th-302 has been researched along with Hypoxia* in 20 studies
2 trial(s) available for th-302 and Hypoxia
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Hypoxia-activated evofosfamide for treatment of recurrent bevacizumab-refractory glioblastoma: a phase I surgical study.
Anti-angiogenic therapy is known to induce a greater degree of hypoxia, including in glioblastoma (GBM). Evofosfamide (Evo) is a hypoxia-activated prodrug which is reduced, leading to the release of the alkylating agent bromo-isophosphoramide mustard. We assessed the safety, tolerability, preliminary efficacy, and biomarkers of Evo plus bevacizumab (Bev) in Bev-refractory GBM.. Twenty-eight patients with Bev-refractory GBM were enrolled in a dose escalation study receiving from 240 mg/m2 (cohort 1) to 670 mg/m2 (cohort 4) of Evo every 2 weeks in combination with Bev. Patients deemed surgical candidates underwent a single dose of Evo or placebo with pimonidazole immediately prior to surgery for biomarker evaluation, followed by dose escalation upon recovery. Assessments included adverse events, response, and survival.. Evo plus Bev was well tolerated up to and including the maximum dose of 670 mg/m2, which was determined to be the recommended phase II dose. Overall response rate was 17.4%, with disease control (complete response, partial response, and stable disease) observed in 14 (60.9%) of the 23 patients. The ratio of enhancement to non-enhancement was significant on log-rank analysis with time to progression (P = 0.023), with patients having a ratio of less than 0.37 showing a median progression-free survival of 98 days versus 56 days for those with more enhancement.. Evo plus Bev was well tolerated in patients with Bev-refractory GBM, with preliminary evidence of activity that merits further investigation. Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Brain Neoplasms; Combined Modality Therapy; Drug Resistance, Neoplasm; Female; Follow-Up Studies; Glioblastoma; Humans; Hypoxia; Male; Middle Aged; Neoplasm Recurrence, Local; Nitroimidazoles; Phosphoramide Mustards; Prognosis; Salvage Therapy | 2018 |
Phase I study of evofosfamide, an investigational hypoxia-activated prodrug, in patients with advanced leukemia.
Tumor hypoxia causes resistance to radiation and chemotherapy. Evofosfamide (TH-302) has exhibited specific hypoxia-dependent cytotoxicity against primary acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) samples in vitro. Based on these findings, a Phase I study of evofosfamide was designed for patients with relapsed/refractory leukemia (NCT01149915). In this open-label study, patients were treated with evofosfamide as a 30-60 min/day infusion on Days 1-5 of a 21-day cycle (Arm A, n = 38) or as a continuous infusion over 120 hr over Days 1-5 of a 21-day cycle (Arm B, n = 11). Forty-nine patients were treated including 39 (80%) with AML and 9 (18%) with ALL. Patients had received a median of five prior therapies. In Arm A, the dose-limiting toxicities (DLTs) were grade 3 esophagitis, observed at a dose of 550 mg/m(2) . The maximum tolerated dose (MTD) was a daily dose of 460 mg/m(2) . In Arm B, the DLTs were grade 3 stomatitis and hyperbilirubinemia, observed at a daily dose of 460 mg/m(2) . The continuous infusion MTD was a daily dose of 330 mg/m(2) . Hypoxia markers HIF-1α and CAIX were highly expressed in leukemic bone marrow and were significantly reduced after evofosfamide therapy. The combined overall response rate in Arms A and B was 6% (2 CR/CRi and 1 PR), with all responses seen in Arm A. Evofosfamide has shown limited activity in heavily pretreated leukemia patients. Further evaluation investigating evofosfamide in combination with cytotoxic or demethylating agents is warranted. Am. J. Hematol. 91:800-805, 2016. © 2016 Wiley Periodicals, Inc. Topics: Adult; Aged; Bone Marrow; Esophagitis; Female; Humans; Hyperbilirubinemia; Hypoxia; Leukemia; Leukemia, Myeloid, Acute; Male; Maximum Tolerated Dose; Middle Aged; Nitroimidazoles; Phosphoramide Mustards; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prodrugs; Salvage Therapy; Stomatitis; Young Adult | 2016 |
18 other study(ies) available for th-302 and Hypoxia
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Evofosfamide and Gemcitabine Act Synergistically in Pancreatic Cancer Xenografts by Dual Action on Tumor Vasculature and Inhibition of Homologous Recombination DNA Repair.
Topics: Animals; Carcinoma, Pancreatic Ductal; Cell Line, Tumor; Deoxycytidine; Gemcitabine; Heterografts; Humans; Hypoxia; Mice; Pancreatic Neoplasms; Prodrugs; Recombinational DNA Repair | 2023 |
TH-302-loaded nanodrug reshapes the hypoxic tumour microenvironment and enhances PD-1 blockade efficacy in gastric cancer.
Hypoxia, a common characteristic of the tumour microenvironment, is involved in tumour progression and immune evasion. Targeting the hypoxic microenvironment has been implicated as a promising antitumour therapeutic strategy. TH-302 can be selectively activated under hypoxic conditions. However, the effectiveness of TH-302 in gastric cancer combined immunotherapy remains unclear.. We designed mPEG-PLGA-encapsulated TH-302 (TH-302 NPs) to target the hypoxic area of tumour tissues. A particle size analyzer was used to measure the average size and zeta potential of TH-302 NPs. The morphology was observed by transmission electron microscopy and scanning electron microscopy. The hypoxic area of tumour tissues was examined by immunofluorescence assays using pimonidazole. Flow cytometry analysis was performed to measure the levels of TNF-α, IFN-γ, and granzyme B. The synergistic antitumour activity of the combination of TH-302 NPs with anti-PD-1 (α-PD-1) therapy was assessed in vitro and in vivo. Haematoxylin and eosin staining of major organs and biochemical indicator detection were performed to investigate the biological safety of TH-302 NPs in vivo.. TH-302 NPs inhibited the proliferation and promoted the apoptosis of gastric cancer cells under hypoxic conditions. In vitro and in vivo experiments confirmed that TH-302 NPs could effectively alleviate tumour hypoxia. TH-302 NPs exhibited high bioavailability, effective tumour-targeting ability and satisfactory biosafety. Moreover, the combination of TH-302 NPs with α-PD-1 significantly improved immunotherapeutic efficacy in vivo. Mechanistically, TH-302 NPs reduced the expression of HIF-1α and PD-L1, facilitated the infiltration of CD8. TH-302 NPs alleviated the hypoxic tumour microenvironment and enhanced the efficacy of PD-1 blockade. Our results provide evidence that TH-302 NPs can be used as a safe and effective nanodrug for combined immunotherapy in gastric cancer treatment. Topics: CD8-Positive T-Lymphocytes; Granzymes; Humans; Hypoxia; Nanoparticles; Programmed Cell Death 1 Receptor; Stomach Neoplasms; Tumor Microenvironment; Tumor Necrosis Factor-alpha | 2023 |
Predicting response to combination evofosfamide and immunotherapy under hypoxic conditions in murine models of colon cancer.
The goal of this study is to develop a mathematical model that captures the interaction between evofosfamide, immunotherapy, and the hypoxic landscape of the tumor in the treatment of tumors. Recently, we showed that evofosfamide, a hypoxia-activated prodrug, can synergistically improve treatment outcomes when combined with immunotherapy, while evofosfamide alone showed no effects in an Topics: Adenocarcinoma; Animals; Cell Hypoxia; Cell Line, Tumor; Colonic Neoplasms; Disease Models, Animal; Hypoxia; Immunotherapy; Mice; Tumor Microenvironment | 2023 |
Hypoxia is a common characteristic of many tumor microenvironments, and it has been shown to promote suppression of antitumor immunity. Despite strong biological rationale, longitudinal correlation of hypoxia and response to immunotherapy has not been investigated.. In this study, we probed the tumor and its surrounding microenvironment with. The results generated from this work provide an immediately translatable paradigm for measuring and targeting hypoxia to increase response to immune checkpoint therapy and using hypoxia imaging to guide combinatory therapies. Topics: Cell Hypoxia; CTLA-4 Antigen; Humans; Hypoxia; Misonidazole; Neoplasms; Nitroimidazoles; Phosphoramide Mustards; Positron-Emission Tomography; Programmed Cell Death 1 Receptor; Tumor Microenvironment | 2022 |
Deep-learning and MR images to target hypoxic habitats with evofosfamide in preclinical models of sarcoma.
Topics: Animals; Artificial Intelligence; Cell Line, Tumor; Deep Learning; Disease Models, Animal; Doxorubicin; Ecosystem; Female; Humans; Hypoxia; Magnetic Resonance Imaging; Mice; Mice, Inbred C3H; Mice, SCID; Nitroimidazoles; Phosphoramide Mustards; Prodrugs; Sarcoma; Soft Tissue Neoplasms; Xenograft Model Antitumor Assays | 2021 |
An Intratumor Pharmacokinetic/Pharmacodynamic Model for the Hypoxia-Activated Prodrug Evofosfamide (TH-302): Monotherapy Activity is Not Dependent on a Bystander Effect.
Topics: Algorithms; Animals; Antineoplastic Agents; Biological Transport; Bystander Effect; Cell Culture Techniques; Cell Line, Tumor; Chromatography, Liquid; Humans; Hydroxylamine; Hypoxia; Models, Biological; Nitroimidazoles; Phosphoramide Mustards; Prodrugs; Tandem Mass Spectrometry | 2019 |
Radiotherapy Synergizes with the Hypoxia-Activated Prodrug Evofosfamide: In Vitro and In Vivo Studies.
Evofosfamide (TH-302) is a hypoxia-activated prodrug (HAP) that releases the DNA-damaging bromo-isophosphoramide mustard (Br-IPM) moiety selectively under hypoxic conditions. Since solid tumors are known to have hypoxic regions, HAPs in combination with chemotherapy or radiotherapy (XRT) will be beneficial. We tested the oxygen dependence of release kinetics of Br-IPM using electron paramagnetic resonance (EPR) with spin trapping by monitoring redox cycling of the nitroimidazole moiety of TH-302, and oxygen dependence of TH-302 on in vitro cytotoxicity at different levels of hypoxia was also examined. Two tumor implants (SCCVII and HT29) in mice were studied.. TH-302 fragmentation to release Br-IPM was noticed at oxygen levels <76 mmHg, which increased with higher levels of hypoxia. Enhanced cellular cytotoxicity was also observed at oxygen levels <76 mmHg. In vivo pO. We examined the kinetics of redox cycling versus fragmentation of TH-302. The combination of oxygen-dependent XRT with TH-302 is effective even in tumors with significant hypoxia.. Imaging studies identifying the magnitude of hypoxia in tumors indicated that the responsiveness to TH-302 and the antitumor effect of TH-302 were enhanced by combining with XRT in both the TH-302-sensitive SCCVII tumor and -resistant HT29 tumor. Antioxid. Redox Signal. 28, 131-140. Topics: Animals; Cell Hypoxia; Cell Line, Tumor; Cell Survival; Disease Models, Animal; DNA Damage; Humans; Hypoxia; Mice; Nitroimidazoles; Oxidation-Reduction; Phosphoramide Mustards; Prodrugs; Radiotherapy; Tumor Burden; Xenograft Model Antitumor Assays | 2018 |
Administration of Hypoxia-Activated Prodrug Evofosfamide after Conventional Adjuvant Therapy Enhances Therapeutic Outcome and Targets Cancer-Initiating Cells in Preclinical Models of Colorectal Cancer.
Topics: Animals; Biomarkers; Caspases; Cell Hypoxia; Cell Line, Tumor; Cell Proliferation; Chemoradiotherapy; Colorectal Neoplasms; Disease Models, Animal; Drug Evaluation, Preclinical; Drug Synergism; Female; Humans; Hypoxia; Male; Mice; Neoplastic Stem Cells; Nitroimidazoles; Phenotype; Phosphoramide Mustards; Positron-Emission Tomography; Prodrugs; Standard of Care; Wnt Signaling Pathway; Xenograft Model Antitumor Assays | 2018 |
Efficacy of the hypoxia-activated prodrug evofosfamide (TH-302) in nasopharyngeal carcinoma in vitro and in vivo.
Tumor hypoxia is considered an important factor in metastasis and disease relapse. Evofosfamide is a hypoxia-activated prodrug that selectively targets the hypoxic regions of solid tumors. As hypoxia-inducible factor-1α (HIF-1α) is overexpressed in nasopharyngeal carcinoma (NPC) tissues, we performed the present study to evaluate the efficacy profile of evofosfamide in NPC.. We evaluated the efficacy of evofosfamide as a single agent or combined with cisplatin (DDP) in the NPC cell lines CNE-2, HONE-1 and HNE-1, and in nude mouse xenograft tumor models.. Our results present preclinical evidence for targeting the selective hypoxic portion of NPC by evofosfamide as a single agent and combined with DDP and provide rationale for the potential clinical application of evofosfamide for the treatment of nasopharyngeal carcinoma. Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Cell Hypoxia; Cell Line, Tumor; Cell Survival; Cisplatin; Humans; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Male; Mice, Inbred BALB C; Mice, Nude; Nasopharyngeal Carcinoma; Nasopharyngeal Neoplasms; Nitroimidazoles; Phosphoramide Mustards; Prodrugs; Treatment Outcome; Xenograft Model Antitumor Assays | 2018 |
Intravital Imaging to Monitor Therapeutic Response in Moving Hypoxic Regions Resistant to PI3K Pathway Targeting in Pancreatic Cancer.
Application of advanced intravital imaging facilitates dynamic monitoring of pathway activity upon therapeutic inhibition. Here, we assess resistance to therapeutic inhibition of the PI3K pathway within the hypoxic microenvironment of pancreatic ductal adenocarcinoma (PDAC) and identify a phenomenon whereby pronounced hypoxia-induced resistance is observed for three clinically relevant inhibitors. To address this clinical problem, we have mapped tumor hypoxia by both immunofluorescence and phosphorescence lifetime imaging of oxygen-sensitive nanoparticles and demonstrate that these hypoxic regions move transiently around the tumor. To overlay this microenvironmental information with drug response, we applied a FRET biosensor for Akt activity, which is a key effector of the PI3K pathway. Performing dual intravital imaging of drug response in different tumor compartments, we demonstrate an improved drug response to a combination therapy using the dual mTORC1/2 inhibitor AZD2014 with the hypoxia-activated pro-drug TH-302. Topics: Animals; Benzamides; Cell Line, Tumor; Drug Resistance, Neoplasm; Drug Therapy, Combination; Female; Fluorescence Resonance Energy Transfer; Humans; Hypoxia; Intravital Microscopy; Mice; Mice, Inbred BALB C; Morpholines; Nanoparticles; Nitroimidazoles; Pancreatic Neoplasms; Phosphatidylinositol 3-Kinases; Phosphoramide Mustards; Proto-Oncogene Proteins c-akt; Pyrimidines; Signal Transduction; Transplantation, Heterologous; Tumor Microenvironment | 2018 |
Synthesis and biological evaluation of hypoxia-activated prodrugs of SN-38.
We designed new hypoxia-activated prodrugs by conjugating (1-methyl-2-nitro-1H-imidazol-5-yl)methanol with 7-ethyl-10-hydroxy camptothecin (SN-38). Initially, we improved the method of multi-gram scale synthesis of (1-methyl-2-nitro-1H-imidazol-5-yl)methanol, which increased the yield to 42% compared to 8% by the original synthesis method. The improved method was used to synthesize evofosfamide (TH-302) and hypoxia-activated prodrugs of SN-38. Two different linkages between (1-methyl-2-nitro-1H-imidazol-5-yl)methanol and SN-38 were evaluated that afforded different hypoxia-selectivity and toxicity. Compound 16 (IOS), containing an ether linkage, was considered to be a promising hypoxia-selective antitumor agent. Topics: Animals; Antineoplastic Agents; Camptothecin; Cell Line, Tumor; Drug Design; Ether; Humans; Hypoxia; Irinotecan; Methods; Mice; Microsomes, Liver; Prodrugs; Structure-Activity Relationship | 2017 |
Design, synthesis, and biological evaluation of pyrrolobenzodiazepine-containing hypoxia-activated prodrugs.
The ability of various pyrrolobenzodiazepine(PBD)-containing cytotoxic compounds to function as hypoxia-activated prodrugs was assessed. These molecules incorporated a 1-methyl-2-nitro-1H-imidazole hypoxia-activated trigger (present in the clinically evaluated compound TH-302) in a manner that masked a reactive imine moiety required for cytotoxic activity. Incubation of the prodrugs with cytochrome P450-reductase under normoxic and hypoxic conditions revealed that some, but not all, were efficient substrates for the enzyme. In these experiments, prodrugs derived from PBD-monomers underwent rapid conversion to the parent cytotoxic compounds under low-oxygen conditions while related PBD-dimers did not. The ability of a given prodrug to function as an efficient cytochrome P450-reductase substrate correlated with the ratio of cytotoxic potencies measured for the compound against NCI460 cells under normoxic and hypoxic conditions. Topics: Benzodiazepines; Cell Line, Tumor; Cell Survival; Dose-Response Relationship, Drug; Drug Design; Humans; Hypoxia; Molecular Structure; NADPH-Ferrihemoprotein Reductase; Prodrugs; Pyrroles; Structure-Activity Relationship | 2017 |
Hypoxia-activated prodrug TH-302 decreased survival rate of canine lymphoma cells under hypoxic condition.
We tested the hypotheses that hypoxic stimulation enhances growth potentials of canine lymphoma cells by activating hypoxia-inducible factor 1α (HIF-1α), and that the hypoxia-activated prodrug (TH-302) inhibits growth potentials in the cells. We investigated how hypoxic culture affects the growth rate, chemoresistance, and invasiveness of canine lymphoma cells and doxorubicin (DOX)-resistant lymphoma cells, and influences of TH-302 on survival rate of the cells under hypoxic conditions. Our results demonstrated that hypoxic culture upregulated the expression of HIF-1α and its target genes, including ATP-binding cassette transporter B1 (ABCB1), ATP-binding cassette transporter G2 (ABCG2), platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), and survivin, and enhanced the growth rate, DOX resistance, and invasiveness of the cells. Additionally, TH-302 decreased the survival rate of the cells under hypoxic condition. Our studies suggest that hypoxic stimulation may advance the tumorigenicity of canine lymphoma cells, favoring malignant transformation. Therefore, the data presented may contribute to the development of TH-302-based hypoxia-targeting therapies for canine lymphoma. Topics: Animals; Antineoplastic Agents; ATP-Binding Cassette Transporters; Cell Hypoxia; Cell Line, Tumor; Cell Survival; Dogs; Gene Expression Regulation, Neoplastic; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Lymphoma; Nitroimidazoles; Phosphoramide Mustards; Platelet-Derived Growth Factor; Prodrugs; Up-Regulation; Vascular Endothelial Growth Factor A | 2017 |
Hypoxia-Activated Prodrug TH-302 Targets Hypoxic Bone Marrow Niches in Preclinical Leukemia Models.
To characterize the prevalence of hypoxia in the leukemic bone marrow, its association with metabolic and transcriptional changes in the leukemic blasts and the utility of hypoxia-activated prodrug TH-302 in leukemia models.. Hyperpolarized magnetic resonance spectroscopy was utilized to interrogate the pyruvate metabolism of the bone marrow in the murine acute myeloid leukemia (AML) model. Nanostring technology was used to evaluate a gene set defining a hypoxia signature in leukemic blasts and normal donors. The efficacy of the hypoxia-activated prodrug TH-302 was examined in the in vitro and in vivo leukemia models.. Metabolic imaging has demonstrated increased glycolysis in the femur of leukemic mice compared with healthy control mice, suggesting metabolic reprogramming of hypoxic bone marrow niches. Primary leukemic blasts in samples from AML patients overexpressed genes defining a "hypoxia index" compared with samples from normal donors. TH-302 depleted hypoxic cells, prolonged survival of xenograft leukemia models, and reduced the leukemia stem cell pool in vivo In the aggressive FLT3/ITD MOLM-13 model, combination of TH-302 with tyrosine kinase inhibitor sorafenib had greater antileukemia effects than either drug alone. Importantly, residual leukemic bone marrow cells in a syngeneic AML model remain hypoxic after chemotherapy. In turn, administration of TH-302 following chemotherapy treatment to mice with residual disease prolonged survival, suggesting that this approach may be suitable for eliminating chemotherapy-resistant leukemia cells.. These findings implicate a pathogenic role of hypoxia in leukemia maintenance and chemoresistance and demonstrate the feasibility of targeting hypoxic cells by hypoxia cytotoxins. Topics: Animals; Antineoplastic Agents; Bone Marrow; Cell Line, Tumor; Disease Models, Animal; Gene Expression Profiling; Gene Expression Regulation, Leukemic; Humans; Hypoxia; Leukemia; Magnetic Resonance Imaging; Mice; Nitroimidazoles; Phosphoramide Mustards; Prodrugs; Treatment Outcome; Tumor Microenvironment; Xenograft Model Antitumor Assays | 2016 |
MR Imaging Biomarkers to Monitor Early Response to Hypoxia-Activated Prodrug TH-302 in Pancreatic Cancer Xenografts.
TH-302 is a hypoxia-activated prodrug known to activate selectively under the hypoxic conditions commonly found in solid tumors. It is currently being evaluated in clinical trials, including two trials in Pancreatic Ductal Adenocarcinomas (PDAC). The current study was undertaken to evaluate imaging biomarkers for prediction and response monitoring of TH-302 efficacy in xenograft models of PDAC. Dynamic contrast-enhanced (DCE) and diffusion weighted (DW) magnetic resonance imaging (MRI) were used to monitor acute effects on tumor vasculature and cellularity, respectively. Three human PDAC xenografts with known differential responses to TH-302 were imaged prior to, and at 24 h and 48 hours following a single dose of TH-302 or vehicle to determine if imaging changes presaged changes in tumor volumes. DW-MRI was performed at five b-values to generate apparent diffusion coefficient of water (ADC) maps. For DCE-MRI, a standard clinically available contrast reagent, Gd-DTPA, was used to determine blood flow into the tumor region of interest. TH-302 induced a dramatic decrease in the DCE transfer constant (Ktrans) within 48 hours after treatment in the sensitive tumors, Hs766t and Mia PaCa-2, whereas TH-302 had no effect on the perfusion behavior of resistant SU.86.86 tumors. Tumor cellularity, estimated from ADC, was significantly increased 24 and 48 hours after treatment in Hs766t, but was not observed in the Mia PaCa-2 and SU.86.86 groups. Notably, growth inhibition of Hs766t was observed immediately (day 3) following initiation of treatment, but was not observed in MiaPaCa-2 tumors until 8 days after initiation of treatment. Based on these preclinical findings, DCE-MRI measures of vascular perfusion dynamics and ADC measures of cell density are suggested as potential TH-302 response biomarkers in clinical trials. Topics: Animals; Biomarkers, Tumor; Cell Line, Tumor; Female; Humans; Hypoxia; Magnetic Resonance Imaging; Mice; Mice, SCID; Nitroimidazoles; Pancreatic Neoplasms; Phosphoramide Mustards; Prodrugs; Time Factors; Xenograft Model Antitumor Assays | 2016 |
Engineered Breast Cancer Cell Spheroids Reproduce Biologic Properties of Solid Tumors.
Solid tumors develop as 3D tissue constructs. As tumors grow larger, spatial gradients of nutrients and oxygen and inadequate diffusive supply to cells distant from vasculature develops. Hypoxia initiates signaling and transcriptional alterations to promote survival of cancer cells and generation of cancer stem cells (CSCs) that have self-renewal and tumor-initiation capabilities. Both hypoxia and CSCs are associated with resistance to therapies and tumor relapse. This study demonstrates that 3D cancer cell models, known as tumor spheroids, generated with a polymeric aqueous two-phase system (ATPS) technology capture these important biological processes. Similar to solid tumors, spheroids of triple negative breast cancer cells deposit major extracellular matrix proteins. The molecular analysis establishes presence of hypoxic cells in the core region and expression of CSC gene and protein markers including CD24, CD133, and Nanog. Importantly, these spheroids resist treatment with chemotherapy drugs. A combination treatment approach using a hypoxia-activated prodrug, TH-302, and a chemotherapy drug, doxorubicin, successfully targets drug resistant spheroids. This study demonstrates that ATPS spheroids recapitulate important biological and functional properties of solid tumors and provide a unique model for studies in cancer research. Topics: Antineoplastic Agents; Biomarkers, Tumor; Cell Engineering; Cell Line, Tumor; Doxorubicin; Drug Resistance, Neoplasm; Extracellular Matrix Proteins; Female; Humans; Hypoxia; Neoplastic Stem Cells; Nitroimidazoles; Phosphoramide Mustards; Polymers; Prodrugs; Spheroids, Cellular; Triple Negative Breast Neoplasms | 2016 |
Pharmacokinetics of TH-302: a hypoxically activated prodrug of bromo-isophosphoramide mustard in mice, rats, dogs and monkeys.
To characterize the pharmacokinetics of the prodrug, TH-302, and its active metabolite, bromo-IPM (Br-IPM), in nonclinical species.. TH-302 was administered in single oral, intraperitoneal and intravenous bolus doses to mice, rats, dogs and monkeys as well as in acute and chronic safety studies in rats and dogs as a 30-min intravenous infusion given once a week for 3 weeks. Assessments were made using liquid chromatography-tandem mass spectrometry.. TH-302 was extensively distributed with high systemic clearance exceeding hepatic plasma flow in all species studied, resulting in half-lives ranging between 8 min (mice) and over 4 h (rats). In rats, TH-302 exhibited linear kinetics following intravenous administration and good oral bioavailability. In acute and chronic safety studies, there was no accumulation of TH-302 following once weekly dosing for 3 weeks in the rat and dog. Br-IPM plasma concentrations were a small fraction of the TH-302 plasma concentrations with significantly smaller percentages present in dogs than in rats. Allometric scaling predicted that the systemic clearance and steady-state volume of distribution in humans would be 38.8 l/h/m(2) and 34.3 l/m(2), respectively, resulting in a terminal elimination half-life of about 36 min. These values were similar to those observed in patients with solid tumors (27.1 l/h/m(2), 23.5 l/m(2) and 47 min).. TH-302 exhibited good safety, efficacy and pharmacokinetic properties in nonclinical species, translating into favorable properties in humans. Topics: Administration, Oral; Animals; Dogs; Drug Evaluation, Preclinical; Female; Half-Life; Humans; Hypoxia; Infusions, Intravenous; Injections, Intraperitoneal; Injections, Intravenous; Macaca fascicularis; Male; Mice; Mice, Inbred Strains; Mice, Nude; Molecular Structure; Nitroimidazoles; Phosphoramide Mustards; Predictive Value of Tests; Prodrugs; Rats; Rats, Sprague-Dawley; Species Specificity; Tissue Distribution | 2012 |
Targeting the multiple myeloma hypoxic niche with TH-302, a hypoxia-activated prodrug.
Hypoxia is associated with increased metastatic potential and poor prognosis in solid tumors. In this study, we demonstrated in the murine 5T33MM model that multiple myeloma (MM) cells localize in an extensively hypoxic niche compared with the naive bone marrow. Next, we investigated whether hypoxia could be used as a treatment target for MM by evaluating the effects of a new hypoxia-activated prodrug TH-302 in vitro and in vivo. In severely hypoxic conditions, TH-302 induces G(0)/G(1) cell-cycle arrest by down-regulating cyclinD1/2/3, CDK4/6, p21(cip-1), p27(kip-1), and pRb expression, and triggers apoptosis in MM cells by up-regulating the cleaved proapoptotic caspase-3, -8, and -9 and poly ADP-ribose polymerase while having no significant effects under normoxic conditions. In vivo treatment of 5T33MM mice induces apoptosis of the MM cells within the bone marrow microenvironment and decreases paraprotein secretion. Our data support that hypoxia-activated treatment with TH-302 provides a potential new treatment option for MM. Topics: Animals; Apoptosis; Blotting, Western; Bone Marrow; Caspases; Cell Cycle; Cell Cycle Proteins; Cell Proliferation; Humans; Hypoxia; Male; Mice; Mice, Inbred C57BL; Multiple Myeloma; Neovascularization, Pathologic; Nitroimidazoles; Oxygen; Phosphoramide Mustards; Prodrugs; Tumor Cells, Cultured; Vascular Endothelial Growth Factor A | 2010 |