Clinical Anti-tumor Therapy Research Articles

Systemic delivery of tannic acid-ferric-masked oncolytic adenovirus reprograms tumor microenvironment for improved therapeutic efficacy in glioblastoma.

Glioblastoma (GBM) represents the most aggressive primary brain tumor, and urgently requires effective treatments. Oncolytic adenovirus (OA) shows promise as a potential candidate for clinical antitumor therapy, including in the treatment of GBM. Nevertheless, the systemic delivery of OA continues to face challenges, leading to significantly compromised antitumor efficacy. In this study, we developed an innovative approach by encapsulating CXCL11-armed OA with tannic acid and Fe3+ (TA-Fe3+) to realize the systemic delivery of OA. The nanocarrier's ability to protect the OA from elimination by host immune response was evaluated in vitro and in vivo. We evaluated the antitumor effect and safety profile of OA@TA-Fe3+ in a GBM-bearing mice model. OA@TA-Fe3+ effectively safeguarded the virus from host immune clearance and extended its circulation in vivo. After targeting tumor sites, TA-Fe3+ could dissolve and release Fe3+ and OA. Fe3+-induced O2 production from H2O2 relieved the hypoxic state, and promoted OA replication, leading to a remarkable alteration of tumor immune microenvironment and enhancement in antitumor efficacy. Moreover, the systemic delivery of OA@TA-Fe3+ was safe without inflammation or organ damage. Our findings demonstrated the promising potential of systemically delivering the engineered OA for effective oncolytic virotherapy against GBM.

Mitoxantrone Combined with Engineered TRAIL-Nanovesicles for Enhanced Cancer Immunotherapy Via Converting Apoptosis into Pyroptosis.

Pyroptosis, a highly inflammatory form of programmed cell death, has emerged as a promising target for cancer immunotherapy. However, in the context of pyroptosis execution, while both caspase-3 and GSDME are essential, it is noteworthy that GSDME is frequently under-expressed in cold tumors. To overcome this limitation, engineered cellular nanovesicles (NVs) presenting TRAIL on their membranes (NVTRAIL) are developed to trigger the upregulation of cleaved caspase-3. When strategically combined with the chemotherapeutic agent mitoxantrone (MTO), known for its ability to enhance GSDME expression, MTO@NVTRAIL can convert cancer cells from apoptosis into pyroptosis, inhibit the tumor growth and metastasis successfully in primary tumor. The microparticles released by pyroptotic tumor cells also exhibited certain cytotoxicity against other tumor cells. In addition, tumor cells exposed to the combination treatment of MTO@NVTRAIL in vitro have also demonstrated potential utility as a novel form of vaccine for cancer immunotherapy. Flow analysis of the tumor microenvironment and draining lymph nodes reveals an increased proportion of matured dendritic cells and activation of T cells. In summary, the research provided a reference and alternative approach to induce cancer pyroptosis for clinical antitumor therapy based on engineered cellular nanovesicles and chemotherapy.

Research progress on anti-tumor effects by traditional Chinese medicine based on "soothing" or "blockage" regulation of tumor vessels

Regulation of tumor vessels has become one of the most common strategies for clinical anti-tumor therapy. In recent years, studies have found that the anti-tumor effect of limotherapy, which routinely inhibits tumor angiogenesis, is not ideal and may even deteriorate the tumor microenvironment, causing tumor resistance and distal metastasis and increasing the risk of tumor metastasis and recurrence. However, the proper use of anti-angiogenic drugs can promote the normalization of tumor vessels, improve the structure and function of tumor vessels, increase the number of functional vessels in the tumor, and reduce the number of ineffective vessels. It is beneficial to promote the penetration of anti-tumor drugs into the tumor, improve the microenvironment of tumor hypoxia and immunosuppression, and enhance the anti-tumor effect. Traditional Chinese medicine(TCM) has a long history of understanding the etiology and pathogenesis of tumors and has accumulated rich experience in tumor treatment, with significant clinical advantages and broad application prospects. In this study, from the perspective of bidirectional "soothing" or "blockage" regulation of tumor vessels, the commonly used molecular targets were sorted out, and the research status of anti-tumor regulation of tumor vessels by monomer-single herb-compound(herb pair) of TCM in recent years was summarized. The research on the anti-tumor effects of TCM compounds and active ingredients by regulating tumor vessels combined with other therapies was analyzed and sorted out, so as to provide ideas for the clinical application of TCM in regulating functions and anti-tumor effects of tumor vessels.

Ring finger protein 10 improves pirarubicin-induced cardiac inflammation by regulating the AP-1/Meox2 signaling pathway

ObjectivesPirarubicin (THP) is widely used in clinical antitumor therapy, but its cardiotoxicity seriously affects the therapeutic effect in patients. In the study, we investigated the role of ring finger protein 10 (RNF10) in cardiotoxicity induced by THP. Materials and methodsA cardiac toxicity model in Sprague-Dawley (SD) rats induced by THP was established. Changes in diet, weight, electrocardiogram (ECG), and echocardiography were observed. Serum levels of brain natriuretic peptide (BNP), creatine kinase MB (CK-MB), cardiac troponin T (cTnT), and lactate dehydrogenase (LDH) were measured. The expression of RNF10 in myocardium was observed by immunohistochemistry. The expressions of RNF10, activator protein-1 (AP-1), mesenchyme homeobox 2 (Meox2), total nuclear factor (NF)-κB p65 (T-P65), phosphorylated NF-κB p65 (PP65), monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor (TNF)-α, interleukin (IL)-6, and mature IL-1β were detected by Western blot. A THP-induced H9c2 myocardial cell injury model was established. RNF10 was downregulated or overexpressed by RNF10 siRNA and a RNF10 lentiviral vector, respectively. Then, cell viability was measured. The expression of RNF10 in H9c2 cells was observed by immunofluorescence. All of the above signaling pathways were verified by Western blots. FindingsTHP caused a series of cardiotoxic manifestations in SD rats. Our studies suggested that THP caused cardiac inflammation by inhibiting the expression of RNF10, while overexpression of RNF10 antagonized the cardiotoxicity induced by THP. SignificanceOur study showed RNF10 improved THP-induced cardiac inflammation by regulating the AP-1/Meox2 signaling pathway. RNF10 may be a new target to treat THP-induced cardiotoxicity.

Localized Microsphere/Hydrogel for Tumor Immunotherapy of Cardiac Glycoside with Minimal Toxicity.

It has been reported that cardiac glycosides (CGs) commonly used in clinical practice can inhibit tumor growth by inducing immunogenic cell death (ICD), and their positive benefits have been documented in several clinical trials of drug combinations. However, the inherent cardiogenic side effects need to be addressed before CGs can be truly applied in clinical antitumor therapy. In this study, a dual controlled release microsphere/hydrogel platform (OL-M/Gel) was constructed to precisely control the output of oleandrin (OL, one of the representative CGs) in situ in tumors. With the help of this intelligent drug release platform, OL can be released in vitro and in vivo in a sustained and stable manner. The ability of OL to induce ICD and the subsequent antigen presentation and cytotoxic T-cell cascades was first stated, which resulted in potent tumor growth suppression without significant side effects. In addition, the inhibition of autologous tumor recurrence and metastasis by OL-M/Gel was also revealed. This study is expected to break through the inherent bottleneck of CGs and promote their clinical transformation in the field of antitumor treatment.

Activating cGAS-STING pathway with ROS-responsive nanoparticles delivering a hybrid prodrug for enhanced chemo-immunotherapy

cGAS-STING pathway, as an essential intracellular immune response pathway, has attracted much attention in tumor immunotherapy. However, low metabolic stability of conventional STING agonists limits their clinical application. Recent study shows that chemotherapeutic drugs cisplatin and camptothecin (CPT) can activate cGAS-STING pathway and induce immune response by DNA damage. Nevertheless, the ability of chemotherapeutic drugs to activate STING is so weak that new strategies are required to improve drug delivery efficiency for enhanced DNA damage, and then efficiently activate cGAS-STING pathway. Herein, we have developed a hybrid platinum prodrug (CPT-Pt (IV)) which can be triggered to release cisplatin and CPT in tumor cells. CPT-Pt (IV) with high hydrophobicity is further self-assembled with a ROS sensitive polymer (P1) and mPEG2k-DSPE into ROS responsive nanoparticles (NPs). NPs could accumulate in the tumor site to release cisplatin and CPT, resulting in DNA double damage and finally activating cGAS-STING pathway, inducing DC cells maturation and increasing tumor infiltration of CD8+ T cells on colorectal cancer mouse model. This study showed that common DNA targeted drugs can activate the cGAS-STING pathway in situ via nano delivery system, and enhance the effect of chemotherapy and immunotherapy, which provide a new strategy for clinical antitumor therapy.

Etching Bulk Covalent Organic Frameworks into Nanoparticles of Uniform and Controllable Size by the Molecular Exchange Etching Method for Sonodynamic and Immune Combination Antitumor Therapy.

To improve the therapeutic effect of sonodynamic therapy (SDT), more effective and stable sonosensitizers and therapeutic strategies are still required. A covalent organic framework (COF) sonosensitizer is developed by using a new nanoscale COF preparation strategy. This strategy uses molecular etching based on the imine exchange reaction to etch the bulk COF into nanoparticles and has universal applicability to imine-bond-based COF. The regular COF structure can prevent the loss of sonodynamic performance caused by the aggregation of porphyrin molecules and improve the chemical stability of the porphyrin unit. In addition, the coordination of Fe3+ to COF endows the nanoparticle with chemodynamic therapy performance and glutathione consumption ability. The combination of enhanced SDT and α-PD-L1 antibody achieves a good antitumor effect. The innovative nanoscale COF sonosensitizer preparation strategy provides a new avenue for clinical antitumor therapy.

Research Progress of Xiaoaiping Injection on Anti-tumor

Xiaoaiping injection is an injection solution of effective substances extracted from the traditional Chinese medicine Tongguanteng, which has the effects of reducing inflammation and phlegm, clearing heat, and detoxifying. Xiaoaiping injection has no apparent side effects, and the price of Xiaoaiping injection is low. Xiaoaiping injection is commonly used in clinical anti-tumor therapy in China and is often combined with tumor therapy such as surgery, chemotherapy, radiotherapy, and targeted therapy, and it has an excellent curative effect. Doctors and patients widely praise it. This paper summarizes the therapeutic effect of Xiaoaiping injection in treating breast cancer, liver cancer, lung cancer, and esophageal cancer in clinical and animal experiments. Many studies have supported that Xiaoaiping injection can regulate the proliferation and apoptosis of tumor cells, reduce tumor angiogenesis, and improve human immunity to achieve anti-tumor effects. During combined chemotherapy treatment, Xiaoaiping injection can also alleviate the adverse reactions caused by chemotherapy and significantly improve patient's quality of life. This paper summarizes the research on the anti-tumor therapy of Xiaoaiping injection, which provides a basis for the clinical promotion of the drug and assistance in developing traditional Chinese medicine.

Autophagy-Associated Immunogenic Modulation and Its Applications in Cancer Therapy.

Autophagy, a lysosome-mediated cellular degradation pathway, recycles intracellular components to maintain metabolic balance and survival. Autophagy plays an important role in tumor immunotherapy as a “double-edged sword” that can both promote and inhibit tumor progression. Autophagy acts on innate and adaptive immunity and interacts with immune cells to modulate tumor immunotherapy. The discovery of autophagy inducers and autophagy inhibitors also provides new insights for clinical anti-tumor therapy. However, there are also difficulties in the application of autophagy-related regulators, such as low bioavailability and the lack of efficient selectivity. This review focuses on autophagy-related immunogenic regulation and its application in cancer therapy.

Metabolic Reprogramming in the Tumor Microenvironment With Immunocytes and Immune Checkpoints.

Immune checkpoint inhibitors (ICIs), Ipilimumab, Nivolumab, Pembrolizumab and Atezolizumab, have been applied in anti-tumor therapy and demonstrated exciting performance compared to conventional treatments. However, the unsatisfactory response rates, high recurrence and adaptive resistance limit their benefits. Metabolic reprogramming appears to be one of the crucial barriers to immunotherapy. The deprivation of required nutrients and altered metabolites not only promote tumor progression but also confer dysfunction on immune cells in the tumor microenvironment (TME). Glycolysis plays a central role in metabolic reprogramming and immunoregulation in the TME, and many therapies targeting glycolysis have been developed, and their combinations with ICIs are in preclinical and clinical trials. Additional attention has been paid to the role of amino acids, lipids, nucleotides and mitochondrial biogenesis in metabolic reprogramming and clinical anti-tumor therapy. This review attempts to describe reprogramming metabolisms within tumor cells and immune cells, from the aspects of glycolysis, amino acid metabolism, lipid metabolism, nucleotide metabolism and mitochondrial biogenesis and their impact on immunity in the TME, as well as the significance of targeting metabolism in anti-tumor therapy, especially in combination with ICIs. In particular, we highlight the expression mechanism of programmed cell death (ligand) 1 [PD-(L)1] in tumor cells and immune cells under reprogramming metabolism, and discuss in detail the potential of targeting key metabolic pathways to break resistance and improve the efficacy of ICIs based on results from current preclinical and clinical trials. Besides, we draw out biomarkers of potential predictive value in ICIs treatment from a metabolic perspective.

Delivery of miR-26a Using an Exosomes-Based Nanosystem Inhibited Proliferation of Hepatocellular Carcinoma.

Background: MicroRNA (abbreviated miRNA)-based treatment holds great promise for application as clinical antitumor therapy, but good carriers for delivery of the miRNA drug are lacking. Exosomes secreted by mesenchymal stem cells (MSCs) have proved to be safe, and exogenously modified exosomes may potentially represent an excellent drug delivery vehicle.Methods: In this study, we designed a delivery nano system using single-stranded variable fragment (scFv)-modified exosomes derived from human cord blood MSCs. Genetic engineering technology was used to obtain anti-Glypican 3 (GPC3) scFv-modified exosomes, which were then loaded with miR-26a mimics through electroporation.Results: Results of electron microscopy and dynamic light scattering indicated that the diameter of the drug-carrying exosomes was about 160 nm. Furthermore, anti-GPC3 scFv-modified exosomes effectively delivered miR-26a to GPC3-positive hepatocellular carcinoma cells, thereby inhibiting cell proliferation and migration by regulating the expression of downstream target genes of miR-26a. The exosomes-based nano system displayed favorable anti-tumor effect in vivo with no obvious side effects.Conclusion: Our data provided a new perspective for the use of exosome delivery systems for miRNA-based antitumor therapy.

Combination of Chidamide-Mediated Epigenetic Modulation with Immunotherapy: Boosting Tumor Immunogenicity and Response to PD-1/PD-L1 Blockade

Improving tumor immunogenicity is critical for increasing the responsiveness of triple-negative breast cancer (TNBC) to anti-PD-(L)1 treatment. Here, we verified that chidamide (CHI), an epigenetic modulator, could elicit immunogenic cell death within TNBC to enhance cancer immunogenicity and elicit an antitumor immune response. Additionally, CHI increased the expression level of PD-L1, MHC I, and MHC II on cancer cells, which contributed to T-cell recognition and PD-1/PD-L1 blockade therapy response. The synergistic antitumor efficacy of CHI and PD-L1 blockade therapy was further explored through liposomes co-delivering CHI and BMS-202 (a small-molecule PD-L1 inhibitor). The liposomes possessed good biocompatibility, security, and controllable drug release and endowed therapeutics drugs with favorable tumor accumulation. Furthermore, the drug-loaded liposomes could obviously boost the antitumor immunity of TNBC through CHI-enhanced tumor immunogenicity and BMS-202-mediated PD-L1 blockade, thereby effectively inhibiting the growth of primary and metastatic tumors with an inhibitory rate of metastasis of up to 96%. In summary, this work provided a referable and optional approach for clinical antitumor therapy based on the combination of an epigenetic modulator and PD-1/PD-L1 blockade therapy.

MK2206 attenuates atherosclerosis by inhibiting lipid accumulation, cell migration, proliferation, and inflammation.

Cardiovascular disease is a common comorbidity in patients with cancer, and the main leading cause of noncancer-related deaths in cancer survivors. Considering that current antitumor drugs usually induce cardiovascular injury, the quest for developing new antitumor drugs, especially those with cardiovascular protection, is crucial for improving cancer prognosis. MK2206 is a phase II clinical anticancer drug and the role of this drug in cardiovascular disease is still unclear. Here, we revealed that MK2206 significantly reduced vascular inflammation, atherosclerotic lesions, and inhibited proliferation of vascular smooth muscle cell in ApoE-/- mice in vivo. We demonstrated that MK2206 reduced lipid accumulation by promoting cholesterol efflux but did not affect lipid uptake and decreased inflammatory response by modulating inflammation-related mRNA stability in macrophages. In addition, we revealed that MK2206 suppressed migration, proliferation, and inflammation in vascular smooth muscle cells. Moreover, MK2206 inhibited proliferation and inflammation of endothelial cells. The present results suggest that MK2206, as a promising drug in clinical antitumor therapy, exhibits anti-inflammatory and antiatherosclerotic potential. This report provides a novel strategy for the prevention of cardiovascular comorbidities in cancer survivors.

Application of photodynamic therapy in cancer: challenges and advancements

Although great achievements have been made in the past decades in medicine, cancer remains a worldwide public health issue. Surgery is usually accompanied by shortcomings such as residual lesions and poor treatment effects, and the successive appearance of other treatment methods, such as radiotherapy and chemotherapy, has not changed the postoperative recurrence rate, toxicity, and side effects. However, the advent of photodynamic therapy has greatly improved this situation. Photodynamic therapy is an emerging tumor diagnosis and treatment technology with good application prospects, photodynamic therapy uses a specific wavelength of light to excite a photosensitizer to generate reactive oxygen species, damage tumor blood vessels and promote tumor cell apoptosis, exerting an antitumor effect. Photodynamic therapy has become a new clinical anti-tumor therapy due to its clear efficacy, few side effects, and easy use in combination with other therapies. In this review, we summarized the main mechanism, current challenges, and advancements of photodynamic therapy.

MicroRNA-26a inhibits multiple myeloma cell growth by suppressing cyclin-dependent kinase 6 expression.

MicroRNA-26a (miR-26a) has been reported to be involved in the tumorigenesis of several tumors, but its biological function and molecular mechanism in multiple myeloma (MM) are still unknown. In this study, we found that overexpression of miR-26a obviously inhibited MM cell growth, and delayed tumor growth in xenografts. Further studies showed that overexpression of miR-26a induced cell cycle arrest at G0/G1 phase in MM cells. MiR-26a mimic down-regulated the expression levels of CDK6 and E2F1, but up-regulated p53 and p21 expression. In contrast, overexpression of CDK6 decreased the effect of miR-26a mimic on MM cell survival. Moreover, miR-26a targeted CDK6 mRNA and thus suppressed CDK6 protein expression. Overexpression of miR-26a also enhanced the cytotoxic action of doxorubicin against MM. These results demonstrated that miR-26a was involved in the development of MM through regulating CDK6 signaling pathway, and indicated that miR-26a could be as a novel target for anti-tumor therapy in clinic as a single strategy or in combination with other anti-tumor drugs in MM.

Effect of chitosan based glycolipid-like nanocarrier in prevention of developing acquired drug resistance in tri-cycle treatment of breast cancer

Multi-cycle treatment strategies were frequently applied in anti-tumor therapy in clinic. However, numerous tumors developed drug resistance during this process, and few researches paid attention to the multi-cycle treatment process when a nano carrier was adopted. In this research, a glycolipid-like nanocarrier encapsulating anti-tumor drug doxorubicin (DOX) was adopted to perform a long term drug stimulation in vitro cell line and a tri-cycle treatment on xenograft tumors to explore its effect in process of developing drug resistance. As expected, tumors treated by free doxorubicin hydrochloride (DOX·HCl) showed obvious increase of P-glycoprotein, while for tumors treated by nanocarrier encapsulated doxorubicin, the P-glycoprotein level stayed low as untreated group. Further exploration found that MDR1 gene transcription got involved in the resistance induction mechanism as its mRNA levels in DOX·HCl stimulated cells were thousands of times of those in parent cell. It concluded that tri-cycle therapy with the glycolipid-like nanocarrier would not result in acquired drug resistance. These results also implied that nano-drug delivery possessed ability in avoiding acquiring drug resistance ability during long-term treatment which may have potential use in clinic.

Baicalein Protects Rats with Diabetic Cardiomyopathy Against Oxidative Stress and Inflammation Injury via Phosphatidylinositol 3-Kinase (PI3K)/AKT Pathway

BackgroundThe aim of this study was to explore the effect of baicalein on diabetic cardiomyopathy (DCM) rats and the mechanisms involved, and to determine the theoretical basis for clinical anti-tumor therapy.Material/MethodsDCM rat model was induced with a single injection of streptozotocin. Then, DCM rats were treated with baicalein alone or co-treated with baicalein and PI3K/Akt inhibitor. Myocardial pathological changes were detected by HE and Masson staining. The activities of SOD, GSH-Px, and MDA in myocardial tissue were measured by biochemical tests. The levels of TNF-α, IL-1β, and cTn-I were examined by ELISA. NADP+/NADPH ratio was measured with the NADP+/NADPH assay kit. RT-PCR was used to detect the levels of PI3K and Akt. The levels of Bax, Bcl-2, Caspase-3, GSK-3β, PI3K, and Akt were detected by Western blot.ResultsBaicalein could improve pathological injury. SOD and GSH-Px activity decreased while the level of MDA increased in myocardial tissue. Baicalein treatment enhanced SOD activity in a dose-dependent manner but markedly reduced MDA. Similar changes were observed in both serum inflammatory factors and the NADP+/NADPH ratio. After adding PI3K-Akt inhibitor, the levels of PI3K and Akt mRNA expression were significantly decreased, but were not significantly different from the DCM group. Levels of Bcl-2, PI3K, p-GSK-3β/GSK-3β, and p-Akt were decreased in the DCM group, while the levels of Bax and Caspase-3 were obviously increased.ConclusionsBaicalein can protect DCM rats against damage from oxidative stress and inflammation in myocardial tissue, and PI3K/Akt signaling pathway may be involved to mediating these effects.

Lumbrokinase/paclitaxel nanoparticle complex: potential therapeutic applications in bladder cancer.

BackgroundLumbrokinase (LK) is an enzyme complex with antithrombotic, antioxidant, antitumor, and immunomodulatory effects. It has been extensively studied and used in clinical anti-tumor therapy. However, its half-life is short, its bioavailability is low, and its toxicity and side effects are great, which greatly limit its clinical application. Therefore, LK is often combined with other drugs (such as immune agents, hormones, or Chinese herbal medicine) to reduce its dosage and side effects and to improve its anti-tumor effects.Methods and resultsHere, we described an LK/paclitaxel (PTX) nanocarrier based on poly(ethylene glycol)-b-(poly(ethylenediamine l-glutamate)-g-poly(ε-benzyoxycarbonyl-l-lysine)-r-poly(l-lysine)) (PEG-b-(PELG-g-(PZLL-r-PLL))). In the present study, LK and PTX were loaded by electrostatic and/or hydrophobic effects under mild conditions, thereby increasing the half-life and bioavailability of the drugs via the sustained release and enhancement of tumor site enrichment by the LK/PTX/PEG-b-(PELG-g-(PZLL-r-PLL)) complex through passive targeting. In this study, using bladder cancer cells (J82 cells) and rat bladder cancer model as the object, the structure of the nanocarrier, the relationship between drugs composition and antitumor properties were systematically studied.ConclusionWe propose that the block copolymer PEG-b-(PELG-g-(PZLL-r-PLL)) may function as a potent nanocarrier for augmenting anti-bladder cancer pharmacotherapy, with unprecedented clinical benefits.

Inhibitory effect of Gypsophila oldhamiana gypsogenin on NCI-N87 gastric cancer cell line

Gastric cancer is one of the major cancers threatening people’s lives worldwide. Recent studies showed that Gypsophila oldhamiana gypsogenin (GOG) exhibits inhibition effects and cytotoxic activities against different cell lines. The aim of this study was to explore the inhibitory effect and dose response of GOG on gastric cancer cell line NCI-N87 and to provide the theoretical basis for clinical anti-tumor therapy. The experiments showed that GOG could inhibit the proliferation and promote the apoptosis of human gastric cancer cell line NCI-N87. GOG could dose dependently reduce the expression of vascular endothelial growth factor (VEGF) and matrix metalloprotein (MMP)-9 proteins, while increase the expression of caspase-3 and Bax proteins. Compared with model group, tumor volume (TV), relative tumor volume (RTV), and relative tumor increment rate (T/C) in the mid-dose and high-dose GOG groups were significantly reduced, and the inhibition rate (IR) in the two groups was significantly increased. The results indicated that the anti-tumor effect of GOG on gastric cancer cells may be related with the downregulation of caspase-3 and Bax and the upregulation of MMP-9 and VEGF.

Optimization of antitumor treatment conditions for transcutaneous CO2 application: An in vivo study.

Carbon dioxide (CO2) therapy can be applied to treat a variety of disorders. We previously found that transcutaneous application of CO2 with a hydrogel decreased the tumor volume of several types of tumors and induced apoptosis via the mitochondrial pathway. However, only one condition of treatment intensity has been tested. For widespread application in clinical antitumor therapy, the conditions must be optimized. In the present study, we investigated the relationship between the duration, frequency, and treatment interval of transcutaneous CO2 application and antitumor effects in murine xenograft models. Murine xenograft models of three types of human tumors (breast cancer, osteosarcoma, and malignant fibrous histiocytoma/undifferentiated pleomorphic sarcoma) were used to assess the antitumor effects of transcutaneous CO2 application of varying durations, frequencies, and treatment intervals. In all human tumor xenografts, apoptosis was significantly induced by CO2 treatment for ≥10min, and a significant decrease in tumor volume was observed with CO2 treatments of >5min. The effect on tumor volume was not dependent on the frequency of CO2 application, i.e., twice or five times per week. However, treatment using 3- and 4-day intervals was more effective at decreasing tumor volume than treatment using 2- and 5-day intervals. The optimal conditions of transcutaneous CO2 application to obtain the best antitumor effect in various tumors were as follows: greater than 10 min per application, twice per week, with 3- and 4-day intervals, and application to the site of the tumor. The results suggest that this novel transcutaneous CO2 application might be useful to treat primary tumors, while mitigating some side effects, and therefore could be safe for clinical trials.