• Biomolecules & Therapeutics
• /
• v.23 no.6
• /
• pp.493-509
• /
• 2015

Antibody-drug conjugates utilize the antibody as a delivery vehicle for highly potent cytotoxic molecules with specificity for tumor-associated antigens for cancer therapy. Critical parameters that govern successful antibody-drug conjugate development for clinical use include the selection of the tumor target antigen, the antibody against the target, the cytotoxic molecule, the linker bridging the cytotoxic molecule and the antibody, and the conjugation chemistry used for the attachment of the cytotoxic molecule to the antibody. Advancements in these core antibody-drug conjugate technology are reflected by recent approval of Adectris$^{(R)}$(anti-CD30-drug conjugate) and Kadcyla$^{(R)}$(anti-HER2 drug conjugate). The potential approval of an anti-CD22 conjugate and promising new clinical data for anti-CD19 and anti-CD33 conjugates are additional advancements. Enrichment of antibody-drug conjugates with newly developed potent cytotoxic molecules and linkers are also in the pipeline for various tumor targets. However, the complexity of antibody-drug conjugate components, conjugation methods, and off-target toxicities still pose challenges for the strategic design of antibody-drug conjugates to achieve their fullest therapeutic potential. This review will discuss the emergence of clinical antibody-drug conjugates, current trends in optimization strategies, and recent study results for antibody-drug conjugates that have incorporated the latest optimization strategies. Future challenges and perspectives toward making antibody-drug conjugates more amendable for broader disease indications are also discussed.

• Journal of Korean Biological Nursing Science
• /
• v.4 no.2
• /
• pp.69-77
• /
• 2002

The purpose of this study was to identify the relationship of symptom distress and natural killer cell cytotoxicity in breast cancer patients who had been radiation therapy and/or chemotherapy after surgery. Symptom distress measured by modified Lee's(1994) physical symptom questionnaire. For measuring the natural killer cell cytotoxic activity. 8ml to 10ml blood was collected from the subjects. Mononuclear cell was isolated by centrifuge of the blood and cultured by putting $Cr^{51}$, and reacted with target cell, K562 cell. Amount of $Cr^{51}$ was measured, and %lysis was calculated. The results were as follows. 1) Symptom distress score was 42.18, which is moderate symptom distress. 2) Natural killer cell cytotoxic activities were 42.18%lysis(effector : target cell ratio=100 : 1) and 28.05%lysis(effector : target cell ratio=50 : 1). 3) Correlation coefficients of symptom distress and natural killer cell cytotoxic activity were $-.134{\sim}-.461$. Though significant correlation was not found between total score of symptom distress and natural killer cell cytotoxic activity, 3('pain' 'feel hot on radiation site' and 'difficulty in breathing') of 19 symptom distress items and natural killer cell cytotoxic activity showed significant negative correlation(p<.05). These findings suggest that 1) breast cancer patients who had been radiation therapy and/or chemotherapy after surgery have moderate symptom distress and decreased natural killer cell cytotoxic activity. 2) The symptom distress was not related to natural killer cell cytotoxic activity.

• Journal of Korean Biological Nursing Science
• /
• v.4 no.2
• /
• pp.59-68
• /
• 2002

The purpose of this study was to determine the effect of exercise program on natural killer cell cytotoxic activity(NKCA) in breast cancer patients who had been radiation therapy after surgery. The subjects in the experimental group consisted of 11 breast cancer patients, while the subjects in the control group consisted of 15. Subjects in the experimental group participated in exercise program for 8 weeks. Exercise program consisted of shoulder stretching, arm weight training and treadmill walking exercise. They started to exercise on treadmill for 20 minutes per day, 3 times a week at 40% of maximum heart rate, and increased intensity and duration of exercise so that they were running 30 minutes/day at 60% of maximum heart rate from the 3rd week to the 8th week. Natural killer cell cytotoxic activity were determined before and after the exercise program. For measuring the natural killer cell cytotoxic activity, 8ml to 10ml blood was collected from the subjects. Mononuclear cell was isolated by centrifuge of the blood and cultured by putting $Cr^{51}$, and reacted with target cell, K562 cell. Baseline demographic and medical data were compared between groups with the Fisher's exact test and Mann-Whitney U test. For effects of the exercise program, repeated measures ANOVA was used. The result was as follows; Natural killer cell cytotoxic activity(NKCA) in experimental group comparing with control group significantly increased after the exercise program in case of effector cell : target cell ratio is 100 : 1(p<0.05). The above result suggest that the exercise program for breast cancer patients undergoing radiation therapy after breast surgery may increase the natural killer cell cytotoxic activity.

• Molecules and Cells
• /
• v.45 no.8
• /
• pp.513-521
• /
• 2022

Cytotoxic T lymphocyte antigen-4 (CTLA-4) is an immune checkpoint molecule that is mainly expressed on activated T cells and regulatory T (Treg) cells that inhibits T-cell activation and regulates immune homeostasis. Due to the crucial functions of CTLA-4 in T-cell biology, CTLA-4-targeted immunotherapies have been developed for autoimmune disease as well as cancers. CTLA-4 is known to compete with CD28 to interact with B7, but some studies have revealed that its downstream signaling is independent of its ligand interaction. As a signaling domain of CTLA-4, the tyrosine motif plays a role in inhibiting T-cell activation. Recently, the lysine motif has been shown to be required for the function of Treg cells, emphasizing the importance of CTLA-4 signaling. In this review, we summarize the current understanding of CTLA-4 biology and molecular signaling events and discuss strategies to target CTLA-4 signaling for immune modulation and disease therapy.

• Journal of Chest Surgery
• /
• v.56 no.2
• /
• pp.67-74
• /
• 2023

Perioperative treatment with conventional cytotoxic chemotherapy for resectable non-small cell lung cancer (NSCLC) has proven clinical benefits in terms of achieving a higher overall survival (OS) rate. With its success in the palliative treatment of NSCLC, immune checkpoint blockade (ICB) has now become an essential component of treatment, even as neoadjuvant or adjuvant therapy in patients with operable NSCLC. Both pre- and post-surgery ICB applications have proven clinical efficacy in preventing disease recurrence. In addition, neoadjuvant ICB combined with cytotoxic chemotherapy has shown a significantly higher rate of pathologic regression of viable tumors compared with cytotoxic chemotherapy alone. To confirm this, an early signal of OS benefit has been shown in a selected population, with programmed death ligand 1 expression ≥50%. Furthermore, applying ICB both pre- and post-surgery enhances its clinical benefits, as is currently under evaluation in ongoing phase III trials. Simultaneously, as the number of available perioperative treatment options increases, the variables to be considered for making treatment decisions become more complex. Thus, the role of a multidisciplinary team-based treatment approach has not been fully emphasized. This review presents up-to-date pivotal data that lead to practical changes in managing resectable NSCLC. From the medical oncologist's perspective, it is time to dance with surgeons to decide on the sequence of systemic treatment, particularly the ICB-based approach, accompanying surgery for operable NSCLC.

• Oncology Letters
• /
• v.41 no.5
• /
• pp.2625-2635
• /
• 2019

The majority of natural killer (NK) cells serve an important role in eliminating malignant cells. The cytotoxic effects of NK cells were first identified against leukemia cells, and it is now hypothesized that they may have a critical role in leukemia therapy. The cellular functions of NK cells are mediated by their cell surface receptors, which recognize ligands on cancer cells. The role of NK cells is specifically regulated by the activating or inhibitory killer cell immunoglobulin-like receptors (KIRs) on their surface, which bind to the human leukocyte antigen (HLA) class I ligands present on the target cells. The association between KIR and HLA is derived from the diversity of KIR/HLA gene profiles present in different individuals, and this determines the cytotoxic effect of NK cells on cancer cells. Chronic myeloid leukemia (CML) is a hematological leukemia characterized by the hyper-proliferation of myeloid cells, with the majority of patients with CML presenting with abnormal immune cells. Tyrosine kinase inhibitors are the present standard therapy for CML, but are associated with numerous adverse side effects. Various studies have proposed CML therapy by immunotherapeutic approaches targeting the immune cells. This review summarizes the contents of NK cells and the association between KIR/HLA and leukemia, especially CML. This is followed by a discussion on the development of NK cell immunotherapy in hematological malignancies and research into strategies to enhance NK cell function for CML treatment.

• YAKHAK HOEJI
• /
• v.55 no.1
• /
• pp.75-79
• /
• 2011

The replication competent adenoviral vector (AV), AdLPCDIRESE1A was generated and reported previously to have cytotoxic effects in some cell lines. In AdLPCDIRESE1A, the expression of cytosine deaminse (CD) and E1A genes are under the control of tumor-specific L-plastin promoter. CD enzyme can deaminate the nontoxic prodrug 5-fluorocytosine (5-FC) to the toxic 5-fluorouracil (5-FU). E1A gene is essential for viral replication. Primary liver cancer, most of which is hepatocellular carcinoma (HCC), is the third common leading cancer in Korea. Thus, we have conducted in vitro preclinical study to evaluate effectiveness of AdLPCDIRESE1A on HCC. The efficacy of cytotoxicity was measured by generation of cytopathic effect (CPE) and cell counting. We infected HepG2 cells with various MOI of vector alone or concurrent with 5-FC. Exposure of cells to AdLPCDIRESE1A generated a significant cytotoxic effect as compared to the control. Almost 83% of the cell had manifested the characteristic cytotoxic effect on day 9 after infection of cells with 10 MOI of vector. We also observed the additive cytotoxic effects when AdLPCDIRESE1A vector had been coadministrated with 5-FC. The results suggest that the use of AdLPCDIRESE1A/5FC may be value in treatment of liver cancer. Further animal studies are needed for clinical trial.

• Asian Pacific Journal of Cancer Prevention
• /
• v.14 no.4
• /
• pp.2599-2605
• /
• 2013

The study aimed to evaluate immune-stimulating effects of a well-known Thai folkloric remedy when used for adjuvant therapy with conventional chemotherapeutics for treatment of breast cancer. Immunostimulating influence of the remedy (215 mg/kg body weight per day) on NK cell activity and TNF-${\alpha}$ release from the monocytes/macrophages were investigated in a total of 15 healthy women and 13 female patients with breast cancer (Group 1). The effect of breast tumor surgery on NK cell activity was further investigated in 18 female patients with breast cancer (Group 2). NK cell cytotoxic activity was determined by chromium release cytotoxic assay using K562, an erythroleukemic cell line. TNF-${\alpha}$ release from monocytes/macrophages separated from blood samples was determined through a biological assay using actinomycin D-treated L929 mouse fibroblast cells in the presence and absence of LPS. Baseline NK cell activity of the monocytes/macrophages separated from Group 2 patients expressed as %cytotoxicity was significantly lower than in the healthy subjects at E:T ratios of 100:1 and 25:1. In healthy subjects, there was no change in NK cell cytotoxic activity (%cytotoxicity or LU) following 1 and 2 weeks of treatment with the remedy compared with the baseline at various E:T ratios but the binding activity (%binding) was significantly increased after 2 weeks of treatment. The addition of one or two conventional chemotherapeutic regimens did not significantly reduce the NK cytotoxic activity but did affect release of TNF-${\alpha}$ in both unstimulated and LPS-stimulated samples. Surgery produced a significant suppressive effect on NK cell activity. The use of the remedy as an adjunct therapy may improve therapeutic efficacy and safety profiles of conventional chemotherapeutic regimens through stimulation of the immune system in cancer patients.

• BMB Reports
• /
• v.48 no.11
• /
• pp.609-617
• /
• 2015

NAD(P)H:quinone oxidoreductase (NQO1), an obligatory two-electron reductase, is a ubiquitous cytosolic enzyme that catalyzes the reduction of quinone substrates. The NQO1- mediated two-electron reduction of quinones can be either chemoprotection/detoxification or a chemotherapeutic response, depending on the target quinones. When toxic quinones are reduced by NQO1, they are conjugated with glutathione or glucuronic acid and excreted from the cells. Based on this protective effect of NQO1, the use of dietary compounds to induce the expression of NQO1 has emerged as a promising strategy for cancer prevention. On the other hand, NQO1-mediated two-electron reduction converts certain quinone compounds (such as mitomycin C, E09, RH1 and β-lapachone) to cytotoxic agents, leading to cell death. It has been known that NQO1 is expressed at high levels in numerous human cancers, including breast, colon, cervix, lung, and pancreas, as compared with normal tissues. This implies that tumors can be preferentially damaged relative to normal tissue by cytotoxic quinone drugs. Importantly, NQO1 has been shown to stabilize many proteins, including p53 and p33ING1b, by inhibiting their proteasomal degradation. This review will summarize the biological roles of NQO1 in cancer, with emphasis on recent findings and the potential of NQO1 as a therapeutic target for the cancer therapy.

• YAKHAK HOEJI
• /
• v.52 no.4
• /
• pp.252-258
• /
• 2008

The cytotoxic effect of benzoic acid and related compounds on the growth of normal cell lines and human oral epithelioid cell line was evaluated by the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) and 2,3-bis-[2-methoxy-4-nitro-5-sulfophenyl]-2H-tetrazolium-5-caboxanilide (XTT) methods. 3,4,5-Trihydroxybenzoic acid decreased the cell viability of human oral epithelioid cells and the cell adhesion activity of human oral epithelioid cells. Under the light microscopy, 100 ${\mu}M$ 3,4,5-trihydroxybenzoic acid showed the highest cytotoxic activity. From these results, we can propose that 3,4,5-trihydroxybenzoic acid has a potential anticancer activity.