Human Tumor Xenograft Models for Preclinical Assessment of Anticancer Drug Development

Joohee Jung 한국독성학회 2014 Toxicological Research Vol.30 No.1

Xenograft models of human cancer play an important role in the screening and evaluation of candidates for new anticancer agents. The models, which are derived from human tumor cell lines and are classified according to the transplant site, such as ectopic xenograft and orthotopic xenograft, are still utilized to evaluate therapeutic efficacy and toxicity. The metastasis model is modified for the evaluation and prediction of cancer progression. Recently, animal models are made from patient-derived tumor tissue. The patient-derived tumor xenograft models with physiological characters similar to those of patients have been established for personalized medicine. In the discovery of anticancer drugs, standard animal models save time and money and provide evidence to support clinical trials. The current strategy for using xenograft models as an informative tool is introduced.

A cisplatin-incorporated liposome that targets the epidermal growth factor receptor enhances radiotherapeutic efficacy without nephrotoxicity

JUNG, JOOHEE,JEONG, SEONG-YUN,PARK, SEOK SOON,SHIN, SEOL HWA,JU, EUN JIN,CHOI, JINHYANG,PARK, JAESOOK,LEE, JAE HEE,KIM, INKI,SUH, YOUNG-AH,HWANG, JUNG JIN,KURODA, SHUN’ICHI,LEE, JUNG SHIN,SONG, SI YEO Spandidos Publications 2015 International journal of oncology Vol.46 No.3

<P>Radiotherapy (RT) is one of the major modalities for non???small cell lung cancer (NSCLC), but its efficacy is often compromised by cellular resistance caused by various mechanisms including the overexpression of epidermal growth factor receptor (EGFR). Although cis???diamminedichloroplatinum(???) (cisplatin, CDDP) has been well characterized as an effective radiosensitizer, its clinical application is limited by its severe nephrotoxic effects. In our current study, we developed a CDDP???incorporated liposome (LP) conjugated with EGFR antibodies (EGFR:LP???CDDP) and evaluated its potential to radiosensitize EGFR???overexpressing cells without exerting nephrotoxic effects. EGFR:LP???CDDP showed higher cytotoxicity than non???targeting liposomal CDDP (LP???CDDP) in the cells expressing EGFR in vitro. In an A549 cell???derived xenograft tumor mouse model, increased delays in tumor growth were observed in the mice treated with a combination of EGFR:LP???CDDP and radiation. Notably, the EGFR:LP???CDDP???treated animals showed no differences in body weight loss, survival rates of nephrotoxicity compared with untreated control mice. In contrast, the use of CDDP caused lower body weights and poorer survival outcomes accompanied by a significant level of nephrotoxicity [e.g., decreased kidney weight, increased blood urea nitrogen (BUN) and creatinine, and pathological change]. These findings suggest the feasibility of using EGFR:LP???CDDP to radiosensitize cells in a targeted manner without inducing nephrotoxic effects. This compound may therefore have clinical potential as part of a tailored chemoradiotherapy strategy.</P>

Establishing a colorectal cancer liver metastasis patientderived tumor xenograft model for the evaluation of personalized chemotherapy

Joohee Jung,Jisup Kim,Hyun Kyung Lim,Kyoung Mee Kim,Yun Sun Lee,Joon Seong Park,Dong Sup Yoon 대한외과학회 2017 Annals of Surgical Treatment and Research(ASRT) Vol.93 No.4

Purpose: In order to suggest optimal anticancer drugs for patient-tailored chemotherapy, we developed a colorectal cancer (CRC)-liver metastasis patient-derived tumor xenograft (PDTX) model. Methods: Tissue obtained from a patient with CRC-liver metastasis (F0) was transplanted in a nonobese female mouse with diabetic/severe combined immune deficiency (F1) and the tumor tissue was retransplanted into nude mice (F2). When tumor volumes reached ~500 mm3, the F2 mice were randomly divided into 4 groups (n = 4/group) of doxorubicin, cisplatin, docetaxel, and nontreated control groups. The tumor tissues were investigated using H&E staining, terminal deoxynucleotidyl transferase dUTP nick end labeling assays, and immunohistochemistry. To determine where the mutant allele frequencies varied across the different passages, we isolated genomic DNA from the primary tumor, liver metastasis, and PDTX models (F1/F2). Results: The physiological properties of the tumor were in accord with those of the patient’s tumors. Anticancer drugs delayed tumor growth, inhibited proliferation, and caused apoptosis. Histological assessments revealed no observable heterogeneity among the intragenerational PDTX models. Target exon sequencing analysis without high-quality filter conditions revealed some genetic variations in the 83 cancer-related genes across the generations. However, when de novo mutations were defined as a total count of zero in F0 and ≥5 in F2, exactly prognostic impact of clone cancer profiling (EGFR, KRAS, BRAF, PIK3CA, NRAS, APC and TP53) were detected in the paired. Conclusion: A CRC liver metastasis PDTX model was established for the evaluation of chemotherapeutic efficacy. This model retained the physiological characters of the patient tumors and potentially provides a powerful means of assessing chemotherapeutic efficacy.

Induction of p53-mediated senescence is essential for the eventual anticancer therapeutic effect of RH1

Joohee Jung,Do Young Song,Jung Jin Hwang,Heon Joo Park,Jung Shin Lee,Si Yeol Song,정성윤,최은경 대한약학회 2019 Archives of Pharmacal Research Vol.42 No.9

RH1 (2, 5-diaziridinyl-3-(hydroxymethy)-6-methyl-1, 4-benzoquinone) is a bioreductive anticancerdrug. The mechanism underlying its therapeutic propertieshas not yet been elucidated. In this study, we aimed todetermine whether RH1 exerts its anticancer effect via p53-mediated apoptosis and senescence in vitro and in vivo. RH1 displayed dose-dependent biphasic effects in vitro,i.e., it induced apoptosis at higher dose and senescence atlower dose accompanied by marked activation of p53. Thus, RH1 primarily induced cell death by apoptosis. Thecytotoxicity of RH1 was inhibited in A549 cells treatedwith the p53-inhibitor pifithrin-a or transfected p53 siRNAand in human colon cancer HCT116 isogenic (p53-/-)cells. At sub-lethal doses of RH1, the cells survived andunderwent senescence. The senescent cells showed flattenedand enlarged morphology, and exhibited blue color insenescence-associated b-galactosidase staining. Thesechanges were found to be related to p53. RH1-inducedsenescence decreased in A549-E6 cells (suppressed p53level) and HCT 116 p53-/- cells. The growth of A549xenograft tumors in nude mice was significantly delayed byintraperitoneal injection of RH1, and senescent cells wereobserved in these xenograft tumors. These results suggestthat the in vivo anticancer therapeutic effect of RH1 ismediated by senescence via p53 activation.

Establishing a colorectal cancer liver metastasis patient-derived tumor xenograft model for the evaluation of personalized chemotherapy

Jung, Joohee,Kim, Jisup,Lim, Hyun Kyung,Kim, Kyoung Mee,Lee, Yun Sun,Park, Joon Seong,Yoon, Dong Sup The Korean Surgical Society 2017 Annals of Surgical Treatment and Research(ASRT) Vol.93 No.4

<P><B>Purpose</B></P><P>In order to suggest optimal anticancer drugs for patient-tailored chemotherapy, we developed a colorectal cancer (CRC)-liver metastasis patient-derived tumor xenograft (PDTX) model.</P><P><B>Methods</B></P><P>Tissue obtained from a patient with CRC-liver metastasis (F0) was transplanted in a nonobese female mouse with diabetic/severe combined immune deficiency (F1) and the tumor tissue was retransplanted into nude mice (F2). When tumor volumes reached ~500 mm<SUP>3</SUP>, the F2 mice were randomly divided into 4 groups (n = 4/group) of doxorubicin, cisplatin, docetaxel, and nontreated control groups. The tumor tissues were investigated using H&E staining, terminal deoxynucleotidyl transferase dUTP nick end labeling assays, and immunohistochemistry. To determine where the mutant allele frequencies varied across the different passages, we isolated genomic DNA from the primary tumor, liver metastasis, and PDTX models (F1/F2).</P><P><B>Results</B></P><P>The physiological properties of the tumor were in accord with those of the patient's tumors. Anticancer drugs delayed tumor growth, inhibited proliferation, and caused apoptosis. Histological assessments revealed no observable heterogeneity among the intragenerational PDTX models. Target exon sequencing analysis without high-quality filter conditions revealed some genetic variations in the 83 cancer-related genes across the generations. However, when <I>de novo</I> mutations were defined as a total count of zero in F0 and ≥5 in F2, exactly prognostic impact of clone cancer profiling (EGFR, KRAS, BRAF, PIK3CA, NRAS, APC and TP53) were detected in the paired.</P><P><B>Conclusion</B></P><P>A CRC liver metastasis PDTX model was established for the evaluation of chemotherapeutic efficacy. This model retained the physiological characters of the patient tumors and potentially provides a powerful means of assessing chemotherapeutic efficacy.</P>

Recent Advances of MALDI-Mass Spectrometry Imaging in Cancer Research

Jung, Joohee Korean Society for Mass Spectrometry 2019 Mass spectrometry letters Vol.10 No.3

For several decades, cancer has been the primary cause of mortality worldwide. New diagnosis and regimens have been developed to improve the chemotherapeutic efficacy and the quality of life of the patients. However, cancer tissues are complex and difficult to assess. Understanding the various properties of the tumor and its environment is crucial for cancer and pharmaceutical research. Several analytical techniques have been providing new insights into cancer research. Recently, matrix-assisted laser desorption ionization (MALDI)-mass spectrometry imaging (MSI), an advanced analytical technique, has been applied to translational research. Proteomic and lipidomic profiling obtained by MALDI-MSI has been critical for biomarker discovery and for monitoring heterogenous tumor tissues. In this review, we discuss technical approaches, benefits and recent applications of MALDI-MSI as a valuable tool in cancer research, namely for diagnosis, therapy, prognosis.

Inhibitory Activities of Palmatine from Coptis chinensis Against Helicobactor pylori and Gastric Damage

Jung, Joohee,Choi, Jae Sue,Jeong, Choon-Sik Korean Society of ToxicologyKorea Environmental Mu 2014 Toxicological Research Vol.30 No.1

Helicobacter pylori (H. pylori) is the most important factor of gastric disease in clinical practice. Moreover, smoking, stress and a poor diet may be additive factors for gastric damage. With these factors, increasing infection of H. pylori triggers gastritis, gastric ulcers and gastric cancer. To develop a new protective agent, we are concerned with plant-derived extract. The extract of Coptis chinensis (C. chinensis) and its constituents were investigated to assess their protective activities against gastric damage. The C. chinensis extract showed a scavenging effect against 2, 2-diphenyl-1-picrylhydrazyl (DPPH) and superoxide radicals, inhibition of H. pylori colonization and antiulcerogenic activities in rat. In particular, palmatine derived from C. chinensis was found to be the novel protective agent. It is better than the C. chinensis extract, berberine, a well-known constituent of C. chinensis. We suggest that palmatine from the root cortex of C. chinensis may be a good candidate for the development of new pharmaceuticals to prevent gastric disease.

Role of G Protein-Coupled Estrogen Receptor in Cancer Progression

Jung, Joohee Korean Society of ToxicologyKorea Environmental Mu 2019 Toxicological Research Vol.35 No.3

Cancer is the leading cause of mortality worldwide. In cancer progression, sex hormones and their receptors are thought to be major factors. Many studies have reported the effects of estrogen and estrogen receptors (ERs) in cancer development and progression. Among them, G protein-coupled estrogen receptor (GPER), a G protein-coupled receptor, has been identified as an estrogen membrane receptor unrelated to nuclear ER. The mechanism of GPER, including its biological action, function, and role, has been studied in various cancer types. In this review, we discuss the relation between GPER and estrogen or estrogen agonists/antagonists and cancer progression.

Recent Advances of MALDI-Mass Spectrometry Imaging in Cancer Research

Joohee Jung 사단법인 한국질량분석학회 2019 Mass spectrometry letters Vol.10 No.3

For several decades, cancer has been the primary cause of mortality worldwide. New diagnosis and regimens have been developed to improve the chemotherapeutic efficacy and the quality of life of the patients. However, cancer tis-sues are complex and difficult to assess. Understanding the various properties of the tumor and its environment is crucial for cancer and pharmaceutical research. Several analytical techniques have been providing new insights into cancer research. Recently, matrix-assisted laser desorption ionization (MALDI)-mass spectrometry imaging (MSI), an advanced analytical technique, has been applied to translational research. Proteomic and lipidomic profiling obtained by MALDI-MSI has been critical for biomarker discovery and for monitoring heterogenous tumor tissues. In this review, we discuss technical approaches, benefits and recent applications of MALDI-MSI as a valuable tool in cancer research, namely for diagnosis, therapy, prognosis.

Inhibitory Activities of Palmatine from Coptis chinensis Against Helicobactor pylori and Gastric Damage

Joohee Jung,Jae Sue Choi,Choon-Sik Jeong 한국독성학회 2014 Toxicological Research Vol.30 No.1

Helicobacter pylori (H. pylori) is the most important factor of gastric disease in clinical practice. Moreover, smoking, stress and a poor diet may be additive factors for gastric damage. With these factors, increasing infection of H. pylori triggers gastritis, gastric ulcers and gastric cancer. To develop a new protective agent, we are concerned with plant-derived extract. The extract of Coptis chinensis (C. chinensis) and its constituents were investigated to assess their protective activities against gastric damage. The C. chinensis extract showed a scavenging effect against 2, 2-diphenyl-1-picrylhydrazyl (DPPH) and superoxide radicals, inhibition of H. pylori colonization and antiulcerogenic activities in rat. In particular, palmatine derived from C. chinensis was found to be the novel protective agent. It is better than the C. chinensis extract, berberine, a well-known constituent of C. chinensis. We suggest that palmatine from the root cortex of C. chinensis may be a good candidate for the development of new pharmaceuticals to prevent gastric disease.