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Cancer Aug 2019The purpose of this study was to evaluate risk and response-based multi-agent therapy for patients with rhabdomyosarcoma (RMS) at first relapse.
BACKGROUND
The purpose of this study was to evaluate risk and response-based multi-agent therapy for patients with rhabdomyosarcoma (RMS) at first relapse.
METHODS
Patients with RMS and measurable disease at first relapse with unfavorable-risk (UR) features were randomized to a 6-week phase 2 window with 1 of 2 treatment schedules of irinotecan with vincristine (VI) (previously reported). Those with at least a partial response to VI continued to receive 44 weeks of multi-agent chemotherapy including the assigned VI regimen. UR patients who did not have measurable disease at study entry, did not have a radiographic response after the VI window, or declined VI window therapy received 31 weeks of multi-agent chemotherapy including tirapazamine (TPZ) at weeks 1, 4, 10, 19, and 28. Favorable-risk (FR) patients received 31 weeks of the same multi-agent chemotherapy without VI and TPZ.
RESULTS
One hundred thirty-six eligible patients were enrolled. For 61 patients not responding to VI, the 3-year failure-free survival (FFS) and overall survival (OS) rates were 17% (95% confidence interval [CI], 8%-29%) and 24% (13%-37%), respectively. For 30 UR patients not treated with VI, the 3-year FFS and OS rates were 21% (8%-37%) and 39% (20%-57%), respectively. FR patients had 3-year FFS and OS rates of 79% (47%-93%) and 84% (50%-96%), respectively. There were no unexpected toxicities.
CONCLUSIONS
Patients with UR RMS at first relapse or disease progression have a poor prognosis when they are treated with this multi-agent therapy, whereas FR patients have a higher chance of being cured with second-line therapy.
Topics: Child; Disease Progression; Female; Humans; Male; Recurrence; Rhabdomyosarcoma; Risk Factors; Survival Analysis
PubMed: 31067356
DOI: 10.1002/cncr.32122 -
Oncotarget Sep 2020Metastatic melanoma cells overexpressing gap junctions were assayed for their ability to propagate cell death by a novel combination therapy that generates reactive...
Metastatic melanoma cells overexpressing gap junctions were assayed for their ability to propagate cell death by a novel combination therapy that generates reactive oxygen species (ROS) by both 1) non-thermal plasma (NTP) and 2) tirapazamine (TPZ) under hypoxic conditions. Results demonstrate additive-to-synergistic effects of combination therapy compared to each agent individually. NTP induces highly localized cell death in target areas whereas TPZ partially reduces viability over the total surface area. However, when high gap junction expression was induced in melanoma cells, effects of combination NTP+TPZ therapy was augmented, spreading cell death across the entire plate. Similarly, studies of human metastatic melanoma in a mouse tumor model demonstrate that the combined effect of NTP+TPZ causes a 90% reduction in tumor volume, specifically in the model expressing gap junctions. Treatment with NTP+TPZ increases gene expression in the apoptotic pathway and oxidative stress while decreasing genes related to cell migration. Immune response was also elicited through differential regulation of cytokines and chemokines, suggesting potential for this therapy to induce a cytotoxic immune response with fewer side effects than current therapies. Interestingly, the gap junction protein, Cx26 was upregulated following treatment with NTP+TPZ and these gap junctions were shown to maintain functionality during the onset of treatment. Therefore, we propose that gap junctions both increase the efficacy of NTP+TPZ and perpetuate a positive feedback mechanism of gap junction expression and tumoricidal activity. Our unique approach to ROS induction in tumor cells with NTP+TPZ shows potential as a novel cancer treatment.
PubMed: 32973969
DOI: 10.18632/oncotarget.27732 -
ACS Nano Feb 2017Poor tumor penetration is a major challenge for the use of nanoparticles in anticancer therapy. Moreover, the inability to reach hypoxic tumor cells that are distant...
Poor tumor penetration is a major challenge for the use of nanoparticles in anticancer therapy. Moreover, the inability to reach hypoxic tumor cells that are distant from blood vessels results in inadequate exposure to antitumor therapeutics and contributes to development of chemoresistance and increased metastasis. In the present study, we developed iRGD-modified nanoparticles for simultaneous tumor delivery of a photosensitizer indocyanine green (ICG) and hypoxia-activated prodrug tirapazamine (TPZ). The iRGD-modified nanoparticles loaded with ICG and TPZ showed significantly improved penetration in both 3D tumor spheroids in vitro and orthotopic breast tumors in vivo. ICG-mediated photodynamic therapy upon irradiation with a near-IR laser induced hypoxia, which activated antitumor activity of the codelivered TPZ for synergistic cell-killing effect. In vivo studies demonstrated that the nanoparticles could efficiently deliver the drug combination in 4T1 orthotopic tumors. Primary tumor growth and metastasis were effectively inhibited by the iRGD-modified combination nanoparticles with minimal side effects. The results also showed the anticancer benefits of codelivering ICG and TPZ in a single nanoparticle formulation in contrast to a mixture of nanoparticles containing individual drugs. The study demonstrates the benefits of combining tumor-penetrating nanoparticles with hypoxia-activated drug treatment and establishes a delivery platform for PDT and hypoxia-activated chemotherapy.
Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Proliferation; Drug Delivery Systems; Drug Screening Assays, Antitumor; Hypoxia; Indocyanine Green; Injections, Intravenous; Mice; Molecular Structure; Nanoparticles; Photochemotherapy; Photosensitizing Agents; Prodrugs; Reactive Oxygen Species; Tirapazamine; Tissue Distribution; Tumor Cells, Cultured
PubMed: 28165223
DOI: 10.1021/acsnano.6b08731 -
Theranostics 2020Abnormal tumor microenvironment, such as hypoxia, interstitial hypertension and low pH, leads to unexpected resistance for current tumor treatment. The development of...
Abnormal tumor microenvironment, such as hypoxia, interstitial hypertension and low pH, leads to unexpected resistance for current tumor treatment. The development of versatile drug delivery systems which present responsive characteristics to tumor microenvironment (TME) has been extensively carried out, but remains challenging. In this study, zeolitic imidazolate framework-8 (ZIF-8) coated ZnS nanoparticles have been designed and prepared for co-delivery of ICG/TPZ molecules, denoted as ZSZIT, for HS-amplified synergistic therapy. The ZSZ nanoparticles were characterized using SEM, TEM and XRD. The viabilities of cancer cells cultured with ZSZIT under normoxia/hypoxia conditions were evaluated by cell counting kit-8 (CCK-8) assay. In addition, anti-tumor effect was also performed using male Balb/c nude mice as animal model. ZSZIT shows cascade PDT and hypoxia-activated chemotherapeutic effect under an 808nm NIR irradiation. Meanwhile, ZSZIT degrades under tumor acidic environment, and HS produced by ZnS cores could inhibit the expression of catalase, which subsequently favors the hypoxia and antitumor effect of TPZ drug. Both and studies demonstrate the HS-sensitized synergistic antitumor effect based on cascade PDT/chemotherapy. This cascade HS-sensitized synergistic nanoplatform has enabled more effective and lasting anticancer treatment.
Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Drug Carriers; Drug Compounding; Drug Synergism; Humans; Hydrogen Sulfide; Indocyanine Green; Male; Metal Nanoparticles; Metal-Organic Frameworks; Mice; Neoplasms; Photochemotherapy; Prodrugs; Tirapazamine; Tumor Hypoxia; Tumor Microenvironment; Xenograft Model Antitumor Assays; Zeolites
PubMed: 32685012
DOI: 10.7150/thno.45079 -
National Science Review Apr 2024Tirapazamine (TPZ) has been approved for multiple clinical trials relying on its excellent anticancer potential. However, as a typical hypoxia-activated prodrug (HAP),...
Tirapazamine (TPZ) has been approved for multiple clinical trials relying on its excellent anticancer potential. However, as a typical hypoxia-activated prodrug (HAP), TPZ did not exhibit survival advantages in Phase III clinical trials when used in combination therapy due to the insufficient hypoxia levels in patients' tumors. In this study, to improve the therapeutic effects of TPZ, we first introduced urea to synthesize a series of urea-containing derivatives of TPZ. All urea-containing TPZ derivatives showed increased hypoxic cytotoxicity (9.51-30.85-fold) compared with TPZ, while maintaining hypoxic selectivity. TPZP, one of these derivatives, showed 20-fold higher cytotoxicity than TPZ while maintaining a similar hypoxic cytotoxicity ratio. To highly efficiently deliver TPZP to the tumors and reduce its side effects on healthy tissues, we further prepared TPZP into a nanodrug with fibrin-targeting ability: FT11-TPZP-NPs. CA4-NPs, a vascular disrupting agent, was used to increase the fibrin level within tumors and exacerbate tumor hypoxia. By being combined with CA4-NPs, FT11-TPZP-NPs can accumulate in the hypoxia-aggravated tumors and activate sufficiently to kill tumor cells. After a single-dose treatment, FT11-TPZP-NPs + CA4-NPs showed a high inhibition rate of 98.1% against CT26 tumor models with an initial volume of ∼480 mm and four out of six tumors were completely eliminated; it thereby exerted a significant antitumor effect. This study provides a new strategy for improving the therapeutic effect of TPZ and other HAPs in anticancer therapy.
PubMed: 38440219
DOI: 10.1093/nsr/nwae038 -
European Journal of Medicinal Chemistry Feb 2017Carbonic anhydrase IX (CAIX) is a hypoxia-regulated and tumor-specific protein that maintains the pH balance of cells. Targeting CAIX might be a valuable approach for...
Carbonic anhydrase IX (CAIX) is a hypoxia-regulated and tumor-specific protein that maintains the pH balance of cells. Targeting CAIX might be a valuable approach for specific delivery of cytotoxic drugs, thereby reducing normal tissue side-effects. A series of dual-target compounds were designed and synthesized incorporating a sulfonamide, sulfamide, or sulfamate moiety combined with several different anti-cancer drugs, including the chemotherapeutic agents chlorambucil, tirapazamine, and temozolomide, two Ataxia Telangiectasia and Rad3-related protein inhibitors (ATRi), and the anti-diabetic biguanide agent phenformin. An ATRi derivative (12) was the only compound to show a preferred efficacy in CAIX overexpressing cells versus cells without CAIX expression when combined with radiation. Its efficacy might however not solely depend on binding to CAIX, since all described compounds generally display low activity as carbonic anhydrase inhibitors. The hypothesis that dual-target compounds specifically target CAIX expressing tumor cells was therefore not confirmed. Even though dual-target compounds remain an interesting approach, alternative options should also be investigated as novel treatment strategies.
Topics: Animals; Antineoplastic Agents; Ataxia Telangiectasia Mutated Proteins; Carbonic Anhydrase IX; Carbonic Anhydrase Inhibitors; Cell Line, Tumor; Dogs; Drug Design; Drug Screening Assays, Antitumor; Gene Expression Regulation, Neoplastic; Humans; Madin Darby Canine Kidney Cells
PubMed: 27823879
DOI: 10.1016/j.ejmech.2016.10.037 -
Molecules (Basel, Switzerland) Oct 2019Benzimidazoles belong to a new class of bioreductive agents with cytotoxic activity towards solid tumor cells, especially in their first stage of growth, which is...
Benzimidazoles belong to a new class of bioreductive agents with cytotoxic activity towards solid tumor cells, especially in their first stage of growth, which is characterized by low oxygen concentration. Bioreductive agents represent a class of prodrugs that target hypoxic tumor cells. Their bioactivity depends on the reactivity of their functional chemical groups. Their efficacy requires metabolic reduction and subsequent generation of toxic prodrugs. Chemoresistance of tumor cells is a major problem for successful antitumor therapy for many types of tumors, especially for breast cancer. The present study was performed to assess the effect of the antiproliferation activity of the tested benzimidazoles by way of NF-κB expression inhibition. The activity of the tested compounds on T47D and MCF7 cells was examined by WST, western blot, NF-κB transactivation assay, and apoptotic cell population analysis. Compound 3 was highly cytotoxically active against T47D cells, especially in hypoxic conditions. Its IC of 0.31 ± 0.06 nM, although weaker than tirapazamine, was significantly higher than the other tested compounds (2.4-3.0 fold). The increased bax protein expression upon exposure to the tested compounds indicated intercellular apoptotic pathway activity, with tumor cell death by way of apoptosis. Increased bax protein synthesis and apoptotic cell dominance upon treatment, especially with N-oxide derivatives (92% apoptotic cells among T47D cell populations during treatment with compound 3), were correlated with each other. Additionally, both increased bax protein and decreased NF-κB protein expression supported antiproliferative activity via NF-κB-DNA binding inhibition associated with the tested compounds. Compound 3 appeared to be the strongest inhibitor of NF-κB expression in hypoxic conditions (the potency against NF-κB expression was about 75% of that of tirapazamine). The present studies involving this class of heterocyclic small molecules proved their potential usefulness in anticancer therapy as compounds be able to limit tumor cell proliferation and reverse drug resistance by NF-κB repression.
Topics: Benzimidazoles; Cell Death; Cell Line, Tumor; Cell Proliferation; Genes, Reporter; Humans; Inhibitory Concentration 50; NF-kappa B; Transcription, Genetic; bcl-2-Associated X Protein
PubMed: 31671914
DOI: 10.3390/molecules24213902 -
Materials Today. Bio Apr 2024The short lifespan of active oxygen species and depressed O level during ferroptosis treatment in tumor cells weaken ferroptosis therapy. How to improve the utilization...
The short lifespan of active oxygen species and depressed O level during ferroptosis treatment in tumor cells weaken ferroptosis therapy. How to improve the utilization efficiency of active oxygen species generated in real time is pivotal for anticancer treatment. Herein, the tirapazamine (TPZ) loaded polydopamine-Fe nanoparticles (PDA-Fe-TPZ) was modified with unsaturated liposome (Lip), which was constructed to overcome the drawbacks of traditional ferroptosis therapy. The Lip@PDA-Fe-TPZ nanoliposomes can react with HO to produce •OH by Fenton reaction, which then attacks Lip and transforms into radical intermediate (L•) and phospholipid peroxide radical (LOO•) to avoid the annihilation of •OH. The introduced Lip enhances lipid peroxidation and promotes oxygen consumption, resulting in increased hypoxia at tumor site. The introduced TPZ can be triggered by reductase in tumor cells under hypoxia, which can reduce to transient oxidative free radicals by reductase enzymes and destroy the structure of the surrounding biomacromolecules, thus achieving the synergistic treatment of ferroptosis and chemotherapy. In this work, we organically combined enhanced ferrroptosis with hypoxic activated chemotherapy to achieve efficient and specific tumor killing effect, which can sever as a promising treatment of cancer in the future.
PubMed: 38445012
DOI: 10.1016/j.mtbio.2024.101009 -
Journal of Pharmacy & Bioallied Sciences 2021Tumor hypoxia, a predominant feature of solid tumor produces drug resistance that significantly impacts a patient's clinical outcomes. Hypoxia-inducible factor 1-alpha...
OBJECTIVE
Tumor hypoxia, a predominant feature of solid tumor produces drug resistance that significantly impacts a patient's clinical outcomes. Hypoxia-inducible factor 1-alpha (HIF1α) is the major mutation involved in establishing the microenvironment. As a consequence of its involvement in pathways that enable rapid tumor growth, it creates resistance to chemotherapeutic treatments. The propensity of medications to demonstrate drug action often diverges according to the genetic composition. The aim of this study is therefore to examine the effect of population-dependent drug response variations using mutation models.
METHODS
Genetic variations distinctive to major super-populations were identified, and the mutated gene was acquired as a result of incorporating the variants. The mutated gene sequence was transcribed and translated to obtain the target amino acid sequence. To investigate the effects of mutations, protein models were developed using homology modeling. The target templates for the backbone structure were identified by characterization of primary and secondary protein structures. The modeled proteins were then validated for structural confirmation and flexibility. Potential models were used for interaction studies with hypoxia-specific molecules (tirapazamine, apaziquone, and ENMD) using docking analysis. To verify their stability under pre-defined dynamic conditions, the complexes were subjected to molecular dynamics simulation.
RESULTS
The current research models demonstrate with the pharmacogenomic-based mutation of HIF1α the impact of individual variants in altering the person-specific drug response under tumor hypoxic conditions. It also elucidates that the therapeutic effect is altered concerning population-dependent genetic changes in the individual.
CONCLUSION
The study, therefore, asserts the need to set up a personalized drug design approach to enhance tumor hypoxia treatment efficacy.
PubMed: 35399804
DOI: 10.4103/jpbs.jpbs_766_21 -
Frontiers in Chemistry 2021Radiotherapy (RT) is a standard treatment strategy for many cancer types, but the need to frequently apply high doses of ionizing radiation in order to achieve...
Radiotherapy (RT) is a standard treatment strategy for many cancer types, but the need to frequently apply high doses of ionizing radiation in order to achieve therapeutic efficacy can cause severe harm to healthy tissues, leading to adverse patient outcomes. In an effort to minimize these toxic side effects, we herein sought to design a novel approach to the low-dose RT treatment of hypoxic tumors using a Tirapazamine (TPZ)-loaded exosome (EXO) nanoplatform (MT). This MT platform was synthesized via loading EXOs with TPZ, which is a prodrug that is activated when exposed to hypoxic conditions. MT application was able to achieve effective tumor inhibition at a relatively low RT dose (2 Gy) that was superior to standard high-dose (6 Gy) RT treatment with specific targeting to the hypoxic region of tumor. RT-mediated oxygen consumption further aggravated hypoxic conditions to improve TPZ activation and treatment efficacy. Together, our findings demonstrate the clinical promise of this MT platform as a novel tool for the efficient radiosensitization and treatment of cancer patients.
PubMed: 34458237
DOI: 10.3389/fchem.2021.710250