Mild Temperature Hyperthermia Research Articles

NIR-Light-Triggered Mild-Temperature Hyperthermia to Overcome the Cascade Cisplatin Resistance for Improved Resistant Tumor Therapy.

Currently, cisplatin resistance has been recognized as a multistep cascade process for its clinical chemotherapy failure. Hitherto, it remains challenging to develop a feasible and promising strategy to overcome the cascade drug resistance (CDR) issue for achieving fundamentally improved chemotherapeutic efficacy. Herein, a novel self-assembled nanoagent is proposed, which is constructed by Pt(IV) prodrug, cyanine dye (cypate), and gadolinium ion (Gd3+), for systematically conquering the cisplatin resistance by employing near-infrared (NIR) light activated mild-temperature hyperthermia in tumor targets. The proposed nanoagents exhibit high photostability, GSH/H+-responsive dissociation, preferable photothermal conversion, and enhanced cellular uptake performance. In particular, upon 785-nm NIR light irradiation, the generated mild temperature of ≈ 43 °C overtly improves the cell membrane permeability and drug uptake, accelerates the disruption of intracellular redox balance, and apparently enhances the formation of Pt-DNA adducts, thereby effectively overcoming the CDR issue and achieves highly improved therapeutic efficacy for cisplatin-resistant tumor ablation.

Smart "Thrombus": Self-Localizing UCST-Type Microcage.

Embolization is often used to block blood supply for controlling the growth of fibroids and malignant tumors, but limited by embolic agents lacking spontaneous targeting and post-treatment removal. So we first adopted nonionic poly(acrylamide-co-acrylonitrile) with an upper critical solution temperature (UCST) to build up self-localizing microcages by inverse emulsification. The results showed that these UCST-type microcages behaved with the appropriate phase-transition threshold value around 40 °C, and spontaneously underwent an expansion-fusion-fission cycle under the stimulus of mild temperature hyperthermia. Given the simultaneous local release of cargoes, this simple but smart microcage is expected to act as a multifunctional embolic agent for tumorous starving therapy, tumor chemotherapy, and imaging.

The Efficacy of Radiation is Enhanced by Metformin and Hyperthermia Alone or Combined Against FSaII Fibrosarcoma in C3H Mice.

The effects of mild-temperature hyperthermia (MTH) and metformin, alone or in combination, on the efficacy of high-dose hypofractionated radiation against experimental tumors were investigated. FSaII fibrosarcoma grown subcutaneously in the hind legs of C3H mice was irradiated with a single 15 Gy dose using a 60Co irradiator. The radio frequency capacitive method was used to heat the tumors at 41.0°C for 30 min. Metformin was intraperitoneally (i.p.) administered daily to tumor-bearing mice at a dose of 150 mg/kg. The expression levels of hypoxia-inducible factor-1α (HIF-1α), vascular endothelial growth factor (VEGF), and programmed cell death-ligand 1 (PD-L1) were determined by immunohistochemical staining of the excised tumor tissues. The apoptosis of tumor cells in vivo was quantified by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining and cleaved caspase-3 staining of the excised tumor tissues. Irradiation of tumors markedly increased the expression of HIF-1α, VEGF, and PD-L1, and MTH and metformin used either alone or in combination significantly abrogated the radiation-induced upregulation of these proteins. MTH and metformin alone or combined increased the radiation-induced apoptosis in tumor cells and enhanced the radiation-induced suppression of tumor growth. The findings indicated that the increased tumor response to 15 Gy irradiation by MTH and metformin alone or in combination was due, in part, to the abrogation of the radiation-induced upregulation of HIF-1α and its downstream targets VEGF and PD-L1.

Thermal analysis of different shape nanoparticles on hyperthermia therapy on breast cancer in a porous medium: A fractional model

Cancer is clearly a major cause of disease and fatality around the world, yet little is known about how it starts and spreads. In this study, a model in mathematical form of breast cancer guided by a system of (ODE’S) ordinary differential equations is studied in depth to examine the thermal effects of various shape nanoparticles on breast cancer hyperthermia therapy in the existence of a porous media with fractional derivative connection, when utilizing microwave radiative heating. The unsteady state is determined precisely using the Laplace transform approach to crop a more decisive examination of temperature dissemination of blood temperature inside the breast tissues. Durbin's and Zakian's techniques are used to find Laplace inversion. Mild temperature hyperthermia is used in the treatment, which promotes cell death by increasing cell nervousness to radiation therapy and flow of blood in tumor. In the graphical findings, we can witness the distinct behavior of hyperthermia therapy on tumor cells by applying various metabolic heat generation rates across various time intervals to attain the optimal therapeutic temperature point. Particularly, we used graphs to visualize the behavior of different Nanoparticles with different shaped during hypothermia therapy. In comparison to other nanoparticles and shapes, it demonstrates that gold nanoparticles with a platelet shape are the best option for improving heat transmission. Which assess of heat transfer up to 16.412%.

A Fractional Analysis of Hyperthermia Therapy on Breast Cancer in a Porous Medium along with Radiative Microwave Heating

Cancer is a prominent source of mortality and morbidity globally, but little is known about how it develops and spreads. Tumor cells are unable to thrive in high-temperature environments, according to recent research. Hyperthermia is the name for this therapy method. This study provides insights into hyperthermia therapy on breast cancer in the presence of a porous material with fractional derivative access when using radiative microwave heating. The mathematical model is formulated by PDE, while the time-fractional Caputo derivative is applied to make our equation more general as compared to the classical model. To produce a more efficient analysis of blood temperature distributions inside the tissues of the breast, the unsteady state is calculated by using the Laplace transform technique. The Laplace inversion is found by Durbin’s and Zakian’s algorithms. The treatment involves mild temperature hyperthermia, which causes cell death by enhancing cell sensitivity to radiation therapy and blood flow in the tumor. The variations of different parameters to control the temperate profile during therapy are discussed; we can also see how a fractional parameter makes our study more realistic for further experimental study.

Effects of Heat Therapy on Prostate Cancer Cells Subjected to 4 Gy Radiation

Background Despite many advancements in treatment options, radiation therapy remains a common treatment for individuals diagnosed with prostate cancer. However, radiation resistance presents a significant challenge for many patients. Due to its numerous effects on cancer cell growth and survival, heat therapy has been studied as a potential mechanism to improve radiation efficacy. However, the modality of heat therapy varies widely between studies, and the majority of heat therapy research relies on non-physiological temperatures (>43º C). We hypothesized that mild temperature hyperthermia would improve the efficacy of radiation of prostate cancer cells in vitro. Methods Clonogenic survival was assessed using human prostate cancer (PC-3) cells in vitro. Cells were grown in tissue culture flasks maintained in a 37º C incubator with 5% CO2 and randomized into 3 groups: normothermic (NT; n=8), acute hyperthermia (HTA; n=8), and chronic hyperthermia (HTC; n=8). NT cells were maintained in a normal incubator until radiation. For heat treatments, HTA cells were heated to 41.0º C in a separate incubator for 1 h immediately prior to radiation. HTC cells were heated to 41.0º C in a separate incubator for 1 h each session, for a total of 3 heat treatments, each separated by 48 h, with the final heat treatment occurring 24 h prior to radiation. Immediately following a single dose of 4 Gy radiation, each group of cells were counted and plated into 60 mm culture dishes at densities of both 500 cells/plate and 1000 cells/plate, with 5 replicates plated per density. Following 8 days of incubation, cells were fixed and stained and colonies of greater than 50 cells were counted. Results The survival fractions were determined from the average of the two plating densities. Clonogenic cell survival was significantly reduced in HTA vs. NT (11.6% ± 2% vs. 19.3% ± 1%, p<0.05) and in HTC vs. NT (8.3% ± 2% vs. 19.3% ± 1%, p<0.05). Cell survival between HTA and HTC was not different (p>0.05). Conclusions These results suggest that both acute and chronic mild hyperthermia improve the efficacy of 4 Gy radiation in PC-3 cells. While exact mechanisms are yet to be elucidated, it is thought that hyperthermia at lower temperature induces DNA damage, inhibits DNA damage repair, or alters cell cycle progression, which individually or in combination with one another, may potentiate the effects of radiation. Mild temperature hyperthermia prior to radiation may be an effective neo-adjuvant to increase the radiosensitivity of prostate cancer cells.

Exploring the rationale for thermotherapy in COVID-19

Increased transmissibility of the pandemic severe acute respiratory coronavirus 2 (SARS-CoV-2) has been noted to occur at lower ambient temperatures. This is seemingly related to a better replication of most respiratory viruses, including SARS-CoV-2, at lower-than-core body temperatures (i.e., 33 °C vs 37 °C). Also, intrinsic characteristics of SARS-CoV-2 make it a heat-susceptible pathogen. Thermotherapy has successfully been used to combat viral infections in plants which could otherwise result in great economic losses; 90% of viruses causing infections in plants are positive-sense single-stranded ribonucleic acid (+ssRNA) viruses, a characteristic shared by SARS-CoV-2. Thus, it is possible to envision the use of heat-based interventions (thermotherapy or mild-temperature hyperthermia) in patients with COVID-19 for which moderate cycles (every 8–12 h) of mild-temperature hyperthermia (1–2 h) have been proposed. However, there are potential safety and mechanistic concerns which could limit the use of thermotherapy only to patients with mild-to-moderate COVID-19 to prevent disease progression rather than to treat patients who have already progressed to severe-to-critical COVID-19. Here, we review the characteristics of SARS-CoV-2 which make it a heat-susceptible virus, potential host mechanisms which could be enhanced at higher temperatures to aid viral clearance, and how thermotherapy could be investigated as a modality of treatment in patients with COVID-19 while taking into consideration potential risks.

Usefulness of combination with both continuous administration of hypoxic cytotoxin and mild temperature hyperthermia in boron neutron capture therapy in terms of local tumor response and lung metastatic potential

Purpose: To evaluate the usefulness of combined treatment with both continuous administration of a hypoxic cytotoxin, tirapazamine (TPZ) and mild temperature hyperthermia (MTH) in boron neutron capture therapy (BNCT) in terms of local tumor response and lung metastatic potential, referring to the response of intratumor quiescent (Q) cells.Materials and methods: B16-BL6 melanoma tumor-bearing C57BL/6 mice were continuously given 5-bromo-2’-deoxyuridine (BrdU) to label all proliferating (P) cells. The tumors received reactor thermal neutron beam irradiation following the administration of a 10B-carrier (L-para-boronophenylalanine-10B (BPA) or sodium mercaptoundecahydrododecaborate-10B (BSH)) after single intraperitoneal injection of an acute hypoxia-releasing agent (nicotinamide), MTH (40 °C for 60 min), and 24-h continuous subcutaneous infusion of TPZ or combined treatment with both TPZ and MTH. Immediately after irradiation, cells from some tumors were isolated and incubated with a cytokinesis blocker. The responses of the Q and total (=P + Q) tumor cell populations were assessed based on the frequency of micronuclei using immunofluorescence staining for BrdU. In other tumor-bearing mice, 17 days after irradiation, macroscopic lung metastases were enumerated.Results: BPA-BNCT increased the sensitivity of the total tumor cell population more than BSH-BNCT. However, the sensitivity of Q cells treated with BPA was lower than that of BSH-treated Q cells. With or without a 10B-carrier, combination with continuously administered TPZ with or without MTH enhanced the sensitivity of the both total and Q cells, especially Q cells. Even without irradiation, nicotinamide treatment decreased the number of lung metastases. With irradiation, BPA-BNCT, especially in combination with combined treatment with both TPZ and MTH as well as nicotinamide treatment, showed the potential to reduce the number more than BSH-BNCT.Conclusion: BSH-BNCT combined with TPZ with or without MTH improved local tumor control, while BPA-BNCT in combination with both TPZ and MTH as well as nicotinamide is thought to reduce the number of lung metastases. It was elucidated that control of the chronic hypoxia-rich Q cell population in the primary solid tumor has the potential to impact the control of local tumors as a whole and that control of the acute hypoxia-rich total tumor cell population in the primary solid tumor has the potential to impact the control of lung metastases.

Combined Hyperthermia and Radiation Therapy for Treatment of Hepatocellular Carcinoma.

Background:There is no doubt that hyperthermia is one of the powerful radiosensitizers. Finding a proper mechanism working in hyperthermia/radiation combination is still pronounced challenge.Objectives:This study is focusing on the anti-cancer activities (anti-proliferative, anti-angiogenic and antiapoptotic) of thermoradiotherapy. Materials and Methods:Liver cancer cell line (HepG2) was treated by 37oC, 40oC and 43oC hyperthermia degrees combined with three radiation doses (2 Gy, 4 Gy and 8 Gy) for 24, 48 and 72 hrs. Cell viability, apoptotic/necrotic cell screening, apoptotic (BAX and FasL) and antiapoptotic (BCL-2 and GRP78) genes, and pro-angiogenic mediators [vascular endothelial- (VEGF) and Platelet derived-growth factors (PDGF) ware investigated. Results:Our data showed that 40oC temperature combined with 4 Gy radiation gives a significant decrease (p<0.05) in cell viability. Maximum cytotoxicity was reported 48 hr post-treatment followed by slight restoration of cell viability after 72 hr. Compared with untreated cells, only 5% of viable cells with a high percentage of apoptotic (31%) and necrotic (63%) cells were demonstrated in 40oC/4 Gy/48 hr group. Expression of pro-apoptotic genes (BAX and FasL) were increased after hyperthermia with apparent elevation in 40oC/4 Gy/48 hr group coincides with moderate expression of antiapoptotic BCL-2 and GRP78 genes. A significant reduction (p<0.001; p<0.05) in VEGF and PDGF levels; respectively was shown at 40oC/4 Gy/48 hr group. Conclusions:This pilot study proposed 40oC mild temperature hyperthermia as a favorable hyperthermal condition with 4 Gy radiotherapy in HCC treatment. A further research has to be performed considering an application of more than one session of radiothermal therapy at 40oC/4 Gy for total abrogation of cancer cells.

Clinical and dosimetric evaluation of recurrent breast cancer patients treated with hyperthermia and radiation

Background: Treatment for locally recurrent breast cancer poses a significant challenge because the benefits in local control must be weighed against the increased risk of side effects of the treatment. Frequently, patients have been heavily pre-treated with radiation and several types of chemotherapy. Moreover, they often present with large volumes of bulky disease, further complicating management. Hyperthermia can be used to improve the efficacy of radiation, particularly in the setting of recurrent disease.Methods: We reviewed our clinical and dosimetric experience of breast cancer patients who received hyperthermia and radiation for recurrent breast cancer from 2011 to 2017. Thirty-six patients were treated with hyperthermia and radiation. Median follow-up was 11 months. Thirty patients (83.3%) received prior radiotherapy. The most commonly used radiation fraction scheme was 32 Gy in 8 fractions. The median radiation dose at the time of recurrence was 35.5 Gy (range 20–64 Gy). Mild temperature hyperthermia was delivered two times per week.Results: The median repeat radiation volume was 574 cc (range 11–3620 cc). Electrons, conventional photons, and IMRT radiation techniques were used. IMRT was used for large and complex treatment volumes and showed acceptable doses to organs at risk. The overall response rate was 61.1%. Complete response was observed in 17 patients (47.2%), partial response in 5 patients (13.9%), stable disease in 11 patients (30.6%), and progressive disease in 3 patients (8.3%). Twenty-six patients experienced acute grade 1 and 2 toxicities, primarily pain and erythema; and 26 experienced long-term grade 1 and 2 toxicities, mainly hyperpigmentation and lymphedema. Three patients developed new ulcerations that healed with conservative management. One patient developed pulmonary fibrosis resulting in mild dyspnea on exertion.Conclusion: Hyperthermia and radiation provide good local control with a favorable side effect profile. Thermoradiotherapy may be offered to patients with recurrent breast cancer, including those with extensive volumes of disease.

Role of HIF-1α in response of tumors to a combination of hyperthermia and radiation in vivo

Purpose: Mild temperature hyperthermia (MTH) increases blood flow and oxygenation in tumours. On the other hand, high-dose-per-fraction irradiation damages blood vessels, decreases blood flow and increases hypoxia in tumours. The radiation-induced hypoxia in tumours activates hypoxia-inducible factor-1α (HIF-1α) and its target genes, such as vascular endothelial growth factor (VEGF), promoting revascularization and recurrence. In the present study, we examined the hypothesis that MTH inhibits radiation-induced upregulation of HIF-1α and its target genes by increasing tumour oxygenation.Materials and methods: FSaII fibrosarcoma tumours grown subcutaneously in the legs of C3H mice were used. Tumours were irradiated with 15 Gy using a 60Co irradiator or heated at 41 °C for 30 min using an Oncothermia heating unit. Blood perfusion and hypoxia in tumours were assessed with Hoechst 33342 and pimonidazole staining, respectively. Expression levels of HIF-1α and VEGF were determined using immunohistochemical techniques. Apoptosis of tumour cells was quantitated via TUNEL staining and the effects of treatments on tumour growth rate were assessed by measuring tumour diameters.Results: Irradiation of FSaII tumours with a single dose of 15 Gy led to significantly decreased blood perfusion, increased hypoxia and upregulation of HIF-1α and VEGF. On the other hand, MTH at 41 °C for 30 min increased blood perfusion and tumour oxygenation, thereby suppressing radiation-induced HIF-1α and VEGF in tumours, leading to enhanced apoptosis of tumour cells and tumour growth delay.Conclusion: MTH enhances the anti-tumour effect of high-dose irradiation, at least partly by inhibiting radiation-induced upregulation of HIF-1α.

Gadolinium-doped iron oxide nanoparticles induced magnetic field hyperthermia combined with radiotherapy increases tumour response by vascular disruption and improved oxygenation

The gadolinium-doped iron oxide nanoparticles (GdIONP) with greater specific power adsorption rate (SAR) than Fe3O4 was developed and its potential application in tumour therapy and particle tracking were demonstrated in transgenic adenocarcinoma of the mouse prostate C1 (TRAMP-C1) tumours. The GdIONPs accumulated in tumour region during the treatment could be clearly tracked and quantified by T2-weighted MR imaging. The therapeutic effects of GdIONP-mediated hyperthermia alone or in combination with radiotherapy (RT) were also evaluated. A significant increase in the tumour growth time was observed following the treatment of thermotherapy (TT) only group (2.5 days), radiation therapy only group (4.5 days), and the combined radio-thermotherapy group (10 days). Immunohistochemical staining revealed a reduced hypoxia region with vascular disruption and extensive tumour necrosis following the combined radio-thermotherapy. These results indicate that GdIONP-mediated hyperthermia can improve the efficacy of RT by its dual functions in high temperature (temperature greater than 45 °C)-mediated thermal ablation and mild-temperature hyperthermia (MTH) (temperature between 39 and 42 °C)-mediated reoxygenation.

Effect of Tirapazamine, Metformin or Mild Hyperthermia on Recovery From Radiation-Induced Damage in Pimonidazole-Unlabeled Quiescent Tumor Cells.

BackgroundThe aim of the study was to examine the effect of tirapazamine (TPZ) on recovery from radiation-induced damage in pimonidazole-unlabeled quiescent (Q) tumor cells compared with that of metformin (Met) or mild temperature hyperthermia (MTH).MethodsProliferating (P) cells in EL4 tumors were labeled by continuous 5-bromo-2’-deoxyuridine (BrdU) administration. Tumors received γ-rays at 1 h after pimonidazole administration followed by Met or TPZ treatment or MTH. Twenty-four hours later, the responses of Q and total (P + Q) cells and those of the pimonidazole-unlabeled cells were assessed with micronucleation and apoptosis frequencies using immunofluorescence staining for BrdU and apoptosis frequency using immunofluorescence staining for pimonidazole, respectively.ResultsWith γ-rays only, the pimonidazole-unlabeled cell fraction showed significantly enhanced radio-sensitivity compared with the whole cell fraction more remarkably in Q than total cells. However, a significantly greater decrease in radio-sensitivity in the pimonidazole-unlabeled than the whole cell fraction, evaluated using a delayed assay, was more clearly observed in Q than total cells. Post-irradiation MTH or Met treatment more clearly repressed the decrease in radio-sensitivity in the Q than total cells. Post-irradiation TPZ administration produced a large radio-sensitizing effect on both total and Q cells, especially on Q cells. In pimonidazole-unlabeled cell fractions in both total and Q cells, TPZ suppressed the reduction in sensitivity much more efficiently than MTH or Met without any radio-sensitizing effect.ConclusionPost-irradiation TPZ administration has the potential to both suppress recovery from radiation-induced damage and enhance the radio-sensitivity both in total and Q tumor cells. Post-irradiation TPZ administration may be useful for controlling tumors.

Photoinduced Mild Hyperthermia and Synergistic Chemotherapy by One-Pot-Synthesized Docetaxel-Loaded Poly(lactic-co-glycolic acid)/Polypyrrole Nanocomposites.

Mild hyperthermia has shown great advantages when combined with chemotherapy. The development of a multifunctional platform for the integration of mild hyperthermia capability into a drug-loading system is a key issue for cancer multimodality treatment application. Herein, a facile one-pot in situ fabrication protocol of docetaxel (DTX)-loaded poly(lactic-co-glycolic acid) (PLGA)/polypyrrole (PPy) nanocomposites was developed. While the PLGA nanoparticles (NPs) allow efficient drug loading, the PPy nanobulges embedded within the surface of the PLGA NPs, formed by in situ pyrrole polymerization without the introduction of other template agents, can act as ideal mediators for photoinduced mild hyperthermia. Physiochemical characterizations of the as-prepared nanocomposites, including structure, morphology, photothermal effects, and an in vitro drug release profile, were systematically investigated. Further, 2-deoxyglucose-terminated poly(ethylene glycol) (PEG) was anchored onto the surface of the nanocomposites to endow the nanoplatform with targeting ability to tumor cells, which resulted in a 17-fold increase of NP internalization within human breast cancer cells (MCF-7) as competed with PEG-modified nanocomposites. Mild hyperthermia can be successfully mediated by the nanoplatform, and the temperature can be conveniently controlled by careful modulation of the PPy contents within the nanocomposites or the laser power density. Importantly, we have demonstrated that MCF-7 cells, which are markedly resistant to heat treatment of traditional water-bath hyperthermia, became sensitive to the PLGA/PPy nanocomposite-mediated photothermal therapy under the same mild-temperature hyperthermia. Moreover, DTX-loaded PLGA/PPy-nanocomposite-induced mild hyperthermia can strongly enhance drug cytotoxicity to MCF-7 cells. Under the same thermal dose, photoinduced hyperthermia can convert the interaction between hyperthermia and drug treatment from interference to synergism. This is the first report on the one-pot synthesis of PLGA/PPy nanocomposites by in situ pyrrole polymerization, and such a multifunctional nanoplatform is demonstrated as a high-potential agent for photoinduced mild hyperthermia and enhanced chemotherapy.

Therapeutic potential of using the vascular disrupting agent OXi4503 to enhance mild temperature thermoradiation

Purpose: The response of tissues to radiation with mild temperature hyperthermia is dependent on the interval between the two modalities. This study investigated the effect that the vascular disrupting agent OXi4503 had on this time-interval interaction.Methods: The normal right rear foot of female CDF1 mice or foot-implanted C3H mammary carcinomas were locally irradiated (230 kV X-rays) and heated (41.5 °C for 60 min) by foot immersion in a water bath. OXi4503 (50 mg/kg) was injected intraperitoneally 1.5 h before irradiating. Irradiation was performed either in the middle of the heating period (simultaneous treatment) or at 1 or 4 h prior to starting the heating (sequential treatments). Response was the percentage of mice showing local tumour control at 90 days or skin moist desquamation between days 11–23. From the radiation dose response curves the dose producing tumour control (TCD50) or moist desquamation (MDD50) in 50% of mice was calculated.Results: The TCD50 and MDD50 values for radiation alone were 54 Gy and 29 Gy, respectively. Simultaneously heating the tissues enhanced radiation response, the respective TCD50 and MDD50 values being significantly (chi-square test, p < 0.05) reduced to 33 Gy and 14 Gy. A smaller enhancement was obtained with a sequential treatment in both tissues. OXi4503 enhanced the radiation response of tumour and skin. Combined with radiation and heat, the only effect was in tumours where OXi4503 prevented the decrease in sensitisation seen with the sequential treatment.Conclusion: Combining OXi4503 with a sequential radiation and heat treatment resulted in a 1.4-fold therapeutic gain.

Abstract 850: Vascular based strategies for enhancing tumour response to radiation administered in a stereotactic schedule

Abstract Background: Various agents that influence tumour vasculature have been shown to be capable of enhancing tumour response to radiation administered as single treatments or in limited fractionated schedules. The aim of this pre-clinical study was to investigate the potential of such agents to improve tumour response to a clinically relevant stereotactic radiation schedule. Material and methods: A C3H mammary carcinoma grown in the right rear foot of female CDF1 mice was used in all experiments. Treatments were performed in restrained non-anaesthetised animals when tumours had reached 200 cubic mm in size. Tumours were locally irradiated (230 kV x-rays) with 3 x 15 Gy (each fraction given with an interval of 2-3 days over a one week period). The vascular based strategies were the drug OXi4503 (10 mg/kg intraperitoneally injected 1 hour after irradiating) or mild temperature hyperthermia (MTH; 41.5 degrees C for 60 minutes starting 4 hours after irradiating). OXi4503 or MTH were given either with each of the 3 x 15 Gy irradiations or only the final 15 Gy treatment. Three days after the final irradiation the tumours were subjected to a clamped top-up dose which involved giving graded radiation doses with the tumour bearing leg clamped for 5 minutes before and during irradiation. The percentage of mice in each treatment group showing local tumour control 90 days after irradiating was recorded and the TCD50 values (radiation dose to control 50% of tumours) estimated from the clamped top-up radiation dose response curves. A Chi-squared test (p&amp;lt;0.05) was used to determine significant differences between TCD50 values. Results: The clamped top-up TCD50 value (with 95% confidence intervals) following 3 x 15 Gy was 30 Gy (23-38). This was significantly reduced to 12 Gy (8-19) if OXi4503 was given with all three 15 Gy irradiations and to the same 12 Gy (6-25) value when injected with only the last radiation treatment. Similar effects were seen with 3 or 1 MTH treatments; the respective TCD50 values being 9 Gy (5-17) and 10 Gy (7-15). Combining OXi4503 with MTH, but only administering them with the final 15 Gy irradiation, gave the greatest enhancement with the TCD50 value being 2 Gy (1-9). Conclusions: Vascular based strategies are very effective at improving the efficacy of radiation given in a stereotactic schedule. Surprisingly, this enhancement was independent of the frequency at which these vascular modifiers were administered. The greatest effect was observed by combining complimentary vascular modifying agents. Supported by grants from the Danish Cancer Society and the Danish Council for Independent Research: Medical Sciences. Citation Format: Michael R. Horsman, Thomas Wittenborn. Vascular based strategies for enhancing tumour response to radiation administered in a stereotactic schedule. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 850. doi:10.1158/1538-7445.AM2014-850

Effect of bevacizumab combined with boron neutron capture therapy on local tumor response and lung metastasis.

The aim of the present study was to evaluate the effect of bevacizumab on local tumor response and lung metastatic potential during boron neutron capture therapy (BNCT) and in particular, the response of intratumor quiescent (Q) cells. B16-BL6 melanoma tumor-bearing C57BL/6 mice were continuously administered bromodeoxyuridine (BrdU) to label all proliferating (P) tumor cells. The tumors were irradiated with thermal neutron beams following the administration of a 10B-carrier [L-para-boronophenylalanine-10B (BPA) or sodium mercaptoundecahydrododecaborate-10B (BSH)], with or without the administration of bevacizumab. This was further combined with an acute hypoxia-releasing agent (nicotinamide) or mild temperature hyperthermia (MTH, 40°C for 60 min). Immediately following the irradiation, cells from certain tumors were isolated and incubated with a cytokinesis blocker. The responses of the Q cells and the total (P+Q) cell populations were assessed based on the frequency of micronuclei using immunofluorescence staining for BrdU. In other tumor-bearing mice, 17 days following irradiation, lung metastases were enumerated. Three days following bevacizumab administration, the sensitivity of the total tumor cell population following BPA-BNCT had increased more than that following BSH-BNCT. The combination with MTH, but not with nicotinamide, further enhanced total tumor cell population sensitivity. Regardless of the presence of a 10B-carrier, MTH enhanced the sensitivity of the Q cell population. Regardless of irradiation, the administration of bevacizumab, as well as nicotinamide treatment, demonstrated certain potential in reducing the number of lung metastases especially in BPA-BNCT compared with BSH-BNCT. Thus, the current study revealed that BNCT combined with bevacizumab has the potential to sensitize total tumor cells and cause a reduction in the number of lung metastases to a similar level as nicotinamide.

Significance of Fractionated Administration of Thalidomide Combined With γ-Ray Irradiation in Terms of Local Tumor Response and Lung Metastasis.

BackgroundThe aim of this study was to evaluate the significance of fractionated administration of thalidomide combined with γ-ray irradiation in terms of local tumor response and lung metastatic potential, referring to the response of intratumor quiescent (Q) cells.MethodsB16-BL6 melanoma tumor-bearing C57BL/6 mice were continuously given 5-bromo-2’-deoxyuridine (BrdU) to label all proliferating (P) cells. The tumor-bearing mice then received γ-ray irradiation after thalidomide treatment through a single or two consecutive daily intraperitoneal administrations up to a total dose of 400 mg/kg in combination with an acute hypoxia-releasing agent (nicotinamide) or mild temperature hyperthermia (MTH). Immediately after the irradiation, cells from some tumors were isolated and incubated with a cytokinesis blocker. The responses of the Q and total (= P + Q) cell populations were assessed based on the frequency of micronuclei using immunofluorescence staining for BrdU. In other tumor-bearing mice, 17 days after irradiation, macroscopic lung metastases were enumerated.ResultsThalidomide raised the sensitivity of the total cell population more remarkably than Q cells in both single and daily administrations. Daily administration of thalidomide elevated the sensitivity of both the total and Q cell populations, but especially the total cell population, compared with single administration. Daily administration, especially combined with MTH, decreased the number of lung metastases.ConclusionDaily fractionated administration of thalidomide in combination with γ-ray irradiation was thought to be more promising than single administration because of its potential to enhance local tumor response and repress lung metastatic potential.

Usefulness of Daily Fractionated Administration of Wortmannin Combined With gamma-Ray Irradiation in Terms of Local Tumor Response and Lung Metastasis

Background: To evaluate the usefulness of fractionated administration of wortmannin combined with gamma-ray irradiation in terms of local tumor response and lung metastatic potential, referring to the response of intratumor quiescent (Q) cells. Methods: B16-BL6 melanoma tumor-bearing C57BL / 6 mice were continuously given 5-bromo-2 ' -deoxyuridine (BrdU) to label all proliferating (P) cells. The tumor-bearing mice then received gamma -ray irradiation after wortmannin treatment through a single or 4 consecutive daily intraperitoneal administrations up to a total dose of 4 mg / kg in combination with an acute hypoxia-releasing agent (nicotinamide) or mild temperature hyperthermia (MTH). Immediately after the irradiation, cells from some tumors were isolated and incubated with a cytokinesis blocker. The responses of the Q and total ( = P + Q) cell populations were assessed based on the frequency of micronuclei using immunofluorescence staining for BrdU. In other tumor-bearing mice, 17 days after irradiation, macroscopic lung metastases were enumerated. Results: Wortmannin raised the sensitivity of Q cells more remarkably than the total cell population in both single and daily administrations. Daily administration of wortmannin elevated the sensitivity of both the total and Q cell populations, but especially the total cell population, compared with single administration. Daily administration, especially combined with MTH, decreased the number of lung metastases. Conclusion: Daily fractionated administration of wortmannin in combination with gamma -ray irradiation was thought to be more promising than single administration because of its potential to enhance local tumor response and repress lung metastatic potential. World J Oncol. 2013;4(1):26-36 doi: https://doi.org/10.4021/wjon640w

Common gene expression patterns responsive to mild temperature hyperthermia in normal human fibroblastic cells

Purpose: Heat stress induces complex cellular responses, and its detailed molecular mechanisms still remain to be clarified. The objective of this study was to investigate the molecular mechanisms underlying cellular responses to mild hyperthermia (MHT) in normal human fibroblastic (NHF) cells.Materials and methods: Cells were treated with MHT (41°C, 30 min) and then cultured at 37°C. Gene expression was determined by the GeneChip® system and bioinformatics tools.Results: Treatment of the NHF cell lines, Hs68 and OUMS-36, with MHT did not affect the cell viability or cell cycle. In contrast, many probe sets were differentially expressed by >1.5-fold in both cell lines after MHT treatment. Of the 1,196 commonly and differentially expressed probe sets analysed by k-means clustering, three gene clusters, Up-I, Down-I and Down-II, were observed. Interestingly, two gene networks were obtained from the up-regulated genes in cluster Up-I. The gene network E contained DDIT3 and HSPA5 and was mainly associated with the biological process of endoplasmic reticulum stress, while the network S contained HBEGF and LIF and was associated with the biological process of cell survival. Eighteen genes were validated by quantitative real-time polymerase chain reaction, consistent with the microarray data, in four kinds of NHF cells.Conclusions: Common genes that were differentially expressed and/or acted within a gene network in response to MHT in NHF cells were identified. These findings provide the molecular basis for a further understanding of the mechanisms of the MHT response in NHF cells.