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Yu Z, Zhao X, Qiu S, Zhou S, Li P, Liu N. Hyperthermic Intraperitoneal Chemotherapy May Damage Renal Function and Cause Serum Electrolyte Disturbance: A Retrospective Observational Study. Surg Laparosc Endosc Percutan Tech 2023; 33:302-309. [PMID: 37172024 DOI: 10.1097/sle.0000000000001173] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2023] [Accepted: 03/20/2023] [Indexed: 05/14/2023]
Abstract
OBJECTIVE The objective of this study was to evaluate the efficacy of postoperative hyperthermic intraperitoneal chemotherapy (HIPEC) on bone marrow hematopoiesis, liver and kidney function, and serum electrolytes for patients who underwent open radical gastrectomy, and investigate the variation tendency of above indicators. MATERIALS AND METHODS The clinical data of 153 patients who underwent open radical gastrectomy were retrospectively analyzed and were divided into HIPEC group (n=83) and control group (n=70). Repeated analysis of variance was used to analyze the variation tendency of bone marrow hematopoiesis, liver and kidney function, and serum electrolytes in the HIPEC and control group, respectively, and then made a comparison between the 2 groups. RESULTS There were statistical differences in alanine aminotransferase ( P =0.034), phosphorus ( P+ ) ( P <0.05), potassium (K + ) ( P =0.023), sodium (Na + ) ( P <0.001), and chloride (Cl - ) ( P =0.008) between HIPEC and control group. All outcome indicators changed significantly over time ( P <0.05). No significant difference was found in hemoglobin, white blood cell, platelet, aspartate aminotransferase, total bilirubin, or uric acid between the 2 treatment groups at each time point. On the next day after HIPEC treatment, the levels of blood urea nitrogen, creatinine, and P+ were higher in the HIPEC group, whereas the calcium (Ca + ), magnesium (Mg + ), and K + levels of HIPEC group tended to be lower. However, the effects of HIPEC on alanine aminotransferase, Na + , and Cl - levels needed to be further explored. CONCLUSIONS HIPEC treatment after open radical gastrectomy has no significant effect on hematopoietic bone marrow and liver function but may damage renal function; reduce Ca + , Mg + , K + levels; and increase P+ level.
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Affiliation(s)
- Zhiyuan Yu
- School of Medicine, Nankai University, Tianjin
- Medical School of Chinese PLA
- Senior Department of General Surgery, The First Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Xudong Zhao
- Senior Department of General Surgery, The First Medical Center, Chinese PLA General Hospital, Beijing, China
| | | | - Sixin Zhou
- Senior Department of General Surgery, The First Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Peiyu Li
- School of Medicine, Nankai University, Tianjin
- Medical School of Chinese PLA
- Senior Department of General Surgery, The First Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Na Liu
- Medical School of Chinese PLA
- Senior Department of General Surgery, The First Medical Center, Chinese PLA General Hospital, Beijing, China
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Lokerse WJ, Bolkestein M, Hagen TLT, de Jong M, Eggermont AM, Grüll H, Koning GA. Investigation of Particle Accumulation, Chemosensitivity and Thermosensitivity for Effective Solid Tumor Therapy Using Thermosensitive Liposomes and Hyperthermia. Am J Cancer Res 2016; 6:1717-31. [PMID: 27446503 PMCID: PMC4955068 DOI: 10.7150/thno.14960] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2016] [Accepted: 05/01/2016] [Indexed: 11/24/2022] Open
Abstract
Doxorubicin (Dox) loaded thermosensitive liposomes (TSLs) have shown promising results for hyperthermia-induced local drug delivery to solid tumors. Typically, the tumor is heated to hyperthermic temperatures (41-42 °C), which induced intravascular drug release from TSLs within the tumor tissue leading to high local drug concentrations (1-step delivery protocol). Next to providing a trigger for drug release, hyperthermia (HT) has been shown to be cytotoxic to tumor tissue, to enhance chemosensitivity and to increase particle extravasation from the vasculature into the tumor interstitial space. The latter can be exploited for a 2-step delivery protocol, where HT is applied prior to i.v. TSL injection to enhance tumor uptake, and after 4 hours waiting time for a second time to induce drug release. In this study, we compare the 1- and 2-step delivery protocols and investigate which factors are of importance for a therapeutic response. In murine B16 melanoma and BFS-1 sarcoma cell lines, HT induced an enhanced Dox uptake in 2D and 3D models, resulting in enhanced chemosensitivity. In vivo, therapeutic efficacy studies were performed for both tumor models, showing a therapeutic response for only the 1-step delivery protocol. SPECT/CT imaging allowed quantification of the liposomal accumulation in both tumor models at physiological temperatures and after a HT treatment. A simple two compartment model was used to derive respective rates for liposomal uptake, washout and retention, showing that the B16 model has a twofold higher liposomal uptake compared to the BFS-1 tumor. HT increases uptake and retention of liposomes in both tumors models by the same factor of 1.66 maintaining the absolute differences between the two models. Histology showed that HT induced apoptosis, blood vessel integrity and interstitial structures are important factors for TSL accumulation in the investigated tumor types. However, modeling data indicated that the intraliposomal Dox fraction did not reach therapeutic relevant concentrations in the tumor tissue in a 2-step delivery protocol due to the leaking of the drug from its liposomal carrier providing an explanation for the observed lack of efficacy.
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Hsieh IS, Huang WH, Liou HC, Chuang WJ, Yang RS, Fu WM. Upregulation of drug transporter expression by osteopontin in prostate cancer cells. Mol Pharmacol 2013; 83:968-77. [PMID: 23434829 DOI: 10.1124/mol.112.082339] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Multidrug resistance is a major cause of chemotherapy failure. Recent studies indicate that drug resistance can be rapidly induced by some soluble factors, such as cytokines, chemokines, growth factors, and cell adhesion factors in the tumor microenvironment. Osteopontin (OPN), an extracellular matrix protein, has a functional arginine-glycine-aspartic acid (RGD) domain for binding to integrin. Here we found OPN expression to be upregulated by hypoxic condition in PC-3 prostate tumor cells. OPN increased the mRNA and protein expression of p-glycoprotein (P-gp), a subfamily of ATP-binding cassette transporter in a concentration- and time-dependent manner. The increase in P-gp transporter by OPN was mediated by binding to αvβ3 integrin. Daunomycin (DUN), a chemotherapeutic agent with autofluorescence, was used to evaluate the pump activity, and OPN increased the drug pumping-out activity. OPN inhibited DUN-induced cell death, which was antagonized by αvβ3 monoclonal antibody. Long-term treatment with DUN further enhanced the expression of OPN. Knockdown of endogenous OPN potentiated the DUN-induced apoptosis of PC-3 cells. Furthermore, knockdown of OPN enhanced cell death caused by other drugs, including paclitaxel, doxorubicin, actinomycin-D, and rapamycin, which are also P-gp substrates. The animal studies also showed that OPN knockdown enhanced the cytotoxic action of DUN. These results indicate that OPN is a potential therapeutic target for cancer therapy to reduce drug resistance in sensitive tumors.
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Affiliation(s)
- I-Shan Hsieh
- Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan
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Tang Y, McGoron AJ. Increasing the rate of heating: A potential therapeutic approach for achieving synergistic tumour killing in combined hyperthermia and chemotherapy. Int J Hyperthermia 2013; 29:145-55. [DOI: 10.3109/02656736.2012.760757] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
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Grimm MJ, Zynda ER, Repasky EA. Temperature Matters: Cellular Targets of Hyperthermia in Cancer Biology and Immunology. HEAT SHOCK PROTEINS 2009. [DOI: 10.1007/978-90-481-2976-8_15] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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Szaniszlo P, Rose WA, Wang N, Reece LM, Tsulaia TV, Hanania EG, Elferink CJ, Leary JF. Scanning cytometry with a LEAP: Laser-enabled analysis and processing of live cells in situ. Cytometry A 2006; 69:641-51. [PMID: 16807893 DOI: 10.1002/cyto.a.20291] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
BACKGROUND Scanning cytometry now has many of the features (and power) of multiparameter flow cytometry while keeping its own advantages as an imaging technology. Modern instruments combine capabilities of scanning cytometry with the ability to manipulate cells. A new technology, called LEAP (laser-enabled analysis and processing), offers a unique combination of capabilities in cell purification and selective macromolecule delivery (optoinjection). METHODS LEAP-mediated cell purification and optoinjection effects were assessed in model experiments using adherent and suspension cell types and cell mixtures plated and processed at different densities. Optoinjection effects were visualized by delivering fluorescent dextrans into cells. Results were analyzed using the LEAP instrument's own imaging system as well as by fluorescence and confocal microscopy. RESULTS Live cell samples (adherent and suspension) could be purified to 90-100% purity with 50-90% yield, causing minimal cell damage depending on the cell type and plating density. Nearly one hundred percent of the targeted cells of all cell types examined could be successfully optoinjected with dextrans of 3-70 kDa, causing no visual damage to the cells. Indirect optoinjection effects were observed on untargeted cells within 5-60 microm to targeted areas under conditions used here. CONCLUSIONS LEAP provides solutions in cell purification and targeted macromolecule delivery for traditional and challenging applications where other methods fall short.
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Affiliation(s)
- Peter Szaniszlo
- Department of Microbiology and Immunology, University of Texas Medical Branch at Galveston, USA
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Wartenberg M, Gronczynska S, Bekhite MM, Saric T, Niedermeier W, Hescheler J, Sauer H. Regulation of the multidrug resistance transporter P-glycoprotein in multicellular prostate tumor spheroids by hyperthermia and reactive oxygen species. Int J Cancer 2005; 113:229-40. [PMID: 15389514 DOI: 10.1002/ijc.20596] [Citation(s) in RCA: 56] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
Hyperthermia is an important component of many cancer treatment protocols. In our study the regulation of the multidrug resistance (MDR) transporter P-glycoprotein by hyperthermia was studied in multicellular prostate tumor spheroids. Hyperthermia treatment of small (50-100 microm) tumor spheroids significantly increased P-glycoprotein and mdr-1 mRNA expression with a maximum effect at 42 degrees C, whereas only moderate elevation of P-glycoprotein was found in large (350-450 microm) tumor spheroids. Hyperthermia caused an elevation of intracellular reactive oxygen species (ROS). Inhibition of ROS generation with NADPH-oxidase inhibitors diphenylen iodonium (DPI) and 4-(2-aminoethyl)benzenesulfonyl fluoride (AEBSF) abolished P-glycoprotein expression but did not affect its transcript levels following heat treatment. This indicates that P-glycoprotein levels are controlled by regulating its translation rate or stability. Hyperthermia incubation resulted in a differential activation of p38 mitogen-activated protein kinase (MAPK), extracellular regulated kinase 1,2 (ERK1,2), and c-jun N-terminal kinase (JNK) immediately, 4 hr and 24 hr after treatment. Furthermore, upregulation of hypoxia-inducible factor 1alpha (HIF-1alpha) was observed. Elevation of HIF-1alpha and P-glycoprotein expression following hyperthermia treatment were abolished upon coadministration of the p38 inhibitor SB203580. In contrast the JNK inhibitor SP600125 and the ERK1,2 inhibitor UO126 resulted in increase of HIF-1alpha and P-glycoprotein in the control as well as the hyperthermia-treated samples, indicating negative regulation of intrinsic HIF-1alpha and P-glycoprotein expression by ERK1,2 and JNK signaling cascades. In summary our data demonstrate that hyperthermia-induced upregulation of P-glycoprotein and HIF-1alpha is mediated by activation of p38, whereas ERK1,2 and JNK are involved in repression of P-glycoprotein and HIF-1alpha under control conditions.
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Affiliation(s)
- Maria Wartenberg
- Institute of Neurophysiology, University of Cologne, Cologne, Germany
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Anticancer efficacies of doxorubicin, verapamil and quercetin on FM3A cells under hyperthermic temperature. BIOTECHNOL BIOPROC E 2004. [DOI: 10.1007/bf02942341] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
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Cho CW, Liu Y, Cobb WN, Henthorn TK, Lillehei K, Christians U, Ng KY. Ultrasound-induced mild hyperthermia as a novel approach to increase drug uptake in brain microvessel endothelial cells. Pharm Res 2003; 19:1123-9. [PMID: 12240937 DOI: 10.1023/a:1019837923906] [Citation(s) in RCA: 59] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
PURPOSE Drug delivery to the central nervous system (CNS) is limited by the blood-brain barrier (BBB). Thus, a noninvasive and reversible method to enhance BBB permeation of drugs is highly desirable. In the present work, we studied if ultrasound-induced mild hyperthermia (USHT, 0.4 watts (W)/cm2 at 41 degrees C) can enhance drug absorption in BBB endothelial cells, and we elucidated the mechanism of USHT on cellular accumulation. METHODS To accomplish these aims, we studied the effects of hyperthermia (41 degrees C), USHT, P-glycoprotein (P-gp) modulator (PSC 833), and combination of USHT and PSC 833 on accumulation of P-gp substrate (R123) and non-P-gp substrates (sucrose, 2-deoxyglucose, and antipyrine) in monolayers of primary bovine brain microvessel endothelial cells (BBMEC). RESULTS USHT, through its thermal effect, produces a significant (relative to controls; no USHT) and comparable increase in R123 accumulation with PSC 833. We also demonstrate that USHT increases permeability of hydrophobic (R123 and [14C]-antipyrine) and not hydrophilic molecules ([14C]-sucrose and 2-[3H]-deoxy-D-glucose). The enhanced permeability is reversible and size dependent, as USHT produces a much larger effect on cellular accumulation of [14C]-antitpyrine (molecular weight of 188 D) than that of R123 (molecular weight of 380.8 D). Although USHT increases membrane permeability, it did not affect P-gp activity or the activity of glucose transporters. CONCLUSIONS Our results point to the potential use of USHT as a reversible and noninvasive approach to increase BBB permeation of hydrophobic drugs, including P-gp-recognized substrates.
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Affiliation(s)
- Cheong-Weon Cho
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Health Sciences Center, Denver 80262, USA
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Abstract
AIM: To investigate the expression of metallothioneins (MTs), which were recently thought to have close relationship with tumors, in human hepatocellular carcinoma.
METHODS: Histological specimens of 35 cases of primary human hepatocellular carcinoma with para-neoplastic liver tissue and 5 cases of normal liver were stained for MTs with monoclonal mouse anti-MTs serum (E9) by the immunohistochemical ABC technique.
RESULTS: MTs were stained in the 35 cases of HCC, including 6 cases negative (17.1%), 23 weakly positive (65.7%), and 6 strongly positive (17.1%). But MTs were stained strongly positive in all the five cases of normal liver and 35 cases of para-neoplastic liver tissue. The differences of MTs expression between HCC and normal liver tissue or para-neoplastic liver tissue were highly significant (P < 0.01). The rate of MTs expression in HCC grade I was 100 percent, higher than that in grade II (81%) and grade III and IV (78%). But the differences were not significant (P > 0.05). No obvious correlations between MTs expression in HCC and tumor size, clinical stage or serum alpha fetoprotein concentration were found (P > 0.05).
CONCLUSION: Decrease of MTs expression in HCC may play a role in carcinogenesis of HCC. MTs are stained heterogenously in HCC. We can choose the anticancer agents according to the MTs concentration in HCC, which may improve the results of chemotherapy for HCC.
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Affiliation(s)
- Geng-Wen Huang
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China.
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Abstract
Ultrasound is best known for its imaging capability in diagnostic medicine. However, there have been considerable efforts recently to develop therapeutic uses for it. The purpose of this review is to summarize some of the recent advances made in the area of therapeutic ultrasound as they relate to drug delivery. In particular, this review will focus on the applications of ultrasound to enhance the delivery and effect of three distinctive therapeutic drug classes: chemotherapeutic, thrombolytic, and gene-based drugs. In addition, ultrasound contrast agents have been recently developed for diagnostic ultrasound. New experimental evidence suggests that these contrast agents can be used as exogenous cavitation nuclei for enhancement of drug and gene delivery. Thus, brief review of this new class of agents and their roles in drug delivery will also be provided. By comparison to diagnostic ultrasound, progress in therapeutic use of ultrasound has been somewhat limited. The recent successes in ultrasound-related drug delivery research positions ultrasound as therapeutic tool for drug delivery in the future.
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Affiliation(s)
- Ka-yun Ng
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Health Sciences Center, Campus Box C-238, 4200 East Ninth Avenue, Denver, Colorado 80262, USA.
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Liu Y, Cho CW, Yan X, Henthorn TK, Lillehei KO, Cobb WN, Ng KY. Ultrasound-Induced hyperthermia increases cellular uptake and cytotoxicity of P-glycoprotein substrates in multi-drug resistant cells. Pharm Res 2001; 18:1255-61. [PMID: 11683237 DOI: 10.1023/a:1013025625156] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
PURPOSE Localized hyperthermia has been shown previously to augment the cytotoxicity of some lipophilic anticancer drugs. Because many of the substrates for the multi-drug resistance (MDR) transporter P-glycoprotein (P-gp) are lipophilic in nature, studies were conducted to test the hypothesis that hyperthermia induced by ultrasound could also increase cellular uptake and cytotoxicity of P-gp substrates by P-gp-expressing cells. METHODS To test this hypothesis, we studied the effects of hyperthermia and ultrasound on cellular accumulation of putative P-gp substrates, rhodamine 123 (R123) and doxorubicin (DOX), and cytotoxicity of DOX in the parent and MDR variants of two human cancer cell lines. RESULTS Treatment of cells with hyperthermia or ultrasound (20 min at 41 degrees C) both caused a significant increase over controls (no ultrasound treatment) in R123 and DOX accumulation in the parent and MDR lines of MV522 and KB cells. Ultrasound also substantially increased the antiproliferative effects of DOX in both the parent and MDR variants of MV522 and KB cell lines when compared with controls. Our results also indicated that ultrasound exerted a much greater effect on cellular accumulation of R123 and DOX and cytotoxicity enhancement of DOX in the MDR variants than putative P-gp antagonist such as verapamil. CONCLUSION The present results point to the potential use of ultrasound-induced hyperthermia as a much safer alternative to P-gp antagonist for reversal of MDR.
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Affiliation(s)
- Y Liu
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Health Sciences Center, Denver 80262, USA
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