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Ning S.,Stanford University | Bednarski M.,Stanford University | Oronsky B.,Radiorx Inc. | Scicinski J.,Radiorx Inc. | And 2 more authors.
Cancer Research | Year: 2012

In an effort to develop cancer therapies that maximize cytotoxicity, while minimizing unwanted side effects, we studied a series of novel compounds based on the highly energetic heterocyclic scaffold, dinitroazetidine. In this study, we report the preclinical validation of 1-bromoacetyl-3,3-dinitroazetidine (ABDNAZ), a representative lead compound currently in a phase I clinical trial in patients with cancer. In tumor cell culture, ABDNAZ generated reactive free radicals in a concentration- and time-dependent manner, modulating intracellular redox status and triggering apoptosis. When administered to mice as a single agent, ABDNAZ exhibited greater cytotoxicity than cisplatin or tirapazamine under hypoxic conditions. However, compared with cisplatin, ABDNAZ was better tolerated at submaximal doses, yielding significant tumor growth inhibition in the absence of systemic toxicity. Similarly, when combined with radiation, ABDNAZ accentuated antitumor efficacy along with the therapeutic index. Toxicity studies indicated that ABDNAZ was not myelosuppressive and no dose-limiting toxicity was apparent following daily administration for 14 days. Taken together, our findings offer preclinical proof-ofconcept for ABDNAZ as a promising new anticancer agent with a favorable toxicity profile, either as a chemotherapeutic agent or a radiosensitizer. ©2012 AACR.

Oronsky B.,Radiorx Inc. | Oronsky N.,CFLS LLC | Scicinski J.,Radiorx Inc. | Fanger G.,Radiorx Inc. | And 2 more authors.
Translational Oncology | Year: 2014

In cancer chemotherapy, one axiom, which has practically solidified into dogma, is that acquired resistance to antitumor agents or regimens, nearly inevitable in all patients with metastatic disease, remains unalterable and irreversible, rendering therapeutic rechallenge futile. However, the introduction of epigenetic therapies, including histone deacetylase inhibitors (HDACis) and DNA methyltransferase inhibitors (DNMTIs), provides oncologists, like computer programmers, with new techniques to “overwrite” the modifiable software pattern of gene expression in tumors and challenge the “one and done” treatment prescription. Taking the epigenetic code-as-software analogy a step further, if chemoresistance is the product of multiple nongenetic alterations, which develop and accumulate over time in response to treatment, then the possibility to hack or tweak the operating system and fall back on a “system restore” or “undo” feature, like the arrow icon in the Windows XP toolbar, reconfiguring the tumor to its baseline nonresistant state, holds tremendous promise for turning advanced, metastatic cancer from a fatal disease into a chronic, livable condition. This review aims 1) to explore the potential mechanisms by which a group of small molecule agents including HDACis (entinostat and vorinostat), DNMTIs (decitabine and 5-azacytidine), and redox modulators (RRx-001) may reprogram the tumor microenvironment from a refractory to a nonrefractory state, 2) highlight some recent findings, and 3) discuss whether the current “once burned forever spurned” paradigm in the treatment of metastatic disease should be revised to promote active resensitization attempts with formerly failed chemotherapies. © 2014 Neoplasia Press, Inc.

Oronsky B.T.,Radiorx Inc. | Reid T.,University of California at San Diego | Knox S.J.,Stanford University | Scicinski J.J.,Radiorx Inc.
Translational Oncology | Year: 2012

If there were a stigma scale for chemotherapy, alkylating agents would be ranked at the top of the list. The chemical term alkylation is associated with nonselective toxicity, an association that dates back to the use of nitrogen mustards during World War I as chemical warfare agents. That this stigma persists and extends to compounds that, through selectivity, attempt to "tame" the indiscriminate destructive potential of alkylation is the subject of this review. Selective alkylation, as it is referred to herein, constitutes an extremely nascent and dynamic field in oncology. The pharmaco-dynamic response to this selective strategy depends on a delicate kinetic balance between specificity and the rate and extent of binding. Three representative compounds are presented: RRx-001, 3-bromopyruvate, and TH-302. The main impetus for the development of these compounds has been the avoidance of the serious complications of traditional alkylating agents; therefore, it is the thesis of this review that they should not experience stigma by association. © 2012 Neoplasia Press, Inc. All rights reserved.

Santini J.T.,Radiorx Inc.
Chemical Engineering Progress | Year: 2013

All drug delivery technologies aim to improve drug efficacy, minimize side effects, and reduce the burden of care for patients and physicians. For many drugs, the concentration in the body must be maintained nearly constant over long periods of time. In some cases, however, the best efficacy is achieved with repeated pulses of a drug at predetermined times or with an on-demand schedule based on symptoms or signals from chemical sensors. Pulsatile delivery is required for efficacy for the administration of parathyroid hormone. Frequent injections should be replaced with an alternative drug delivery approach that is less expensive, less invasive, and requires fewer office visits. A potential advantage of implantable devices for drug delivery is that the time between administrations can be greatly increased, which reduces the treatment burden on the patient and physician. Advances in novel device structures and materials, targeted nanoparticles, and gene therapy ensure that additional treatment options will be available in the future.

Oronsky B.T.,Radiorx Inc. | Scicinski J.J.,Radiorx Inc. | Reid T.,University of California at San Diego | Knox S.,Stanford University
Translational Oncology | Year: 2012

This review attempts to move beyond the traditional borders of antiangiogenesis and toward the dynamic, evolving strategies of vascular modulation. This repositioning entails a two-fold paradigm shift: conceptually, to a view of antiangiogenesis as only one part of a larger story, and therapeutically, to approaches which attempt to modulate tumor blood flow instead of simply inhibiting it. Three vascular modulation strategies-provascular, antivascular, and redistributive-are presented with representative compounds. These vascular modulation strategies are described in specific measurable characteristics (blood vessel maturity and type, effect on blood flow, microenvironmental target, molecular target, angiogenic biomarker, and imaging biomarkers) that will help define the tumor types that aremore susceptible to a particular vascular modulation strategy thereby guiding therapeutic agent selection and enabling a personalized medicine approach. © 2012 Neoplasia Press, Inc.

Oronsky B.,Radiorx Inc. | Fanger G.R.,Radiorx Inc. | Oronsky N.,Stanford University | Knox S.,CFLS | Scicinski J.,Radiorx Inc.
Translational Oncology | Year: 2014

Tumors are spatially heterogeneous, with regions of relative hypoxia and normoxia. The tumor microenvironment is an important determinant of both tumor growth and response to a variety of cytotoxic and targeted therapies. In the tumor microenvironment, reactive oxygen species and nitric oxide (NO) are important mediators of the level of expression of many transcription factors and signaling cascades that affect tumor growth and responses to therapy. The primary objective of this review is to explore and discuss the seemingly dichotomous actions of NO in cancer biology as both a tumor promoter and suppressor with an emphasis on understanding the role of persistently low NO concentrations or hyponitroxia as a key mediator in tumor progression. This review will also discuss the potential role of hyponitroxia as a novel therapeutic target to treat cancer and outline an approach that provides new opportunities for pharmacological intervention. © 2014 Neoplasia Press. All rights reserved.

Radiorx Inc. | Date: 2012-05-18

The invention provides organonitro thioether compounds, compositions containing such compounds, isolated organonitro thioether compounds and methods for using such compounds and compositions to treat cancer in a patient. Exemplary organonitro thioether compounds described herein include 2-(3,3-dinitroazetidin-1-yl)-2-oxoethyl thioethers and variants thereof. Another aspect of the invention provides a pharmaceutical composition, comprising a pharmaceutically acceptable carrier and an organonitro thioether compound described herein, such as a compound of Formula I or II. Another aspect of the invention provides a method of treating cancer in a patient. The method comprises administering to a patient in need thereof a therapeutically effective amount of an organonitro thioether compound described herein, such as a compound of Formula I or II, to treat the cancer.

The invention provides methods, compositions, and medical kits comprising a nitrite-reductase promoter, such as an allosteric modulator of hemoglobin, for use in treating medical disorders and preservation of blood products. In one aspect, the invention provides methods, compositions, and medical kits comprising an inorganic nitrite salt and a nitrite-reductase promoter, such as an allosteric modulator of hemoglobin, for use in treating medical disorders, such as cancer, cardiovascular disorders, ischemic conditions, hemolytic conditions, and bacterial infections. Exemplary inorganic nitrite salts include sodium nitrite and arginine nitrite. Exemplary allosteric modulators of hemoglobin described herein include alkyl-substituted and acyl-substituted di-nitroheterocycles.

News Article | April 18, 2013

RadioRx’s focus is on the development of first-in-class compounds that affect capillary blood flow through the manipulation of cellular and blood levels of the free radical nitric oxide or NO and its downstream signaling pathways.

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