) represent a valuable lead in the development of a new anticancer chemotherapeutic agent capable of improving antitumor activity and low nephrotoxicity.

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Liposomes as Acitivators of Lipophilic Platinum (2 ) Complexes: In Sook Han, Young Jae Lee; J Korean Cancer Assoc. 1999;31(1):180-187.

Abstract PDF: PURPOSE
The goal of this study is to understand the activation processes that take place within the liposomal formulation of lipophilic diaminocyclohexane platinum (DACH-Pt) complexes, to identify the activated species of this class of compounds, and to use that information to develop a reproducible liposomal formulation of DACH-Pt complexes.
MATERIALS AND METHODS
Liposomal DACH-Pt complexes were prepared by lyophilization-rehydration method using PC, PG and PA. Their intraliposomal stability and biological activity were determined by HPLC and in vitro/in vivo experiments.
RESULTS
DACH-Pt complexes in a liposomal formulation have shown significant promise in preclinical studies and clinical phase I, II trials. Interestingly, they are prodrugs which converts into one or more undetennined activated platinum species within the liposomes ex vivo. Our studies have shown that the stability of liposomal DACH-Pt complexes is inversely related with the antitumor activity of those complexes. The configuratian of leaving group in the complexes and pH of the liposome suspension affect significantly the degradation/activation process that takes place within the liposomes. DACH-Pt complexes with linear (L10) leaving groups are more stable than complexes with branched ones (B10 and NDDP), but also significantly less potent. The presence of PG and PA in the liposome is a prerequisite for the degradation/activation process of DACH-Pt complexes. As PG and PA formulation gave more dramatic changes of the original complexes than PC alone due to lower pH, the cytotoxicity and antitumor activity at those fonnulations increased against PC alone. DACH-Pt complexes are very stable in liposomes containing PC alone but inactive in vitro/in vivo experiments.
CONCLUSION
These results also support that the active species produced within the liposomal DACH-Pt complexes is DACH-Pt-Cl2.

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Toxicity of Bile Acids on Colon Cancer Cell Lines: Dong Kook Park, Ji Hyun Shin, Ho Jin Jun, Kyeong Jae Kim, Chan Young Lee; J Korean Cancer Assoc. 1999;31(1):126-133.

Abstract PDF: PURPOSE
Cytotoxicity of the bile acids on colon cancer cell lines was studied to know which bile acid was most cytotoxic to colonic mucosal epithelium. We performed agarose gel electrophoresis whether this toxicity was caused by detergent effect of the bile acids or by apoptotic pathway.
MATERIALS AND METHODS
HT29, LoVo, SW620 colon cancer cell lines were exposed to lithocholate, cholate, deoxycholate and chenodeoxycholate with 50, 100, 150, 200, 250, 300 pM as final concentration in DMEM culture media for short time (for 2 hours) and for long time (for 5 days). Agarose gel electrophoresis was performed on each colon cancer cell lines (HT29, LoVo, SW620, SW480) after 1, 2, 3, 4, 5 days exposure to deoxycholate with 150 pM concentration to detect intemucleosomal fragmentation.
RESULTS
There was no toxicity after short time exposure in all bile acids concentration and in all colon cancer cell lines. Of the bile acids, deoxycholate was most toxic for all colon cancer cell lines. And DNA fragmentation was noticed after 2 days exposure with deoxycholate. Only LoVo cell line showed apoptotic DNA pattern after 4 days of exposure with deoxycholate.
CONCLUSION
Bile acids (especially deoxycholate) are suggested to be possible agents to cause apoptosis in colonic mucosal epithelium.

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Clinical Trial

Anti-tumor Effect of the Complex of Acriflavine and Guanosine (AG60): Eun Kyung Hong, Hwan Mook Kim, Kyung Yung Lee, Young Shin Chung, Bo Im Yoo, Sang Geon Kim, E Tay Ahn, Young Bok Han; J Korean Cancer Assoc. 1997;29(1):29-37.

Abstract PDF: PURPOSE
The anti-tumor effect of the complex of acriflavine and guanosine (AG60) was investigated.
MATERIALS AND METHODS
In vitro cytotoxicity of AG60 was measured using SRB assay, and in vivo antitumor activity of AG60 was examined in CDF1 mice intraperitoneally inoculated with the P388 leukemic cells and in ICR mice inguinally implanted with S-180 cells. Tumor size and mean survival time were determined.
RESULTS
AG60 and acriflavine showed strong anti-tumor effect in vitro on lung cancer (A549), renal cancer (UO-31) and colon cancer (COLO205) cells. However, AG60 did not show the cytotoxicity against normal cell line, 3T3. The range of the IC50 of AG60 to the various tumor cell lines was 0.09 microgram/ml through 1.94 microgram/ml. The treatment of ascitic tumor bearing CDF1 mice with AG60 resulted in over 160% increases in the mean survival time. The most effective dose of AG60 was 30 mg/kg body weight in tumor implanted mice. In solid tumor bearing ICR mice tumor growth and progression were suppressed in response to the different doses at 30 days; 69.8% suppression of tumor size in response to acriflavine, 16.0% to guanosine, 87.7% to AG60 and 78.5% to doxorubicin. In addition, 35% increases were observed in the means survival time of AG60 treated group compared with control group.
CONCLUSION
The prominant anti-tumor effects of AG60 shown in this report would represent the possibility of the clinical trials.

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Original Articles

Augmentaion of Cytotoxicity of Anticancer Drugs with Biological Response Modifiers against Human Leukemia Cell Lines: Yun Young Lee, Eui Gun Chun, Jun Young Kil, Ill Kuk Yoon, Kwan Hee Yu, Byung Zun Ahn, Sam Yong Kim; J Korean Cancer Assoc. 1994;26(2):274-285.

Abstract PDF: To investigate the possibility of increased cytotoxicity of anticancer drugs, we treated human leukemia cells with combinations of anticancer drugs and biological response modifiers (BRMs). Using the colorimetric [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] (MTT) assay, we evaluated the chemosensitivity of 8 anticancer drugs(vincristine, vinblastine, adria- mycin, cisplatin, etoposide, cytosine arabinoside, bleomycin, and cyclophosphamide), and the anticancer effects of 3 BRMs(interleukin-2, alpha interferon, and gamma interferon) combined with these anticancer drugs against human leukemia HL-60 and KG-1 cells. The results were as follows; in the chemosensitivity of 8 anticancer drugs, VCR, VBL, ADR, and CPDD were effective, while VP-16, ara-C, Bleo, and CYC produced less than 50% inhibition of HL-60 and KG-1 cells lines. Among 3 BRMs investigated, all of them showed less than 20% inhibition of KG-1 cell lines and none were effective against HL-60 cells. In the anticancer effects of 3 BRMs, all of them showed about 20% inhibitory effects against KG-1 cells, but there were not any effects against HL-60 cells. All of the anticancer drugs markedly increased cytotoxic effects when they were combined with BRM. Especially, the ID values of VCR, VBL, and ADR when combined with BRMs decreased to 67~3%. These results demonstrate that some BRMs can markedly increase the cytotoxicity of VCR, VBL, ADR, CPDD, VP-16, ara-C, Bleo, and CYC and suggest possible clinical usefulwess.

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Natural Killer ( NK ) Cell cytotoxicity According to the Expression of c-erbB-2 Protein in Human Gastric Cancer Cells: Byeong Woo Park, Kang Sup Shim, Sung Hoon Noh, Coong Bai Kim, Kyung Shik Lee; J Korean Cancer Assoc. 1995;27(1):1-8.

Abstract PDF: Although there is still controversy to the relationship between c-erbB-2 protein expression and prognosis of the gastric carcinoma, there were many reports about the poor prognosis with the expression of c-erbB-2 in gastric carcinoma. The mechanisms underlying this phenomenon are not known. However several possibilities such as acquired resistance to 5-Fluorouracil(5-FU) and resistance to the host immune system were suggested. So we performed this study to evaluate whether c-erbB-2 expression can alter the natural killeriNK) cell cytotoxic activity. Using single cell suspensions from primary gastric cancer tissues and malignant ascites due to stomach cancer, the immunohistochemical reactivity to c-cerB-2 protein was examined and we performed the tests for NK cell cytotoxic activity. The c-erbB-2(+) cancer cells were significantly more resistant to NK cell cytotoxic activity than c-erbB-2( ) cancer cells. However there was no significant difference in the resiatance to NK cell cytotoxic activity according to their immunohistochemical staining intensities. These results suggest that the resistance to the NK cel1 cytotoxicity may be one of the possi- ble mechanisms of the poorer prognosis of the c-erbB-2(+ ) gastric cancers.

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