Hypoxic Cell Sensitizer Research Articles

Nanomedicines with high drug availability and drug sensitivity overcome hypoxia-associated drug resistance

Tumor hypoxia heterogeneity, a hallmark of the tumor microenvironment, confers resistance to conventional chemotherapy due to insufficient drug availability and drug sensitivity in hypoxic regions. To overcome these challenges, we develope a nanomedicine, NPHPaPN, constructed with hyaluronic acid (HA) grafted with cisplatin prodrug and PEG-azobenzene for hypoxia-responsive PEG shell deshielding and loaded with a DNA damage repair inhibitor (NERi). After arriving at the tumor site, NPHPaPN deshields the PEG shell in response to hypoxia due to the enzymolysis of azobenzene and thus exposes HA. The exposed HA binds to the highly expressed CD44 on cisplatin-resistant tumor cells and mediates drug internalization, thus increasing drug availability to hypoxic tumor cells. After intracellular hyaluronidase-mediated cleavage, the HA NPs release the cisplatin prodrug and NERi, and cause enhanced DNA damage and consequent cell death, thus enhancing the drug sensitivity of hypoxic tumor cells. Eventually, NPHPaPN achieves distinct tumor growth suppression with an ∼84.4% inhibition rate.

Notch1 signaling modulates hypoxia-induced multidrug resistance in human laryngeal cancer cells.

Laryngeal carcinoma is one of the common malignant tumors of the head and neck. Multidrug resistance (MDR) remains a critical problem in the chemotherapy of patients with laryngeal cancer. This study aims to clarify the role and mechanisms of Notch1 signaling in MDR induced by hypoxia in laryngeal cancer cells. Laryngeal carcinoma cells were cultured under normoxia or hypoxia. Notch1 expression was inhibited by small interfering RNA (siRNA). The mRNA expression of Notch1, Hes1, Hey1, MDR1 and survivin was analyzed by real-time PCR. The protein expression of Notch1, the Notch1 intracellular domain (N1ICD), MDR1/P-gp and survivin was analyzed by Western blotting. Current research has shown that hypoxia can upregulate Notch1 expression and Notch1 signaling activity. Furthermore, suppression of Notch1 expression effectively downregulated Notch1 signaling activity and the expression of the MDR and survivin genes in laryngeal cancer cells under hypoxic conditions (P < 0.05). The Cell Counting Kit-8 (CCK-8) assay results confirmed that the sensitivity of hypoxic laryngeal cancer cells to a variety of drugs could be upregulated by suppressing Notch1 expression (P < 0.05). Additionally, flow cytometry (FCM) showed that suppression of Notch1 expression significantly increased drug-induced apoptosis and intracellular rhodamine 123 (Rh123) accumulation in hypoxic laryngeal carcinoma cells (P < 0.05). Notch1 signalling could be regarded as a pivotal regulator of hypoxia-induced MDR in laryngeal cancer cells through the regulation of survivin-mediated apoptosis resistance and MDR1/P-gp-mediated drug transport.

Nitroaromatics as hypoxic cell radiosensitizers: A 2D-QSAR approach to explore structural features contributing to radiosensitization effectiveness

Hypoxia is the prime component of tumor microenvironment that plays a pivotal role in cancer progression. Nitroaromatic compounds are known to enhance the sensitivity of hypoxic cells to ionizing radiation. The application of computational tools like Quantitative Structure-Activity Relationship (QSAR) can be used to predict newly developed nitroaromatics or compounds with missing data. In the present work, three datasets consisting of 18 nitrofurans, 11 nitrothiophenes and 84 nitroimidazoles were utilised for two-dimensional QSAR modeling to retrieve their structural features essential to elicit radiosensitivity. The work comprises two parts: (i) local modeling using individual datasets; and (ii) global modeling by clubbing the three datasets. The two-dimensional descriptors were calculated using Dragon (version 7.0) software. The developed models were obtained using various feature selection techniques applied in “Small Dataset Modeling” and “Double Cross Validation” tools available from https://dtclab.webs.com/software-tools. Finally, the models were validated using stringent metrics following the Organisation for Economic Co-operation and Development (OECD) guidelines. The developed models are robust, predictive, and are useful tools to predict the radiosensitization of newly developed nitroaromatics. Furthermore, the global model was used to predict two external sets comprising 10 and 47 compounds, and the prediction ability was validated using the “Prediction Reliability Indicator” tool.

Development of a novel acetyl glucose-modified gefitinib derivative to enhance the radiosensitizing effect

Various radiosensitizers are being developed to increase the radiation sensitivity of hypoxic cancer cells, which show resistance to radiation. Previously, we demonstrated that an acetyl glucose-modified nitroimidazole derivative showed a high radiosensitizing effect by inhibiting glucose uptake and glycolysis. Based on this finding, we designed and synthesized novel sugar hybrid radiosensitizers, wherein acetyl glucose was introduced into gefitinib. Among them, UTX-114 had higher autophosphorylation and radiosensitizing activity than gefitinib and inhibited glucose uptake. This result supports our hypothesis that an acetyl glucose moiety improves the radiosensitizing effect of the drug, and UTX-114 can be expected to be a leading compound with a radiosensitizing effect.

Effect of HIF-1αsiRNA-linked AuNRs on radiotherapy of nasopharyngeal carcinoma

The radiation sensitivity of tumor cells is closely related to tumor cell hypoxia. Hypoxia-inducible factor-1α (HIF-1α) is considered a key transcription factor which regulates the sensitivity of hypoxic tumor cells to radiotherapy. On the other hand, some studies have shown that gold nanomaterials improve radiation sensitivity. However, studies on the effect of gold nanomaterials carrying HIF-1αsiRNA on tumor radiotherapy, and the underlying mechanisms are limited. Thus, the present study was aimed at investigating the effect of gold nanocomposites (AuNRs) carrying HIF-1αsiRNA (AuNRs-HIF-1αsiRNA) on the radiation sensitivity of nasopharyngeal carcinoma (NPC) hypoxia cells. The effect of AuNRs-HIF-1αsiRNA on radiation sensitivity of hypoxic NPC cells was determined under X-ray irradiation. The results showed that Au-HIF-1αsiRNA improved the radio-sensitivity of NPC tumor. Thus, this study has demonstrated that gold nanomaterials carrying HIF-1αsiRNA effectively increased the radio-sensitivity of hypoxic tumor, thereby improving the effect of radiotherapy on NPC cells.

Hypoxia-Induced Aquaporin-3 Changes Hepatocellular Carcinoma Cell Sensitivity to Sorafenib by Activating the PI3K/Akt Signaling Pathway.

PurposeHypoxia-induced changes are primarily activated in patients with hepatocellular carcinoma (HCC) and long-term sorafenib exposure, thereby reducing the sensitivity to the drug. Aquaporin-3 (AQP3), a member of the aquaporin family, is a hypoxia-induced substance that affects the chemosensitivity of non-hepatocellular tumors. However, its expression and role in the sensitivity of hypoxic HCC cells to sorafenib-induced apoptosis remain unclear. The purpose of this study was to detect changes in AQP3 expression in hypoxic HCC cells and to determine whether these changes alter the sensitivity of these cells to sorafenib.Materials and MethodsHuh7 and HepG2 hypoxic cell models were established and AQP3 expression was detected using quantitative real-time polymerase chain reaction (qPCR) and Western blotting. Furthermore, the role of AQP3 in cell sensitivity to sorafenib was evaluated via flow cytometry, Western blotting, and a CCK-8 assay.ResultsThe results of qPCR and Western blotting showed that AQP3 was overexpressed in the Huh7 and HepG2 hypoxic cell models. Furthermore, AQP3 protein levels were positively correlated with hypoxia-inducible factor-1α (HIF-1α) levels. Compared with cells transfected with lentivirus-GFP (Lv-GFP), hypoxic cells transfected with lentivirus-AQP3 (Lv-AQP3) were less sensitive to sorafenib-induced apoptosis. However, the sensitivity to the drug increased in cells transfected with lentivirus-AQP3RNAi (Lv-AQP3RNAi). Akt and Erk phosphorylation was enhanced in Lv-AQP3-transfected cells. Compared with UO126 (a Mek1/2 inhibitor), LY294002 (a PI3K inhibitor) attenuated the AQP3-induced insensitivity to sorafenib observed in hypoxic cells transfected with Lv-AQP3. Combined with LY294002-treated cells, hypoxic cells transfected with Lv-AQP3RNAi were more sensitive to sorafenib.ConclusionThe study results show that AQP3 is a potential therapeutic target for improving the sensitivity of hypoxic HCC cells to sorafenib.

Targeted Myoglobin Delivery as a Strategy for Enhancing the Sensitivity of Hypoxic Cancer Cells to Radiation.

SummaryThe effectiveness of cancer radiotherapy is frequently hindered by the hypoxia of the tumor microenvironment. Direct delivery of oxygen to hypoxic tumor tissues is an attractive strategy to overcome this hypoxia-associated radioresistance. Herein, we report the generation of submicron-sized particles comprising myoglobin fused to the crystal-forming domain of Cry3Aa protein for the targeted delivery of oxygen to cancer cells. We demonstrate that myoglobin-containing particles were successfully produced in Bacillus thuringiensis with the assistance of the Cry3Aa domain I. Furthermore, these particles could be genetically modified to incorporate the cell penetrating peptide TAT and cell targeting peptide A549.1, resulting in particles that exhibited improved cellular uptake and targeting toward A549 cells. Notably, these myoglobin-containing particles increased the intracellular oxygen levels of A549 cells and thereby sensitized them to radiation. These findings suggest that the targeted delivery of O2-bound myoglobin could be an effective approach to enhance the efficacy of radiotherapy.

Mitochondrial fission causes cisplatin resistance under hypoxic conditions via ROS in ovarian cancer cells.

Mitochondria undergo fission and fusion continually for survival through the course of cellular adaption processes in response to changes in the surrounding environment. Dysregulated mitochondrial dynamics has been reported in various diseases including cancer. Under hypoxic conditions (<1% O2), the relationship between mitochondrial dynamics and sensitivity to cisplatin (CDDP) was examined in ovarian cancer cells. We found that hypoxia promoted mitochondrial fission and CDDP resistance in ovarian cancer cells. Hypoxia-induced reactive oxygen species (ROS) caused an increase in mitochondrial fission, a response abolished by free radical scavenging with N-acetylcysteine (NAC) and Trolox. Also, treatment of hydrogen peroxide (H2O2) decreased inhibitory p-Drp1 (Ser637) content and increased mitochondrial fission. Suppression of mitochondrial fission enhanced the CDDP sensitivity of hypoxic ovarian cancer cells. Lastly, in tumor spheroids from malignant ascites or tissues of patients with advanced-stage ovarian cancer, pretreatment with Mdivi-1 increased the CDDP sensitivity. Taken together, our results implicate that hypoxia-induced ROS trigger mitochondrial fission and CDDP resistance through downregulation of p-Drp1 (Ser637) and Mfn1 in ovarian cancer cells. Inhibition of Drp1 by Mdivi-1 treatment or si-Drp1 transfection increased CDDP sensitivity of ovarian cancer cells under hypoxia. Therefore, mitochondrial dynamics of cancer cells adapting to the hypoxic tumor microenvironment could be a potential target for anticancer therapy.

Imageable Biomarkers for Radiotherapy Response.

Ideally, each patient with a malignancy who is eligible for radiation therapy should receive the most tumoricidal form of this this treatment with the lowest possible risk of toxicity. To overcome radiotherapy resistance, some patients would benefit from a more aggressive approach. This could be treatment intensification, for example by acceleration of the treatment to prevent the negative effects of accelerated tumor cell proliferation, or by boosting certain areas to specifically address intrinsic radioresistance, or a combination of radiotherapy with, for example, a hypoxic cell sensitizer or chemotherapy to reduce the radiotherapy resistance caused by hypoxia. For some patients, one of these approaches can be beneficial but for others could lead to unacceptable side effects. Therefore, it is highly desirable to make the selection upfront. The use of imageable biomarkers could be the key to a more patient-tailored treatment. Different biomarkers for hypoxia and proliferation that could be valuable for radiotherapy are discussed here, including their mechanism, the imaging procedure, quantification, and the value of the results.

X-Ray responsive nanoparticles with triggered release of nitrite, a precursor of reactive nitrogen species, for enhanced cancer radiosensitization.

Remotely and locally triggered release of therapeutic species by X-ray irradiation is highly desired to enhance the efficacy of radiotherapy. However, the development of such X-ray responsive nanosystems remains a challenge, especially in response to high energy clinically relevant X-ray radiation. Herein, we report novel nitroimidazole ligated gold nanoparticles (AuNPs) that synergistically function to release nitrite, an important precursor for nitric oxide and reactive nitrogen species that sensitize cancer cells, upon radiation with clinically used 6 MeV X-rays, while no release was detected without radiation. These functional AuNPs were prepared with surface-grafted nitroimidazole as the nitrite-releasing agent, cell-penetrating peptide (CPP) to induce nucleus localization, and poly(ethylene glycol) for water solubility. In vitro radiotherapy using such nanoparticles showed enhanced sensitivity of hypoxic cancer cells to X-ray radiation, presumably due to the generation of both reactive oxygen and nitrogen species. The dose modifying factor (DMF) was found to be 0.71 for the dual-functionalized nanoparticle, which indicates that significant lower X-ray doses are required to achieve the same therapeutic effects. Thus, X-ray triggered nitrite release from gold-nitroimidazole nanosystems offers a novel strategy to sensitize cancer cells for improved radiotherapy.

Effects of RNAi-mediated TUSC3 silencing on radiation-induced autophagy and radiation sensitivity of human lung adenocarcinoma cell line A549 under hypoxic condition.

This study examined the effects of RNAi-mediated TUSC3 silencing on radiation-induced autophagy and radiation sensitivity of human lung adenocarcinoma cell line A549 under hypoxic condition. Different CoCl2 concentrations were used to treat A549 cells and establish a CoCl2-induced hypoxic model of A549 cells. MTT and clone formation assays were used to determine the effects of different concentrations of CoCl2 on the growth and proliferation of A549 cells treated by different doses of X-ray irradiation. The siRNA-expressing vector was transfected by liposomes and for silencing of TUSC3. Flow cytometry was used to measure cell cycle changes and apoptosis rate. Real-time quantitative polymerase chain reaction (qRT-PCR) assay was performed to detect the expression of TUSC3 mRNA. Western blotting was applied to detect the changes of TUSC3, LC3, and p62 proteins under different CoCl2 concentrations and after siRNA silencing of TUSC3. The TUSC3 levels in A549 cells increased under hypoxic conditions in a dose-dependent manner (P<0.05). Hypoxia inhibited the growth and proliferation of A549 cells and promoted apoptosis (P<0.05). With an increasing dose of X-ray irradiation, A549 cells showed significantly increased growth and proliferation and decreased apoptosis (P<0.05). After siRNA-TUSC3 was transfected by liposome, the TUSC3 level was substantially inhibited (P<0.05). Silencing TUSC3 inhibited A549 cell growth and proliferation after radiotherapy under hypoxic condition, promoted apoptosis, increased G0/G1 phase cells, and reduced S phase cells (all P<0.05). Hypoxia and radiation along with different CoCl2 concentrations could induce cell autophagy, which increased with concentration and dose, while silencing the TUSC3 gene inhibited autophagy (all P<0.05). RNAi silencing of TUSC3 inhibited growth and proliferation, while enhanced apoptosis and radiation sensitivity of hypoxic A549 lung adenocarcinoma cells.

Effect of Hypoxic Cell Sensitizer on Transcription of hif-1α and its Target Genes in Tumor Cells

Effect of Hypoxic Cell Sensitizer on Transcription of hif-1α and its Target Genes in Tumor Cells

Hypoxic cell sensitization in chemoradiation for cervical cancer

The integration of cisplatin into radiation regimens was first developed in locally advanced cervical cancer, a tumour where there is the added advantage that high dose intracavity radiation can be given as well as external beam therapy (1), and the concept was later extended to head and neck cancers. However, progress since then has been slow with the addition of other radiosensitising drugs like gemcitabine providing only a modest survival advantage (2). Myelosuppression and gastrointestinal toxicity also became dose limiting with the doublet. DiSilvestro and colleagues reported a phase III trial of cisplatin based chemoradiation with or without the hypoxic cell sensitizer tirapazamine in 402 predominantly Caucasian and non-Hispanic patients with stages IB, IIa, IIIB and IVa cervical cancer in 2014 (3). The GOG 219 study took 3.5 years to accrue and was closed in 2009 prematurely on account of lack of study drug.

Simulating hypoxia-induced acidic environment in cancer cells facilitates mobilization and redox-cycling of genomic copper by daidzein leading to pro-oxidant cell death: implications for the sensitization of resistant hypoxic cancer cells to therapeutic challenges

This study was conducted to investigate the mechanism of action involved in the anti-cancer activity of daidzein and identification of cancer specific micro-environment as therapeutic target of this secondary metabolite derived from soy. Our data indicated that daidzein induces cellular DNA breakage, anti-proliferative effects and apoptosis in a concentration-dependent manner. We demonstrated that such a daidzein-induced anti-cancer action involves a copper-dependant pathway in which endogenous copper is mobilized by daidzein and redox-cycled to generate reactive oxygen species which act as an upstream signal leading to pro-oxidant cell death. Further in the context of hypoxia being a resistant factor against standard therapies and that an effect secondary to hypoxia is the intracellular acidification, we show that the anticancer activity of daidzein is modulated positively in acidic pH but copper-specific chelator is still able to inhibit daidzein activity. Moreover, an experimental setup of hypoxia mimic (cobalt chloride) revealed an enhanced sensitivity of cancer cells to the cytotoxic effects of daidzein which was neutralized in the presence of neocuproine. The findings support a paradigm shift from the conventional antioxidant property of dietary isoflavones to molecules capable of initiating a pro-oxidant signaling mediated by reactive oxygen species. Further, the clinical relevance of such an action mechanism in cancer chemoprevention is also proposed. This study identified endogenous copper as a molecular target and acidic pH as a modulating factor for the therapeutic activity of daidzein against cancer. The evidence presented highlights the potential of dietary agents as adjuvants to standard therapeutic regimens.

SENP1 desensitizes hypoxic ovarian cancer cells to cisplatin by up-regulating HIF-1α.

Hypoxia-inducible factor 1 alpha (HIF-1α) is closely related to chemoresistance of ovarian cancers. Although it is reported that HIF-1α can be regulated by Sentrin/SUMO-specific protease 1 (SENP1), the effects of SENP1 on HIF-1α is still controversial. In this study, we identified that SENP1 positively regulated the expression of HIF-1α by deSUMOylation and weakened the sensitivity of hypoxic ovarian cancer cells to cisplatin. These results indicate that SENP1 is a positive regulator of HIF-1α and plays a negative role in ovarian cancer chemotherapy.

Abstract 488: Inhibition of JNK signaling sensitizes hypoxic colon cancer cells to DNA-damaging agents

Abstract BACKGROUND: We have shown that hypoxia induces signaling through stress pathways in the HT29 colon adenocarcinoma cell line, and that modulation of signaling through MKK4/MKK7 exerts the opposite effects on oxaliplatin cytotoxicity under hypoxic conditions: higher sensitivity when MKK4 function is impaired and higher resistance when MKK7 is down- regulated. We also observed differential effects of JNK1 and JNK2 modulation on sensitivity of hypoxic HT29 cells to oxaliplatin treatment which implied a pro-survival function for JNK1. PURPOSE: Here we investigate how modulating signaling through JNK influences the sensitivity of hypoxic HT29 cells to oxaliplatin, SN-38 and 5-FU. We used pharmacological and molecular approaches to inhibit JNK signaling and expanded the cellular model in a panel of colon cancer cell lines. Sensitivity to drugs and induction of stress pathways were investigated in 12 colon cancer cell lines of different genetic backgrounds. We also assessed cell cycle changes and cell death characteristics upon treatment. In addition to HT29-derived cell lines stably expressing dominant negative constructs for MKK4 (HTS13), MKK7 (HTM9), JNK1 (HTJ1.3) and JNK2 (HTJ2.2), we also utilized several colon cancer cell lines (HCT116, RKO1, LoVo and SW620) in which a dominant negative construct for JNK1 or JNK2 was introduced by viral delivery. RESULTS: Our data demonstrate that stress signaling through JNK is induced by hypoxia to various extent and with differing temporal characteristics in all colon cancer cell lines assessed. In HT29 cells, treatment with oxaliplatin or SN-38 alone does not cause significant activation of signaling through JNK, whereas 5-FU treatment leads to induction of this pathway. Inhibition of JNK1 renders HT29 cells more sensitive to oxaliplatin and has no effect upon SN-38 treatment, while inhibition of either isoform sensitizes hypoxic HT29 cells to 5-FU. We also show that pharmacological inhibition of JNK by CC-401 augments cytotoxicity of oxaliplatin, SN-38 and of 5-FU in hypoxic HT29 cells, with CI50 of 0.42, 0.6 and 0.63, respectively. CC-401 and SP600125 have also demonstrated synergy with chemotherapy in other colon cancer cell lines. Finally, we show that colon cancer cell lines differ in their responses to oxaliplatin when JNK1 or JNK2 are down-regulated, from no effect (HCT116, LoVo) to increased sensitivity (HT29, SW620). CONCLUSIONS: Our data demonstrate that inhibition of the JNK pathway is a plausible approach to augment the cytotoxicity of oxaliplatin in colon cancer. However, inhibition of individual isoforms presents a complicated picture. Since enhancement of oxaliplatin cytotoxicity by this approach appears to be model-specific in colon cancer, it should be undertaken following the identification of molecular markers better able to predict the outcome. Citation Format: Irina A. Vasilevskaya, Muthu Selvakumaran, Lucia Cabal-Hierro, Peter J. O'Dwyer. Inhibition of JNK signaling sensitizes hypoxic colon cancer cells to DNA-damaging agents. [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 488. doi:10.1158/1538-7445.AM2014-488

Radiation therapy oncology group gynecologic oncology working group: comprehensive results.

The purpose of this report was to comprehensively describe the activities of the Gynecologic Oncology Working Group within the Radiation Therapy Oncology Group (RTOG). Clinical trials will be reviewed as well as translational science and ancillary activities. During the past 40 years, a myriad of clinical trials have been performed within the RTOG with the aim of improving overall survival (OS) and decreasing morbidity in women with cervical or endometrial cancer. Major study questions have included hyperbaric oxygen, neutron radiotherapy, altered fractionation, hypoxic cell sensitization, chemosensitization, and volume-directed radiotherapy.RTOG 7920 demonstrated improvement in OS in patients with stages IB through IIB cervical carcinoma receiving prophylactic para-aortic irradiation compared to pelvic radiation alone. RTOG 9001 demonstrated that cisplatin and 5-FU chemoradiotherapy to the pelvis for advanced cervix cancer markedly improved OS compared to extended field radiotherapy alone. More recent trials have used radioprotectors, molecular-targeted therapy, and intensity-modulated radiation therapy. Ancillary studies have developed clinical target volume atlases for research protocols and routine clinical use. Worldwide practice patterns have been investigated in cervix, endometrial, and vulvar cancer through the Gynecologic Cancer Intergroup. Translational studies have focused on immunohistochemical markers, changes in gene expression, and miRNA patterns impacting prognosis.The RTOG gynecologic working group has performed clinical trials that have defined the standard of care, improved survival, and added to our understanding of the biology of cervical and endometrial cancers.

Phase III Randomized Trial of Weekly Cisplatin and Irradiation Versus Cisplatin and Tirapazamine and Irradiation in Stages IB2, IIA, IIB, IIIB, and IVA Cervical Carcinoma Limited to the Pelvis: A Gynecologic Oncology Group Study

This prospective, randomized phase III intergroup trial of the Gynecologic Oncology Group and National Cancer Institute of Canada Clinical Trials Group was designed to test the effectiveness and safety of adding the hypoxic cell sensitizer tirapazamine (TPZ) to standard cisplatin (CIS) chemoradiotherapy in locally advanced cervix cancer. Patients with locally advanced cervix cancer were randomly assigned to CIS chemoradiotherapy versus CIS/TPZ chemoradiotherapy. Primary end point was progression-free survival (PFS). Secondary end points included overall survival (OS) and tolerability. PFS was evaluable in 387 of 402 patients randomly assigned over 36 months, with enrollment ending in September 2009. Because of the lack of TPZ supply, the study did not reach its original target accrual goal. At median follow-up of 28.3 months, PFS and OS were similar in both arms. Three-year PFS for the TPZ/CIS/RT and CIS/RT arms were 63.0% and 64.4%, respectively (log-rank P = .7869). Three-year OS for the TPZ/CIS/RT and CIS/RT arms were 70.5% and 70.6%, respectively (log-rank P = .8333). A scheduled interim safety analysis led to a reduction in the starting dose for the TPZ/CIS arm, with resulting tolerance in both treatment arms. TPZ/CIS chemoradiotherapy was not superior to CIS chemoradiotherapy in either PFS or OS, although definitive commentary was limited by an inadequate number of events (progression or death). TPZ/CIS chemoradiotherapy was tolerable at a modified starting dose.

The prospective application of a hypoxic radiosensitizer, doranidazole to rat intracranial glioblastoma with blood brain barrier disruption

BackgroundGlioblastoma is one of the intractable cancers and is highly resistant to ionizing radiation. This radioresistance is partly due to the presence of a hypoxic region which is widely found in advanced malignant gliomas. In the present study, we evaluated the effectiveness of the hypoxic cell sensitizer doranidazole (PR-350) using the C6 rat glioblastoma model, focusing on the status of blood brain barrier (BBB).MethodsReproductive cell death in the rat C6 glioma cell line was determined by means of clonogenic assay. An intracranial C6 glioma model was established for the in vivo experiments. To investigate the status of the BBB in C6 glioma bearing brain, we performed the Evans blue extravasation test. Autoradiography with [14C]-doranidazole was performed to examine the distribution of doranidazole in the glioma tumor. T2-weighted MRI was employed to examine the effects of X-irradiation and/or doranidazole on tumor growth.ResultsDoranidazole significantly enhanced radiation-induced reproductive cell death in vitro under hypoxia, but not under normoxia. The BBB in C6-bearing brain was completely disrupted and [14C]-doranidazole specifically penetrated the tumor regions. Combined treatment with X-irradiation and doranidazole significantly inhibited the growth of C6 gliomas.ConclusionsOur results revealed that BBB disruption in glioma enables BBB-impermeable radiosensitizers to penetrate and distribute in the target region. This study is the first to propose that in malignant glioma the administration of hydrophilic hypoxic radiosensitizers could be a potent strategy for improving the clinical outcome of radiotherapy without side effects.

Electron-Affinic SensitizationVII. A Correlation between Structures, One-Electron Reduction Potentials, and Efficiencies of Nitroimidazoles as Hypoxic Cell Radiosensitizers

Radiosensitization efficiencies for seven different 2-nitroimidazoles including Ro-07-0582 and its urinary metabolite, Ro-05-9963, and two 5-nitroimidazoles including metronidazole, have been determined in hypoxic Chinese Hamster cells, line V79-379A, X-irradiated in vitro. All the compounds were active hypoxic cell sensitizers with the enhancement ratios increasing with drug concentration. The 2-nitroimidazoles were all more efficient than the 5-nitroimidazoles. Overall, the efficiencies, defined as the concentration required to give a particular enhancement ratio, varied by a factor of about 200. Electron-affinities of the sensitizers were determined by pulse radiolysis as the one-electron reduction potentials and these correlate well with the sensitization efficiencies of the compounds. The correlation extends beyond the nitroimidazole series as is shown by data for p-nitroacetophenone, nifuroxime (a nitrofuran) and oxygen itself. The nitroimidazoles varied by a factor of 70 in their octanol/water partition coefficients, but the effect of this parameter on sensitizing efficiency is small compared with the influence of electron affinity.