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Esophageal cancer (EC) is one of the most common cancers with high morbidity and mortality rates. EC includes two histological subtypes, namely esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC). ESCC primarily occurs in East Asia, whereas EAC occurs in Western countries. The currently available treatment strategies for EC include surgery, chemotherapy, radiation therapy, molecular targeted therapy, and combinations thereof. However, the prognosis remains poor, and the overall five-year survival rate is very low. Therefore, achieving the goal of effective treatment remains challenging. In this review, we discuss the latest developments in chemotherapy and molecular targeted therapy for EC, and comprehensively analyze the application prospects and existing problems of immunotherapy. Collectively, this review aims to provide a better understanding of the currently available drugs through in-depth analysis, promote the development of new therapeutic agents, and eventually improve the treatment outcomes of patients with EC.
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In this study, N-terminal site-specific mono-PEGylation of the recombinant lidamycin apoprotein (rLDP) of lidamycin (LDM) was prepared using a polyethyleneglycol (PEG) derivative (M w 20 kDa) through a reactive terminal aldehyde group under weak acidic conditions (pH 5.5). The biochemical properties of mPEG-rLDP-AE, an enediyne-integrated conjugate, were analyzed by SDS-PAGE, RP-HPLC, SEC-HPLC and MALDI-TOF. Meanwhile, in vitro and in vivo antitumor activity of mPEG-rLDP-AE was evaluated by MTT assays and in xenograft model. The results indicated that mPEG-rLDP-AE showed significant antitumor activity both in vitro and in vivo. After PEGylation, mPEG-rLDP still retained the binding capability to the enediyne AE and presented the physicochemical characteristics similar to that of native LDP. It is of interest that the PEGylation did not diminish the antitumor efficacy of LDM, implying the possibility that this derivative may function as a payload to deliver novel tumor-targeted drugs.
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In the present study, a new compound named 17-(6-cinnamamido-hexylamino-)-17-demethoxygeldanamycin (CDG) was obtained by introducing the cinnamic acid (CA) group into the 17-site of geldanamycin (GDM). The anti-cancer effects of CDG in vitro and in vivo were evaluated. MTT assay was used to examine the inhibitory effect of CDG on the proliferation of MCF-7, HepG2, H460 and SW1990 cells. Immunofluorescent staining flow cytometry combined with Annexin V-FITC/PI staining were used to detect apoptotic cells. Transwell assay was used to analyze the effect of CDG on cell invasion and migration ability. Western blotting was used to detect the expression levels of RAF-1, EGFR, AKT, CDK4 and HER-2 of MCF-7, HepG2 and H460 cells. The toxicities of CDG and GDM were evaluated in mice. Using the subcutaneously transplanted MCF-7 xenograft in nude mice, inhibitory effect was evaluated in vivo. The results showed that CDG inhibited the proliferation of cancer cells (IC50: 13.6-67.4 microg.mL-1). After exposure to CDG for 48 h, most cells presented typical morphologic changes of apoptosis such as chromatin condensation or shrunken nucleus. The rates of apoptosis of MCF-7, HepG2, H460 and SW1990 cells incubated with 10 microg.mL-1 CDG were 23.16%, 27.55%, 22.21%, 20.47%, respectively. A dose-dependent reduction of migration of four cell lines was found after exposure to CDG. The decreased levels of RAF-1, EGFR, AKT, CDK4 and HER-2 showed that CDG possessed HSP90 inhibitory effect. The result of animal toxicity test on the mice suggested that CDG had lower toxicity than GDM. Meanwhile, CDG inhibited the growth of MCF-7 xenografts of athymic mice.
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Tea polyphenols (TPs), major biological active constituents of green tea, exert moderate and selective anticancer effects. Molecular mechanisms of TPs in cancer prevention and treatment involve multiple potential molecular targets. TPs inhibit growth factor receptor-mediated signal transduction pathway, decrease the activities of mitogen activated protein kinases and activator protein transcription factor-1, block nuclear factor-kappaB signaling pathway, reduce proteasome activity, lower overexpression of COX-2, subside dihydrofolate reductase and telomerase, and inhibit DNA methylation and matrix metalloproteinases. Furthermore, TPs enhance the inhibitory effect on the growth of cancers by traditional anticancer drugs or targeted antitumor drugs in vitro and in vivo and reverse multidrug resistances of cancer cells to vincristine, doxorubicin, and 5-fluorouracil. Besides, TPs reduce the nephrotoxicity induced by cisplatin, ameliorate irinotecan-induced side effects in the small intestine of mice, and decrease bleomycin-caused DNA damage in human leukocytes. TPs also increase antitumor activity of vaccine through immunological modulation. TPs play roles of the augmentation of antitumor effects, the reversal of multidrug resistance, and the reduction of side effects of chemotherapeutic drugs. TPs could be used as biochemical modulators in cancer therapy.
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This study is to optimize the preparation process of fusion protein Fv-LDP which was expressed in the form of inclusion body and consisted of lidamycin apoprotein LDP and single-chain Fv antibody (scFv) directed against type IV collagenase. The preparation and the dissolution of inclusion body, the immobilized metal affinity chromatography of the target protein and the renaturization by stepwise dialysis were optimized by single-factor analysis or orthogonal design. In addition, the refolded fusion protein Fv-LDP was refined by Sephadex G-75 chromatography followed by fluorescence-activated cell sorter (FACS)-based saturation binding assay to measure its antigen-binding activity. After optimization of the process, the purity of fusion protein Fv-LDP existed in the inclusion body was 63.9% and the corresponding solubility was 95.7%; Under denaturing conditions, the purity of fusion protein Fv-LDP was more than 95% after the purification process. The percentage of monomeric fusion protein Fv-LDP was 60% after the refolding process, while it was further refined to 85% which was 5.6-fold higher than that of the initial refolding condition. The refined fusion protein Fv-LDP could bind to human lung adenocarcinoma PAa cells and human hepatoma BEL-7402 cells with the dissociation constants (Kd) of 0.176 micromol x L(-1) and 0.904 micromol x L(-1), respectively. The preparation process of fusion protein Fv-LDP has been successfully optimized, which provides the experimental basis for the production and future development of fusion protein Fv-LDP, and might serve as a relatively practical system for the preparation of other scFv-based proteins expressed in the form of inclusion body.
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This study is to investigate the effects of ubenimex on tumor cell invasion and apoptosis, dose relationship and mechanism. Immunofluorescence staining was performed to detect the expression of CD13 in HT-1080 cells. MTT assay was used to analyze the effect of ubenimex on cell proliferation. Annexin V-EGFP/PI was used to detect apoptotic cells by flow cytometry. Cell cycle was analyzed using flow cytometry. Ala-pNA was used as substrate to evaluate the effect of ubenimex on the aminopeptidase activity. Transwell assay was used to analyze the effect of ubenimex on cell invasion and migration ability. Western blotting was used to detect the expression level of CD13. MMP activity was analyzed using gelatin zymography. The results showed that ubenimex at high concentration inhibited the proliferation of HT-1080 cells (IC50: 3.8 mg x mL(-1)), and induced cell apoptosis. Cell cycle was blocked at G1 phase. Ubenimex at low concentration inhibited the aminopeptidase activity of HT-1080 cells (IC50: 8.3 microg x mL(-1)) and inhibited cell invasion, but it had no effects on the cell migration and proliferation. Ubenimex had no effects on CD13 expression and MMP activity. In conclusion, ubenimex at low concentration can inhibit the invasion ability of tumor cells by directly inhibiting the aminopeptidase activity; ubenimex at high concentration can inhibit the proliferation of tumor cells and induce cell apoptosis by a CD13-independent pathway.
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The use of monoclonal antibodies (mAbs) for cancer therapy has achieved considerable success in recent years. Approximate 17 monoclonal antibodies have been approved as cancer therapeutics since 1997. Antibody-drug conjugates (ADC) are powerful new treatment options for cancer, and naked antibodies have recently achieved remarkable success. The safety and effectiveness of therapeutic mAbs in oncology vary depending on the nature of the target antigen and the mechanisms of tumor cell killing. This review provides a summary of the current state of antibody-based cancer therapy, including the mechanisms of tumor cell killing by antibodies, tumor antigens as antibody targets, clinical effectiveness of antibodies in cancer patients and nanoparticles-based ADCs.
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This study is to investigate the inhibitory effect of lidamycin (LDM) and its combination with methotrexate (MTX) on lung metastasis of fibrosarcoma by bioluminescence imaging in athymic mice. A stable luciferase transfected HT-1080 cell line was constructed and the capability to establish experimental lung metastasis in athymic mice was confirmed. The optical imaging system was applied to evaluate the formation of lung metastasis in vivo. In addition, metastatic nodules were counted for the evaluation of inhibition rates. As shown, the fluorescent intensity of luciferase-transfected HT-1080 cells was colinear with the cell population and the minimal detected cell population was 100 cells/well. Optical imaging showed that the fluorescent intensity of treated group was apparently lower than that of the control. The inhibition rates of lung metastasis by LDM alone at 0.025 mg x kg(-1) and 0.05 mg x kg(-1) were 53.9% and 75.9%, respectively, while that of MTX alone at 0.5 mg x kg(-1) was 70.2%. The combination of LDM at 0.025 mg x kg(-1) and MTX at 0.5 mg x kg(-1) showed an inhibition rate of 88.7%. The coefficient of drug interaction (CDI) was 0.82. The results herein demonstrated that LDM alone had strong anti-metastasis effect on human fibrosarcoma HT-1080 and the inhibition efficacy is strengthened when combined with MTX.
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This study is to investigate inhibitory effects of lidamycin (LDM) on the proliferation of HERG K+ channel highly expressing cancer cells and its synergy with anticancer drugs. MTT assay was used to examine the inhibitory effects of lidamycin combined with various anticancer drugs on the proliferation of human lung cancer A549 cells, human colon cancer HT-29 cells and herg-stably-transfected A549 cells. Using the xenograft model of subcutaneously transplanted HT-29 in nude mice, inhibitory effect was appraised in vivo. The coefficient of drug interaction (CDI) was used to evaluate the synergistic effect of drug combination. LDM significantly inhibited the proliferation ofA549 cells and HT-29 cells with IC50 values of 2.14 and 4.64 ng mL(-1), respectively. The efficacy in HT-29 cells with high HERG potassium expression level is less potent than that in A549 cells with low expression level. In terms of IC50 values, LDM suppressed the growth of herg-stably-transfected A549 cells less potently than pCDNA3.1-stably-transfected A549 cells. There existed synergistic effects in the combinations of fluorouracil (5-FU) and LDM, doxorubicin (DOX) and LDM, or hydroxycamptothecine (HCPT) and LDM. CDI values of the combinations of 5-FU and LDM were more than 0.75. CDI values of LDM and DOX were more than 0.70, but some CDI values of LDM and HCPT were less than 0.70. As for the CDI values, synergistic effects of the combination of LDM and HCPT were the most potent of the three groups. There is no relationship between the inhibitory effect of the growth of cancer cells by 5-FU and HERG potassium expression level. HERG expression level negatively correlated with inhibitory effect on the proliferation of cancer cells by DOX. HERG expression levels and chemosensitivity were positively correlated for HCPT. In the model of subcutaneously xenograft transplanted HT-29 in vivo, LDM and/or HCPT effectively inhibited the growth of HT-29 in nude mice, and the optimum CDI of the combination of LDM and HCPT was less than 1. HERG expression level negatively correlates the chemosensitivity of cancer cells to LDM. There exist synergistic effects in vitro and in vivo in the combination of LDM and HCPT, which inhibitory effects of the proliferation of cancer cells positively modulated by HERG potassium expression level. HERG K+ channel may become a target of combined therapy for choosing anticancer drugs.
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This study is to investigate the binding capability of lidamycin apoprotein (LDP), an enediyne-associated apoprotein of the chromoprotein antitumor antibiotic family, to human breast cancer and normal tissues, the correlation of LDP binding capability to human breast cancer tissues and the expression of tumor therapeutic targets such as VEGF and HER2. In this study, the binding capability of LDP to human breast cancer tissues was detected with tissue microarray. The correlation study of LDP binding capability to human breast tumor tissues and relevant therapeutic targets was performed on breast cancer tissue microarrays. Immunocytochemical examination was used to detect the binding capability of LDP to human breast carcinoma MCF-7 cells. As a result, tissue microarray showed that LDP staining of 73.2% (30/41) of breast cancer tissues was positive, whereas that of 48.3% (15/31) of the adjacent normal breast specimens was positive. The difference between the tumor and normal samples was significant (Chi2 = 4.63, P < 0.05). LDP immunoreactivity in breast cancer correlated significantly with the overexpression of VEGF and HER2 (P < 0.001 and < 0.01, r = 0.389 and 0.287, respectively). Determined with confocal immunofluorescent analysis, LDP showed the binding capability to mammary carcinoma MCF-7 cells. It is demonstrated that LDP can bind to human breast cancer tissues and there is significant difference between the breast cancer tissues and the corresponding normal tissues. Notably, the binding reactivity shows positive correlation with the expression of VEGF and HER2 in breast carcinoma tissues. The results imply that LDP may have a potential use as targeting drug carrier in the research and development of new anticancer therapeutics. This study may provide reference for drug combination of LDM and other therapeutic agents.
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Objective To explore the effect of recombinant scFv (3G11)directed against type IV collagenase in combination with cisplatin on the therapy of hepatocellular carcinoma.Methods The effects of cisplatin on the type IV collagenase secreted by cancer cells were investigated by gelatin zymography analysis and Western-blot.The antitumor activity of scFv (3G11)in combination with cisplatin was evaluated by MTT assay in vitro and a mouse hepatoma 22 model in vivo.Results Cisplatin inhibited the activity of type IV collagenase.ScFv (3G11)in combination with cisplatin showed significant inhibition effects on the growth of hepatocellular carcinoma both in vitro and in vivo.The coefficient of drug interaction(CDI)was less than 1.Conclusions ScFv (3G11)in combination with cisplatin demonstrated synergetic effects on the therapy of hepatocellular carcinoma.
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Aim To study the mechanism of inhibition of basic fibroblast growth factor (bFGF) related signal transduction by lidamycin in cancer cells. Methods MTT assay was used to determine the growth inhibitory effect of lidamycin (LDM) and adriamycin (ADR) in several cancer cell lines. The inhibition of bFGF bound to its receptor by LDM was measured with [ 125I ]-bFGF binding assay.Intracellular Ca2+ stimulated by bFGF was measured by Fura-3. The formation of bFGF- receptor immune complex and the inhibitory effect of LDM on the activity of PKC isoenzymes induced by bFGF in cancer cells were identified by Western blotting analysis. Results LDM displayed extremely potent growth inhibitory effect on several cancer cell lines in a dose-dependent manner. A comparison of the IC50 values showed that the effect of LDM was 1 000-fold more potent than that of ADR. LDM blocked the specific by anti-FGFR specific antibody, LDM inhibited the formation of bFGF-receptor immune complex. bFGF demonstrated that LDM inhibited the activity of PKC isoenzymes in cancer cells stimulated with bFGF.Conclusion The blocking of bFGF receptors in the signal transduction pathway may be involved in the effect of LDM on cancer cells.
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<p><b>OBJECTIVE</b>Using monoclonal antibody (mAb) Fab' fragment to develop mAb immunoconjugates for cancer.</p><p><b>METHODS</b>Fab' fragment of mAb 3A5 was prepared by digestion of the antibody with pepsin and then reduced by dithiothreitol (DT), while Fab' fragment of mAb 3D6 was obtained by digestion of the antibody with ficin and subsequently reduced by beta-mercaptoethanol. The conjugation between Fab' fragment and pingyangmycin (PYM), an antitumor antibiotic, was mediated by dextran T-40. Immunoreactivity of Fab'-PYM conjugates with cancer cells was determined by ELISA, and the cytotoxicity of those conjugates to cancer cells was determined by clonogenic assay. Antitumor effects of the Fab'-PYM conjugates were evaluated by subcutaneously transplanted tumors in mice.</p><p><b>RESULTS</b>The molecular weight of Fab' fragment was approximately 53 kD, while the average molecular weight of Fab'-PYM conjugate was 170 kD. The Fab'-PYM conjugates showed immunoreactivity with antigen-relevant cancer cells and selective cytotoxicity against target cells. Administered intravenously, Fab'-PYM conjugates were more effective against the growth of tumors in mice than free PYM and PYM conjugated with intact mAb.</p><p><b>CONCLUSION</b>Fab'-PYM conjugate may be capable of targeting cancer cells and effectively inhibiting tumor growth, suggesting its therapeutic potential in cancer treatment.</p>
Subject(s)
Animals , Female , Humans , Mice , Antibiotics, Antineoplastic , Pharmacology , Antibodies, Monoclonal , Pharmacology , Bleomycin , Pharmacology , Carcinoma, Hepatocellular , Pathology , Colonic Neoplasms , Pathology , HT29 Cells , Immunoglobulin Fab Fragments , Pharmacology , Immunotoxins , Pharmacology , KB Cells , Liver Neoplasms , Pathology , Tumor Cells, CulturedABSTRACT
AIM To investigate the therapeutic effect of boanmycin (BAM, bleomycin A6) on colon carcinoma 26 and its hepatic metastasis in mice. METHODS A series of models including subcutaneous transplantation, orthotopic transplantation in cecum subserosa, intra-hepatic transplantation of tumor, and intra-splenic transplantation of tumor accompanied with hepatic metastases were employed. In addition, LEICA Q 500IW image analysis system was used to determine the area of metastatic lesions in the liver in histopathological sections. RESULTS BAM at 5 mg*kg-1 and 2.5 mg*kg-1 inhibited the growth of subcutaneous tumors by 78.7% and 61.9%, and the orthotopic tumors by 99.4% and 90.0%; and the intra-hepatic tumors by 86.9% and 75.7%, respectively. Determined by the numbers of metastatic nodules, BAM at 10 mg*kg-1 and 5 mg*kg-1 inhibited hepatic metastases from intra-splenic transplantation by 97.6% and 56.8%; and evaluated by image analysis of metastatic lesions, by 100% and 63.3%, respectively. CONCLUSION Boanmycin is highly effective in a panel of models including the subcutaneous, orthotopic, intra-hepatic transplanted tumors, and hepatic metastases of murine colon carcinoma 26.
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AIM To study the apoptosis-inducing and growth-inhibitory effect of rhein, an herb-derived compound, and its combination with mitomycin C (MMC) on cultured tumor cells. METHODS MTT assays were used to determine the inhibition of proliferation by drugs in several tumor cell lines. Nucleoside transport and DNA synthesis inhibition were determined by ［3H］ thymidine transport and incorporation assays. Flow cytometry, electrophoresis on agarose gels and morphological assesment were applied to analyze the apoptotic changes. RESULTS The IC50 values of nucleoside transport was 19.1 μg*mL-1 and that of the DNA synthesis inhibited by rhein was 27.4 μg*mL-1. In MTT assay the IC50 values of rhein for KB, hepatoma BEL-7402 and mammary carcinoma MCF-7 cells were 11.5 μg*mL-1, 14.0 μg*mL-1 and 18.4 μg*mL-1 respectively. Synergistic effect of rhein and MMC was found in all the three cell lines. As found, rhein induced apoptosis in KB cells, and the increase of apoptotic cells reached 71.0% at 96 h. The combination of rhein and MMC enhanced the induction of apoptosis significantly. CONCLUSION These results suggest that rhein, as a biochemical modulator, might be potentially useful in cancer chemotherapy.
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C1027, an anticancer antibiotic, showed extremely potent cytotoxicity against cultured cancer cells, being over 10,000-fold more potent than adriamycin. C1027 acted rapidly; DNA synthesis of hepatoma cells was suppressed within 10 mintus of exposure. C1027 consists of two moieties, a new enediyne chromophore and an apoprotein; the chromophore serves as the active part of the molecule. C1027 molecule can be dissociated and reconstituted. The reconstituted C1027 was as potent as natural C1027. Through a newly developed method, enriched conjugation C1027 was conjugated to monoclonal antibodies. As determined by clonogenic assay, the conjugates displayed highly-potent, specific cytotoxicity to target cancer cells. The conjugates exerted marked therapeutic effects against hepatoma and gastric cancer xenografts in nude mice; at tolerable dose, tumor inhibition rate reached 85% (P